cardiovascular medicine

Cardiovascular Medicine

Risk Factors and Primary Prevention of Coronary Artery Disease

Coronary artery disease is the major health problem in the United States andother industrialized countries. In the developing world, the prevalence has beenincreasing and is predicted to continue to do so over the next 20 years. In con-junction with cerebrovascular disease, coronary artery disease is projected tosoon become the leading cause of death worldwide.

EpidemiologyIt is estimated that 60 million persons in the United States (about one fifth ofthe population) have coronary artery disease. More than 1 million acutemyocardial infarctions occur yearly, of which one third are recurrent and 20%to 30% cause sudden death. Coronary artery disease is the most common causeof out-of-hospital death in the United States.

Most coronary events occur in persons older than 65 years of age.Although mortality rates from coronary artery disease have been decreasing inthe United States and other western countries over the past 30 years, the totalburden of coronary artery disease is not decreasing because the number of olderpersons continues to increase. Long-term results of the Framingham HeartStudy predict the lifetime risk for coronary artery disease at 40 years of age tobe 49% in men and 32% in women. At 70 years of age, the lifetime risk is 35%for men and 24% for women (Lloyd-Jones et al.).

Risk factors have been identified that are directly linked to the developmentof coronary artery disease (Table 1) and that may predispose to coronary arterydisease. In addition, several potential risk factors remain the subject of clinicalinvestigation and ongoing epidemiologic research. Emerging important factorsin the pathogenesis of atherosclerosis include inflammation, insulin resistance,and various non–low-density lipoprotein cholesterol lipid moieties. Nevertheless,the classic coronary artery disease risk factors contribute to the increased inci-dence and prevalence of coronary artery disease, and prediction algorithms haverepeatedly confirmed the usefulness of identifying and treating these traditionalrisk factors. For most of the definite risk factors, such as dyslipidemia, effectivetreatment is associated with a decrease in morbidity and mortality from coro-nary artery disease (Shepherd et al.; Downs et al.).

Evolving and new developments in primary prevention include:1. Increasing evidence that dyslipidemia is a crucial factor in coro-

nary artery disease and that lipid lowering is beneficial in healthypersons at increased risk for vascular disease;

2. Because diabetes mellitus is an important and particularly dangerousrisk factor for both coronary artery disease and stroke, patientswith diabetes should receive aggressive primary prevention meas-ures directed toward reducing their coronary artery disease risk;

3. Contrary to prior belief, female hormone replacement therapydoes not reduce the risk of vascular disease;

4. Demonstration of the lack of efficacy for antioxidant therapy with vitamin E, vitamin C, and β-carotene.

1

Lloyd-Jones DM, Larson MG, Beiser A,Levy D. Lifetime risk of developing coronaryheart disease. Lancet. 1999;353:89-92.PMID: 10023892Shepherd J, Cobbe SM, Ford I, Isles CG,Lorimer AR, MacFarlane PW, et al.Prevention of coronary heart disease withpravastatin in men with hypercholes-terolemia. West of Scotland CoronaryPrevention Study Group. N Engl J Med.1995;333:1301-7. PMID: 7566020Downs JR, Clearfield M, Weis S, Whitney E,Shapiro DR, Beere PA, et al. Primary pre-vention of acute coronary events with lova-statin in men and women with average cho-lesterol levels: results of AFCAPS/TexCAPS.Air Force/Texas Coronary AtherosclerosisPrevention Trial. JAMA. 1998;279:1615-22.PMID: 9613910

K E Y P O I N T S

• The current estimated lifetime risk forcoronary artery disease at age 40 yearsis 49% for men and 32% for women;at 70 years, the lifetime risk is 35% for men and 24% for women.

• Newly recognized factors in the patho-genesis of atherosclerosis includeinflammation, insulin resistance, andvarious non–low-density lipoproteincholesterol moieties.

K E Y P O I N T S

• An elevated plasma triglyceride concen-tration is an independent risk factor forcoronary artery disease and should betreated; the desirable concentration is less than 150 mg/dL.

• In patients who are at high risk forcoronary artery disease, hypertensionshould be treated with an angiotensin-converting enzyme inhibitor orangiotensin receptor blocker. However,in black patients, a diuretic should beconsidered as first-line therapy.

• Type 2 diabetes mellitus is now consid-ered a coronary artery disease equiva-lent, and risk factor targets for patientswith diabetes are the same as those inpatients with established coronaryartery disease.

• Calculation of non-HDL cholesterol isrecommended in patients with a plasmatriglyceride concentration greater than200 mg/dL and an LDL cholesterol concentration that is normal or at target level.

• The metabolic syndrome is defined asany three of the following: abdominalobesity, plasma triglyceride levelgreater than 150 mg/dL, HDL cholesterollevel less than 40 mg/dL in men and lessthan 50 mg/dL in women, and a fastingplasma glucose level of 110 mg/dL orgreater; the syndrome confers a majorcardiovascular risk, and affectedpatients should be aggressively treated.

• Measurement of markers of inflamma-tion (such as inflammatory cytokines,C-reactive protein, and adhesion mole-cules) is not recommended for popula-tion screening; however, measurementof highly sensitive C-reactive proteinmay be useful to detect enhancedabsolute risk in patients with intermediate risk according to the Framingham criteria.

Major Risk Factors and Risk Assessment

2

Major Risk Factors and Risk Assessment• Is the concentration of plasma triglycerides an independent risk factor for coronary

artery disease?• What is the first-line therapy for hypertension in patients at high risk for coronary

artery disease?• What are the treatment goals for modifiable coronary artery disease risk factors in

patients with diabetes mellitus?• In which patients is calculation of non–high-density lipoprotein cholesterol

recommended?• What are the defining clinical characteristics of the metabolic syndrome?• Is measurement of newly defined risk factors such as inflammatory mediators (for

example, C-reactive protein), lipid subfractions, and homocysteine indicated in primary prevention of coronary artery disease?

• What is the role of hormone replacement therapy in primary prevention of coronaryartery disease?

An aggressive approach toward primary prevention of coronary artery diseasehas been described by the most recent update of the National CholesterolEducational Program Adult Treatment Panel III (NCEP ATP III). The paneladopted the Framingham Risk Scoring System to assign categories of risk basedon the low-density lipoprotein (LDL) cholesterol level and major risk factors,including age, sex, family history, smoking, hypertension, and low plasma high-density lipoprotein (HDL) cholesterol level (Table 2, Table 3). Patients withdiabetes mellitus are considered to have the same risk as those with overt vasculardisease. A high plasma HDL cholesterol level is considered a negative risk factor.With this risk stratification system, goals are set for initiating treatment for hyper-lipidemia and specific goals are set for decreasing the LDL cholesterol level.

Executive Summary of the Third Report ofThe National Cholesterol EducationProgram (NCEP) Expert Panel onDetection, Evaluation, And Treatment ofHigh Blood Cholesterol In Adults (AdultTreatment Panel III). JAMA.2001;285:2486-97. PMID: 11368702

TABLE 1 Risk Factors for Coronary Artery Disease

Major risk factors

Hypertension

Diabetes

Dyslipidemia (elevated LDL cholesterol, low HDL cholesterol)

Family history of premature vascular disease

Cigarette smoking

Associated predisposing risk factors

Obesity

Metabolic syndrome

Sedentary life style

High-fat diet

Other positive risk factors

Lipoprotein abnormalities (small dense [pattern B] LDL cholesterol, increasedlipoprotein(a), increased postprandial VLDL and IDL)

Elevated homocysteine

Impaired glucose tolerance

Chronic infections

Vascular inflammation

Increased oxidative stress

Renal insufficiency

HDL = high-density lipoprotein; IDL = intermediate-density lipoprotein; LDL = low-density lipoprotein; VLDL = very-low-density lipoprotein


On the basis of recent data, an elevated fasting triglyceride level is now anaccepted independent risk factor and warrants treatment. The NCEP ATP IIIhas decreased the desirable range of triglyceride from less than 200 to less than150 mg/dL and emphasizes that a high triglyceride level may be a risk markerin association with other atherogenic lipid moieties. However, if the LDL cho-lesterol level is also increased, it should be the initial target of therapy.

Many studies indicate that patients are often not prescribed appropriatedrugs, or they are given the appropriate drug but not at a recommendeddosage. Furthermore, therapy is commonly not maintained for more than 1year. Through professional organizations, concerted efforts are being made toclose this gap between guidelines and practice.

Cigarette SmokingCigarette smoking remains the most common preventable cause of illness in theUnited States. Twenty-five percent of Americans smoke. Rates are highest

3

TABLE 2 Estimate of 10-Year Risk for Men (Framingham Point Scores)

Total Cholesterol Points at Age Points at Age Points at Age Points at Age Points at Age Age (y) Points Level (mg/dL) 20–39 Years 40–49 Years 50-59 Years 60–69 Years 70–79 Years

20–34 −9 <160 0 0 0 0 0

35–39 −4 160–199 4 3 2 1 0

40–44 0 200–239 7 5 3 1 0

45–49 3 240–279 9 6 4 2 1

50–54 6 ≥280 11 8 5 3 155–59 8

60–64 10 Nonsmoker 0 0 0 0 0

65–69 11 Smoker 8 5 3 1 1

70–74 12

75–79 13

HDL Cholesterol Systolic BP Level (mg/dL) Points (mm Hg) If Untreated If Treated

≥60 −1 <120 0 0

50–59 0 120–129 0 1

40–49 1 130–139 1 2

<40 2 140–159 1 2

≥160 2 310-Year Risk 10-Year Risk

Point Total (%) Point Total (%)

<0 <1 11 8

0 1 12 10

1 1 13 12

2 1 14 16

3 1 15 20

4 1 16 25

5 2 ≥17 ≥30

6 2

7 3

8 4

9 5

10 6

BP = blood pressure; HDL = high-density lipoprotein


4

among women and young adults; however, recent data confirm that rates ofsmoking among youth have decreased. Passive exposure to tobacco smoke hasbeen shown to have adverse effects. Physical addiction to nicotine and psycho-logical dependence are the primary reasons for continuing to smoke. Smokinginduces up-regulation of nicotine receptors that do not immediately return tobaseline after cessation. Effective therapy to promote smoking cessation andcounter nicotine addiction begins with an inquiry about smoking and includescounseling and pharmacologic therapy with nicotine replacement or bupro-pion. Most smokers make several attempts at smoking cessation before they aresuccessful. A survey of U.S. medical schools found that only 21% of practicingphysicians reported that they received adequate training to help their patientsin smoking cessation (Ferry et al.). Another study reported that only 15% ofsmokers who saw physicians were offered assistance in smoking cessation(Solberg et al.).

Detailed validated tools to aid smoking cessation as well as state andnational smoking cessation resources are available from the National Cancer

Ferry LH, Grissino LM, Runfola PS.Tobacco dependence curricula in US under-graduate medical education. JAMA.1999;282:825-9. PMID: 10478687Solberg LI, Boyle RG, Davidson G,Magnan SJ, Carlson CL. Patient satisfac-tion and discussion of smoking cessationduring office visits. Mayo Clin Proc.2001;76:138-43. PMID: 11213301

TABLE 3 10-Year Risk Estimates for Women (Framingham Point Scores)

Total Points at Age Points at Age Points at Age Points at Age Points at Age Age (y) Points Cholesterol 20–39 Years 40–49 Years 50–59 Years 60–69 Years 70–79 Years

20–34 –7 <160 0 0 0 0 0

35–39 –3 160–199 4 3 2 1 0

40–44 0 200–239 8 6 4 2 1

45–49 3 240–279 11 8 5 3 2

50–54 6 ≥280 13 10 7 4 255–59 8

60–64 10 Nonsmoker 0 0 0 0 0

65–69 12 Smoker 9 7 4 2 1

70–74 14

75–79 16

HDL Cholesterol Systolic BP Level (mg/dL) Points (mm Hg) If Untreated If Treated

≥60 –1 <120 0 0

50–59 0 120–129 1 3

40–49 1 130–139 2 4

<40 2 140–159 3 5

≥160 4 6Point Total 10-Year Risk 10-Year Risk

(%) Point Total (%)

<9 <1 20 11

9 1 21 14

10 1 22 17

11 1 23 22

12 1 24 27

13 2 ≥25 ≥30

14 2

15 3

16 4

17 5

18 6

19 8

BP = blood pressure; HDL = high-density lipoprotein


Institute (http://smokefree.gov), the Centers for Disease Control andPrevention (www://cdc.gov/tobacco), and the office of the U.S. SurgeonGeneral (www://surgeongeneral.gov/tobacco).

HypertensionHypertension is discussed in detail in the Nephrology and Hypertension bookof MKSAP 13, and only issues relevant to primary prevention of cardiovasculardisease will be discussed here. Three important recent concepts merit emphasis:

5

F I G U R E 1 .Cumulative incidence of cardiovascularevents in women (Panel A) and men (Panel B) without hypertension, accordingto blood pressure category at baselineexamination.Vertical bars indicate 95% confidence intervals.Optimal blood pressure is a systolic pressure ofless than 120 mm Hg and a diastolic pressure ofless than 80 mm Hg. Normal blood pressure is a systolic pressure of 120 to 129 mm Hg or adiastolic pressure of 80 to 84 mm Hg. High-normal blood pressure is a systolic pressure of 130 to 139 mm Hg or a diastolic pressure of85 to 89 mm Hg. If the systolic and diastolicpressure readings for a subject were in differentcategories, the higher of the two categories was used.

Reproduced with permission from: Vasan RS, Larson MG,Leip EP, Evans JC, O’Donnell CJ, Kannel WB, Levy D.Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl Med. 2001;345:1291-7.

No. at RiskOptimal 1875 1867 1851 1839 1821 1734 887Normal 1126 1115 1097 1084 1061 974 649High normal 891 874 859 840 812 722 520

2 4 6 8 10 12 140

10

A Women

8

6

4

2

0

Cu

mu

lati

ve In

cid

ence

(%

)

Time (yr)

Optimal

Normal

Highnormal

No. at RiskOptimal 1005 995 973 962 934 892 454Normal 1059 1039 1012 982 952 892 520High normal 903 879 857 819 795 726 441

2 4 6 8 10 12 140

14

B Men

12

10

8

6

4

2

0

Cu

mu

lati

ve In

cid

ence

(%

)

Time (yr)

Optimal

Normal

Highnormal


6

in general, the lower the blood pressure, the better; the choice of antihyper-tensive drug class may have substantial impact on clinical outcomes; and ele-vated systolic pressure is as an important target for therapy, particularly in eld-erly persons. Evidence suggests that hypertension is not adequately controlledin the majority of Americans receiving treatment.

The Framingham Offspring Study, which followed 6859 participants over10 years, demonstrated that adverse clinical events are related to blood pressurecut-points even within the normal range (Figure 1), with the lowest event ratein persons with blood pressure less than 120/80 mm Hg and the highest inpersons with blood pressure values considered “high-normal” (Vasan et al.). Inparticipants older than 65 years, high-normal blood pressure was associatedwith an annual cardiovascular event rate greater than 2% in men and a similarrate in women. Furthermore, previous data from the Hypertension OptimalTreatment (HOT) study, the Systolic Hypertension in the Elderly Program(SHEP) study, and the United Kingdom Prospective Diabetes Study (UKPDS)confirm that persons who achieve lower on-treatment blood pressure fare bet-ter than those with higher on-treatment blood pressure.

The target or optimal blood pressure for healthy persons is less than 120to 125 mm Hg systolic and 80 to 85 mm Hg diastolic. Even lower goals maybe appropriate for high-risk patients with hypertension, such as African-Americans, those with diabetes, overt proteinuria or an elevated creatinine con-centration, or with documented coronary, vascular, or peripheral vascular dis-ease. Much recent data confirm that an elevated pulse pressure or systolic pres-sure is more predictive of adverse outcomes than a high diastolic pressure. TheSeventh Report of the Joint National Committee on Prevention, Detection,Evaluation, and Treatment of High Blood Pressure, released in May 2003, reaf-firmed these precepts of hypertension therapy (Chobanian et al.).

Lifestyle modifications play an important role in treatment of hypertension.These include weight loss, exercise, moderation of alcohol intake, and reduc-tion of sodium intake. Maintenance of adequate potassium intake is important,particularly in persons taking diuretics. The Dietary Approaches to StopHypertension sodium substudy confirmed the benefit of a low-sodium diet plusthe “DASH” diet of fresh fruit, vegetables, low-fat dairy products, wholegrains, poultry, and fish (Vollmer et al.).

Large trials published since the Sixth Joint National Committee examinedthe relative benefits of specific classes of antihypertensive agents with respect tocardiovascular outcomes. The Losartan Intervention For Endpoint reduction inhypertension (LIFE) study compared the rate of cardiovascular events inseverely hypertensive patients with echocardiographic evidence of left ventricu-lar hypertrophy treated with losartan or atenolol over a mean of 4.8 years.Despite similar decreases in blood pressure with the two agents (Figure 2), therate of combined end point was lower in the losartan group primarily due to a24% reduction in stroke. In the LIFE diabetic substudy, the advantages of treat-ment with this angiotensin receptor blocker were even more impressive(Lindholm et al.). The Antihypertensive and Lipid-Lowering Treatment toPrevent Heart Attack Trial (ALLHAT) randomized approximately 45,000patients to a diuretic (chlorthalidone), calcium channel blocker (amlodipine),an angiotensin-converting enzyme inhibitor (lisinopril), and an α-blocker (dox-azosin). The doxazosin arm was prematurely terminated due to an excess ofheart failure. Monotherapy controlled blood pressure in approximately twothirds of patients in each of the three remaining arms, but the treated bloodpressure was slightly higher in the lisinopril group. Among the three arms, nodifference was seen in the primary outcome of coronary heart disease mortalityand nonfatal myocardial infarction. However, there was a slightly higher inci-

Vasan RS, Larson MG, Leip EP, EvansJC, O’Donnell CJ, Kannel WB, Levy D.Impact of high-normal blood pressure on therisk of cardiovascular disease. N Engl J Med.2001;345:1291-7. PMID: 11794147Chobanian AV, Bakris GL, Black HR,Cushman WC, Green LA, Izzo JL Jr, et al.The Seventh Report of the Joint NationalCommittee on Prevention, Detection,Evaluation, and Treatment of High BloodPressure: the JNC 7 report. JAMA.2003;289:2560-72. PMID: 12748199Vollmer WM, Sacks FM, Ard J, Appel LJ,Bray GA, Simons-Morton DG, et al.Effects of diet and sodium intake on bloodpressure: subgroup analysis of the DASH-sodium trial. Ann Intern Med2001;135:1019-28. PMID: 11747380Lindholm LH, Ibsen H, Dahlof B,Devereux RB, Beevers G, de Faire U, et al.Cardiovascular morbidity and mortality inpatients with diabetes in the LosartanIntervention For Endpoint reduction inhypertension study (LIFE): a randomisedtrial against atenolol. Lancet. 2002;359:1004-10. PMID: 11937179


dence of heart failure with amlodipine compared with chlorthalidone. Therewas a higher incidence of combined cardiovascular outcomes, stroke, and heartfailure when lisinopril was compared with chlorthalidone. The latter effect waslimited to the subgroup of black patients.

It seems reasonable to treat hypertension with an angiotensin-convertingenzyme inhibitor or angiotensin receptor blocker in all high-risk patients withhypertension, such as those with diabetes, left ventricular hypertrophy, protein-uria, azotemia, or clinical or subclinical atherosclerotic vascular disease.However, black patients should probably receive a diuretic as first-line therapy.Diuretics are recommended to be a part of all multi-drug regimens.

Type 2 DiabetesIt is estimated that 6% to 8% of the U.S. population has recognized diabetes,and millions of other persons are unaware that they have diabetes or willbecome diabetic. Approximately 95% of diabetic persons have type 2 disease.Diabetes confers a risk for a major coronary event similar to known coronaryartery (Haffner et al.), and most diabetics will die of cardiovascular disease.Because of the high incidence of adverse cardiovascular outcomes, theAmerican Diabetes Association, American Heart Association, and NCEP ATPIII have categorized type 2 diabetes as a major risk factor for coronary arterydisease and a risk equivalent for coronary artery disease. Treatment goals formodifiable risk factors should be identical to those in patients with establishedcardiovascular disease.

7

Haffner SM, Lehto S, Ronnemaa T,Pyorala K, Laakso M. Mortality from coro-nary heart disease in subjects with type 2 dia-betes and in nondiabetic subjects with andwithout prior myocardial infarction. N EnglJ Med. 1998;339:229-34. PMID: 9673301

F I G U R E 2 .Kaplan-Meier curves for primary composite endpoint.

Reproduced with permission from: Dahlof B, Devereux RB,Kjeldsen SE, Julius S, Beevers G, deFaire U, et al. Cardio-vascular morbidity and mortality in the Losartan InterventionFor Endpoint reduction in hypertension study (LIFE): a ran-domised trial against atenolol. Lancet. 2002;359:995-1003.

Number at risk

Losartan

Atenolol

60 12

AtenololLosartan

18 24 30 36 42 48 54 60 66

16

14

12

10

8

6

4

2

0

Pro

po

rtio

n o

f p

atie

nts

wit

h f

irst

eve

nt

(%)

Time (months)

Adjusted risk reduction: 13•0%, p=0•021Unadjusted risk reduction: 14•6%, p=0•009

4605

4524

4460

4392

4312

4247

4189

4112

4047

3897

1889 90

1

4588

4494

4414

4349

4289

4205

4135

4066

3992

3821

1854 87

6

Primary composite endpoint


8

HypertriglyceridemiaCalculation of non-HDL cholesterol content is recommended by the NCEPATP III for patients with high triglyceride levels (>200 mg/dL) and an LDLcholesterol level that is normal or at the target value. Non-HDL cholesterol iscomputed by subtracting the HDL cholesterol level from the total cholesterollevel. The treatment goal for non–HDL cholesterol is a value no more than 30mg/dL above the patient’s LDL cholesterol target value according to NCEPATP III. Some consider non–HDL cholesterol to be a better predictor of coro-nary artery disease than is LDL cholesterol. In addition to LDL cholesterol,non-HDL cholesterol accounts for atherogenic lipid particles, such as interme-diate-density lipoprotein, very-low-density lipoprotein remnants, triglycerides,and lipoprotein(a).

ObesityAn estimated 50% to 60% of the U.S. population is overweight, of whom 23%are obese. The specific definition of overweight is a body mass index of 25 to30 kg/m2. Obesity is diagnosed when the body mass index is greater than 30 kg/m2. Overweight and obesity are a particular problem in ethnic minoritygroups. Young obese men (but apparently not women) experience early athero-sclerosis in proportion to their obesity status. Being overweight in early child-hood or adolescence predicts adult obesity. The reasons for increasing bodyweight in the United States are not entirely clear, but the phenomenon is probablyrelated to both increased energy intake and decreased total energy expenditure.

Overweight and obese persons are at substantially increased risk for cardio-vascular disease, including coronary artery disease, stroke, and heart failure.Recent data from the Framingham Heart Study confirm that obesity is associ-ated with premature death and significantly decreased life expectancy (Peeterset al.). The combination of obesity and smoking results in even worse survivaloutcomes. In addition, other risk factors for coronary artery disease, such ashypertension, dyslipidemia, insulin resistance, and diabetes, tend to cluster inoverweight persons. Overweight and obese persons are at high risk for havingthe metabolic syndrome.

Physical InactivityRegular moderate exercise has been shown to decrease risk for coronary arterydisease and improve the coronary artery disease risk factor profile. TheProspective Epidemiological Study of Myocardial Infarction 5-year observa-tional study in 9800 men demonstrated that greater leisure time and physicalactivity are associated with fewer coronary artery disease events (Wagner et al.).Although a small proportion of sudden deaths occur during vigorous exercise,the incidence of sudden death is inversely related to the degree of exercise par-ticipation (Albert et al.).

One component of the benefit of exercise is based on its effect on risk fac-tor modification. Physical activity is an important component of reducing andmaintaining a desirable body weight. The Diabetes Prevention Program trialdemonstrated that the incidence of new-onset diabetes is inversely related toregular exercise as well as weight loss (Knowler et al.). (Recommendations formaintenance exercise programs are discussed in the Primary Care Medicinebook of MKSAP 13.)

The Metabolic SyndromeThe metabolic syndrome (also known as the dysmetabolic syndrome, Reaven’ssyndrome, and syndrome X) is a variable complex of clinical and metabolic fea-tures that imparts an increased likelihood for coronary artery disease events

Peeters A, Barendregt JJ, Willekens F,Mackenbach JP, Al Mamun A, Bonneux L.Obesity in adulthood and its consequencesfor life expectancy: a life-table analysis. Ann Intern Med. 2003;138:24-32.PMID: 12513041Wagner A, Simon C, Evans A, Ferrieres J,Montaye M, Ducimetiere P, Arveiler D.Physical activity and coronary event inci-dence in Northern Ireland and France: theProspective Epidemiological Study ofMyocardial Infarction (PRIME). Circulation.2002;105:2247-52. PMID: 12010905Albert CM, Mittleman MA, Chae CU,Lee IM, Hennekens CH, Manson JE.Triggering of sudden death from cardiaccauses by vigorous exertion. N Engl J Med.2000;343:1355-61. PMID: 11070099Knowler WC, Barrett-Connor E, FowlerSE, Hamman RF, Lachin JM, Walker EA,et al. Reduction in the incidence of type 2diabetes with lifestyle intervention or met-formin. N Engl J Med. 2002;346:393-403.PMID: 11832527


(Laaka et al.; Isomaa et al.). It occurs in at least 20% of the U.S. population.Among persons older than 60 years, the prevalence may be as high as 40%.Hispanic and African American persons are particularly at risk for the metabolicsyndrome (Grundy).

The NCEP ATP III defines the metabolic syndrome as any three of the fol-lowing factors: abdominal obesity (waist circumference at the iliac crest >40inches in men and >35 inches in women), a triglyceride level greater than 150mg/dL, a low HDL cholesterol level (<40 mg/dL in men and <50 mg/dL inwomen), and a fasting glucose level of 110 mg/dL or greater (Table 4).

Newer Risk Factors for Coronary Artery DiseaseThe list of putative coronary artery disease risk factors is constantly increasing(Table 1). None of these have yet been conclusively proven to cause coronaryartery disease or its progression. Their measurement is not currently recom-mended for routine screening in a primary prevention setting. However, focuson these risk factors may shift with mounting evidence of their importance.

Inflammation and C-Reactive ProteinIt has been fairly well established that inflammation plays a role in atheroscle-rotic disease. C-reactive protein is an acute-phase reactant that is produced bythe liver in response to other inflammatory stimuli. Recent studies confirm thatblood levels of C-reactive protein are related to the likelihood of myocardialinfarction, stroke, and peripheral vascular disease in healthy men and women(Ridker et al.). Other inflammatory markers, such as serum amyloid A, fibrin-ogen, and interleukin-6, are also associated with coronary artery disease. It has not been established whether these reactants are actual risk factors that con-tribute to the pathogenesis of the disease or risk markers that are associated withthe disease, but do not contribute to its pathogenesis. While current data donot support use of these markers of inflammation for widespread screening,highly sensitive C-reactive protein assays may help guide primary prevention therapy.

A recent AHA/CDC Scientific Statement includes the following recom-mendations (Pearson et al.). Among the assays for inflammatory markers, theone for highly sensitive C-reactive protein is the most reliable and well studied.The average of two separate values, ideally obtained 2 weeks apart, should beused for risk stratification by using the following risk tertiles: low risk, less than1.0 mg/dL; moderate risk, 1.0 to 3.0 mg/dL; and high risk, greater than 3.0mg/dL. In patients with a highly sensitive C-reactive protein level greater than10 mg/dL, another cause of inflammation should be sought and treated beforethe value is remeasured. The expert panel concluded that traditional risk assessment should be performed according to the Framingham criteria.Determination of highly sensitive C-reactive protein levels has merit as anoptional test for persons with an intermediate risk of coronary heart disease (10-year risk, 10% to 20%) to guide preventive therapy, such as a statin and aspirin.The panel also concluded that an elevated highly sensitive C-reactive proteinlevel could provide additional incentive for patients to adhere to lifestyle mod-ification regimens. Persons at very low risk (10-year risk <10%) and those athigh risk (10-year risk >20%), as well as those with established coronary, periph-eral, or cerebrovascular disease, do not need C-reactive protein testing becausethe role of risk factor modification is well established. At this time, there is noevidence from randomized controlled trials that decreasing C-reactive proteinlevels reduces ischemic events or disease severity or increases survival.

9

Laaka HM, Laaksonen DE, Laaka TA,Niskanen LK, Kumpusalo E, Tuomilehto J,et al. The metabolic syndrome and total andcardiovascular disease mortality in middle-aged men. JAMA. 2002;288:2709-16.PMID: 12460094Isomaa B, Almgren P, Tuomi T, Forsen B,Lahti K, Nissen M, et al. Cardiovascularmorbidity and mortality associated with the metabolic syndrome. Diabetes Care.2001;24:683-9. PMID: 11315831Grundy SM. Obesity, metabolic syndrome,and coronary atherosclerosis. Circulation.2002;105:2696-8. PMID: 12057978

Ridker PM, Rifai N, Clearfield M, DownsJR, Weis SE, Miles JS, Gotto AM Jr.Measurement of C-reactive protein for thetargeting of statin therapy in the primaryprevention of acute coronary events. N Engl J Med. 2001;344:1959-65.PMID: 11430324Pearson TA, Mensah GA, Alexander RW,Anderson JL, Cannon RO III, Criqui M,et al. Markers of inflammation and cardio-vascular disease: application to clinical andpublic health practice: A statement forhealthcare professionals from the Centers for Disease Control and Prevention and theAmerican Heart Association. Circulation.2003;107:499-511. PMID: 12551878

TABLE 4 Clinical Identification ofthe Metabolic Syndrome

Risk Factor Defining Level

Abdominal obesity Waist circumferance

Men >102 cm (>40 in)

Women >88 cm (>35 in)

Triglyceride level ≥150 mg/dL

HDL cholesterol

Men <40 md/dL

Women <50 mg/dL

Blood pressure ≥130/85 mm Hg

Fasting glucose ≥110 mg/dL

HDL = high-density lipoprotein

Reproduced from: Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final Report. National Instiitutes of Health. NIHPublication No. 02-5215. September 2002. Available at:http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm.


10

Lipid SubfractionsLipid subfractions, such as lipoprotein(a), and low-density lipoprotein particlesize are being studied and appear to have additive value for risk assessment(Sniderman et al.). Lipoprotein(a) is a lipid particle with structural similarityto plasminogen. It has long been suspected to enhance thrombotic activity.Although routine assessment for primary prevention is not yet recommended,measurement of lipoprotein(a) may be warranted in patients with prematurevascular disease or a strong family history. Niacin is the most effective drug todecrease lipoprotein(a) levels.

The value of determining LDL particle size is controversial. Data suggestthat larger, more buoyant LDL particles (pattern A) are less atherogenic,whereas smaller LDL particles (pattern B) are more atherogenic and have agreater oxidation potential. Patients with an elevated triglyceride level are mostlikely to have a preponderance of small LDL particles. Specific therapy to alterthe size distribution of LDL particles is not available. Therefore, the goal inpatients with established pattern B should be to decrease LDL cholesterol con-centration to as low a level as possible.

Postprandial measurements of triglycerides, intermediate-density lipopro-tein, and very-low-density lipoprotein have been studied as predictors of vascu-lar disease but cannot be recommended in routine clinical practice.

HomocysteineEpidemiologic data from case–control and cross-sectional studies suggested adirect relationship between homocysteine levels and coronary vascular disease.However, not all prospective studies have provided convincing evidence of thisrelationship (Christen et al.). Although endothelial dysfunction and aproatherogenic state result from increased homocysteine levels, in patients withvascular disease, elevated homocysteine levels may represent an acute-phasereaction. Until ongoing randomized trials conclusively resolve the question ofwhether intervention with folic acid and B vitamins is beneficial, there is noconsensus as to the need for routine measurement of plasma homocysteine orfor treatment of homocysteinemia. Nevertheless, the apparent absence of anadverse effect of therapy makes it reasonable to administer folic acid with Bvitamins in selected high-risk patients, especially those with premature coronaryartery disease or elderly patients.

Renal DiseaseRenal disease has a strong relationship to cardiovascular risk. Patients with end-stage renal disease have an annual mortality rate from coronary artery disease of20% to 25%. Mild renal insufficiency, as defined by a serum creatinine concen-tration greater than 1.5 mg/dL in women and greater than 2.0 mg/dL in menor a creatinine clearance of less than 70 mL/min, is present in 5% to 10% of thepopulation and may be associated with increased risk for coronary artery dis-ease. Diabetic persons represent 40% of those with mild renal insufficiency, andhypertensive persons account for approximately 30%. Whether efforts to preserve renal function will result in reduced cardiovascular mortality is stillunproven. For example, recent studies examining tight glycemic control in dia-betic patients showed a reduction in the incidence of nephropathy but no sig-nificant decrease in the incidence of myocardial infarction. On the other hand,trials have shown that angiotensin-converting enzyme inhibitors or angio-tension receptor blockers reduce the risk of cardiovascular events in patientswith renal abnormalities (Mann et al.; Brenner et al.).

Sniderman AD, Furberg CD, Keech A,Roeters van Lennep JE, Frohlich J,Jungner I, Walldius G. Apolipoproteinsversus lipids as indices of coronary risk and astargets for statin treatment. Lancet.2003;361:777-80. PMID: 12620753

Christen WG, Ajani UA, Glynn RJ,Hennekens CH. Blood levels of homo-cysteine and increased risks of cardiovasculardisease: causal or casual? Arch Intern Med.2000;160:422-34. PMID: 10695683Mann JF, Gerstein HC, Pogue J, Bosch J,Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med. 2001;134:629-36.PMID: 11304102Brenner BM, Cooper ME, de Zeeuw D,Keane WF, Mitch WE, Parving HH, et al.Effects of losartan on renal and cardio-vascular outcomes in patients with type 2diabetes and nephropathy. N Engl J Med.2001;345:861-9. PMID: 11565518

Therapies in Primary Prevention

InfectionAlthough many reports suggest a relationship between the prevalence of coro-nary artery disease and previous viral or bacterial infection, available data do notsupport use of antibiotics to prevent or slow the progression of coronary arterydisease. Current data are conflicting, and several large randomized clinical trialsof antibiotics are under way.

Oxidative StressThe role of oxidation due to free radical anions in the vasculature has beenextensively investigated. Many atherogenic processes are activated or enhancedin the presence of oxidative stress. Nitric oxide availability is reduced and oxi-dation of LDL cholesterol is increased. Much basic and animal research datasuggest that suppression of oxidative stress should help to slow, reverse, or evenprevent atherothrombotic processes. The oxidative hypothesis resulted innumerous trials of antioxidant agents, particularly vitamins E and C. However,no difference was seen between placebo and antioxidative regimens, includingvitamin E, in at least four major trials encompassing 46,000 persons with vascular disease or at high risk for cardiovascular events (Heart ProtectionStudy). Therefore, therapy with antioxidants, such as vitamin E or C or β-carotene, is currently not recommended for primary or secondary preventionof coronary artery disease.

Therapies in Primary Prevention• What lipid levels indicate the need for initiation of pharmacotherapy for primary

prevention of coronary artery disease?• What are the target lipid levels for treatment in the primary prevention of coronary

artery disease?• Is combination lipid-lowering pharmacotherapy indicated in patients with the

metabolic syndrome?• What is the role of antiplatelet therapy in primary prevention of coronary artery

disease?• Are there any indications for hormone replacement therapy for primary prevention

of coronary artery disease?

Case 1A 46-year-old man requests consultation for “high cholesterol.”Recent laboratory values include a serum total cholesterol of268 mg/dL, LDL cholesterol of 179 mg/dL, HDL cholesterolof 28 mg/dL, triglycerides of 320 mg/dL, and fasting plasmaglucose of 120 mg/dL. He smokes 1 pack of cigarettes per dayand is sedentary. He is moderately overweight with abdominalobesity; his body mass index is 27 kg/m2. Blood pressure is150/95 mm Hg.

The NCEP ATP III guidelines assigns the level of risk based on theFramingham score and sets goals for LDL cholesterol lowering based on thelevel of risk (Table 5).

Lipid LoweringTreatment begins with lifestyle modifications including a diet low in saturatedfat (<7% daily caloric intake); decreased cholesterol intake (<200 mg/d); andincreased intake of soluble fiber, plant stanols, and sterols. Weight control andregular physical activity are important for all persons at risk. Lipid-modifyingdrug therapy is initiated if target LDL cholesterol goals are not reached with

11

MRC/BHF Heart Protection Study of cho-lesterol lowering with simvastatin in 20,536high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22.PMID: 12114036

K E Y P O I N T S

• Pharmacotherapy should be consideredin a patient with coronary artery dis-ease or a risk equivalent or those withtwo or more risk factors and a plasmaLDL cholesterol concentration of 130 mg/dL or greater.

• The LDL goal for therapy is less than100 mg/dL in those with coronary heartdisease or a risk equivalent and lessthan 130 mg/dL in those with two or more risk factors.

• Combination pharmacotherapy may berequired in patients with the metabolicsyndrome to treat the dyslipidemia and the glucose intolerance.

• Low-dose aspirin (≤100 mg/d) is saferthan higher doses and as effective forprimary prevention; aspirin should beconsidered in patients at intermediaterisk or high risk for cardiovascularevents (10-year likelihood ≥10%);patients at low risk for cardiovascularevents should not be advised to takeaspirin as primary prevention.

• Hormone replacement therapy is notrecommended for primary prevention ofcoronary artery disease.

Rubins HB, Robins SJ, Collins D, Fye CL,Anderson JW, Elam MB, et al. Gemfibrozilfor the secondary prevention of coronaryheart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density LipoproteinCholesterol Intervention Trial Study Group.N Engl J Med. 1999;341:410-8.PMID: 10438259


12

standard lifestyle changes. Statins, fibrates, bile acid sequestrants, or nicotinicacid can be used to decrease levels of low-density lipoprotein C. The choice ofagent is determined by the lipid profile and the target lipid goals.

Results from recent trials may suggest an even more aggressive approachthan that recommended in NCEP ATP III. The recommended LDL choles-terol cut-points for initiation of pharmacologic therapy are more restrictive thanthose used in AFCAPS-TexCAPS or the Heart Protection Study. In the HeartProtection Study, many patients had a baseline LDL cholesterol level less than130 mg/dL and some had levels less than 100 mg/dL. These patients experi-enced the same reduction in relative risk as did those with an LDL cholesterollevel of 130 mg/dL or greater, although their actual risk for an event risk wassmaller (Figure 3). Therefore, the results of the Heart Protection Study sug-gest that a statin should be considered in all diabetic patients or those withtreated hypertension who are older than 55 years of age, regardless of baselineLDL cholesterol levels.

Patients with the metabolic syndrome may require more than one class oflipid-lowering drugs. Fibrates are peroxisome proliferator–activated receptor-αactivators used to treat the dyslipidemia seen the metabolic syndrome, which ischaracterized by a low HDL cholesterol level and a high triglyceride level(Rubins et al.). Niacin should be considered for low HDL cholesterol and hightriglyceride levels but must be used with caution because it may worsen glucosetolerance.

The patient in Case 1 has a significant burden of cardiovascular risk, witha Framingham 10-year risk score of 11% and an LDL cholesterol level greaterthan 130 mg/dL. He meets criteria for the metabolic syndrome and NCEPATP III identifies his LDL cholesterol target goal of less than 130 mg/dL.Although appropriate therapeutic lifestyle changes, diet, and an exercise pro-gram is recommended, these measures may not adequately control his dyslipi-demia. Therapy with a statin will lower his LDL cholesterol to target, but HDLcholesterol may not increase. Niacin would be an appropriate choice, with orwithout a statin, but it could precipitate overt diabetes in this patient withimpaired glucose tolerance. A fibrate is unlikely to completely normalize thelipid profile. Consideration of aspirin therapy is appropriate. Chlorthalidone is

TABLE 5 Drug Therapy Considerations and Goals of Therapy for Primary Prevention

LDL Cholesterol

Level to Consider Therapy Primary Goal of Therapy Risk Category 10-Year Risk for CAD (mg/dL) (mg/dL)

Multiple (≥2) risk >20% (includes all CAD risk >100† <100factors equivalents*)

10%–20% ≥130‡ <130

<10% ≥160 <130

0 or 1 risk factor <10% ≥190§ <160

CAD = coronary artery disease; LDL = low-density lipoprotein

*Most patients with coronary artery disease risk equivalents have multiple risk factors and a 10-year risk >20%. They include patients with noncoronary forms of clinical atherosclerosis, diabetes, and multiple (≥2) risk factors with a 10-year risk >20% by Framingham scoring.

†When LDL cholesterol is ≥130 mg/dL, a cholesterol-lowering drug can be started concomitantly with therapeutic lifestyle changes. If baseline LDL cholesterol is 100 to 129 mg/dL, therapeu-tic lifestyle changes should be started immediately. Concomitant use of drugs is optional; several options for drug therapy are available (statins, bile-acid sequestrants, fibrates, nicotinic acid).

‡When LDL cholesterol is in the range of 130 to 159 mg/dL, drug therapy can be used if necessary to reach the LDL cholesterol goal of <130 mg/dL, after an adequate trial of therapeuticlifestyle changes.

§When LDL cholesterol is in the range of 160 to 189 mg/dL, use of cholesterol-lowering drugs is optional, depending on response to therapeutic lifestyle changes.

Reproduced from: Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final Report. National Instiitutes of Health. NIH Publication No. 02-5215. September 2002. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm.


a low-cost initial choice for treatment of his hypertension. Vigorous effects atsmoking cessation are indicated.

Aspirin and Other Antiplatelet AgentsThe widespread administration of aspirin in primary prevention of coronaryartery disease remains controversial for several reasons. The optimal dose ofaspirin has not been established, although recent studies and a recent meta-analysis conclude that low doses (≤100 mg) are safer and as effective as higherdoses. Minor bleeding, mostly gastrointestinal, and a nonsignificant increase inhemorrhagic stroke are adverse effects of regular aspirin administration. Otherunresolved matters include aspirin resistance and a possible adverse interactionbetween aspirin and angiotensin-converting enzyme inhibitors (Lauer).

Recent recommendations are all based on the Framingham risk score butvary among the different organizations that have formulated guidelines. Thereis general agreement that intermediate- to high-risk patients (10-year risk of

13

F I G U R E 3 .Effects of simvastatin therapy on cause-specific mortality.Rate ratios (RR) are plotted (black squares with area proportional to the amount of statistical information in each subdivision) comparing outcome among participants allocated simvastatin to that among those allocated placebo, along with 95% confidence intervals (horizontal lines; ending with arrow when CIextends beyond scale). For particular subtotals and totals, the result and its 95% CI are represented by a diamond, with the RR (95% CI) and its statistical significance given alongside. Squares or diamonds to the left of the solid vertical line indicate benefit with simvastatin, but this is conventionally significant (P <0.05) only if the horizontal line or diamond does not overlap the solid vertical line. A broken vertical line indicates the overall RR for a particular subtotal or total.

Reproduced with permission from: MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet.2002;360:7-22.

Cause of death

Vascular causesCoronary

Other vascular

Subtotal: any vascular

Non-vascular causes

Neoplastic

Respiratory

Other medical

Non-medical

Subtotal: any non-vascular

ANY DEATH

Simvastatin-allocated(10 269)

Placebo-allocated(10 267)

0•4 0•6 0•8 1•0 1•2 1•4

0•83 (0•75–0•91)p<0-0001

0•95 (0•85–1•07)p=0•4

0•87 (0•81–0•94)p=0.0003

Simvastatin better Placebo better

Death rate ratio (95% Cl)

587 (5•7%)

194 (1•9%)

781 (7•6%)

359 (3•5%)

90 (0•9%)

82 (0•8%)

16 (0•2%)

547 (5•3%)

1328 (12•9%)

707 (6•9%)

230 (2•2%)

937 (9•1%)

345 (3•4%)

114 (1•1%)

90 (0•9%)

21 (0•2%)

570 (5•6%)

1507 (14•7%)

Lauer MS. Clinical practice: aspirin for pri-mary prevention of coronary events. N EnglJ Med. 2002;346:1468-74. PMID: 12000818

Grady D, Herrington D, Bittner V,Blumenthal R, Davidson M, Hlatky M,Hsia J, et al. Cardiovascular disease out-comes during 6.8 years of hormone therapy:Heart and Estrogen/progestin ReplacementStudy follow-up (HERS II). JAMA.2002;288:49-57. PMID: 12090862Herrington DM, Reboussin DM,Brosnihan KB, Sharp PC, Shumaker SA,Snyder TE, et al. Effects of estrogenreplacement on the progression of coronary-artery atherosclerosis. N Engl J Med.2000;343:522-9. PMID: 10954759


14

cardiovascular event ≥15%) without overt vascular disease should receive low-dose (<100 mg/d) aspirin. Those at low annual risk for cardiovascular eventsshould not be advised to take aspirin, but the level assigned to low risk variesfrom less than 6% to less than 10% risk over 10 years. When the estimated 10-year risk is 10% to 15%, the decision to take low-dose aspirin can be left to thepatient after careful discussion of the risk–benefit ratio. Independent of theFramingham risk score, the American Diabetic Association has recommendedaspirin administration in all diabetic patients who have one additional risk fac-tor for cardiovascular disease.

Clopidogrel is an effective antiplatelet agent that should be considered forprimary prevention only in high-risk patients who are allergic to or intolerantof aspirin. Aspirin resistance is a reduced antiplatelet effect of aspirin adminis-tration and may explain the absence of a protective effect in some patients. Inthe future, better ways to identify patients with aspirin resistance may lead tothe use of alternative antiplatelet drugs, such as clopidogrel.

Cyclooxygenase-2 inhibitors, which are nonsteroidal anti-inflammatorydrugs selective for the cyclooxygenase-2 pathway, are widely prescribed formusculoskeletal pain. Recently, an analysis of data from the Vioxx Gastro-intestinal Outcomes Research (VIGOR) study demonstrated a higher incidenceof myocardial infarction in patients treated with the cyclooxygenase-2 inhibitorrefocoxib compared to those treated with naproxen (Mukherjee et al.). Althoughthe study was not designed to test the end point of cardiovascular outcomes,one possible inference from the VIGOR study is that this new class of agentsprovides less potent antiplatelet protection than the nonselective cyclooxyge-nase inhibitor. Others have argued the VIGOR results can be explained byantiplatelet effect specific to naproxen that are not seen with other NSAIDS,such as ibuprofen. Not all available data confirm the results of the VIGORstudy, and this issue remains unresolved. However, it is recommended, thatpatients at high risk for coronary artery disease who are receiving a cyclooxy-genase 2 inhibitor also receive low-dose aspirin. It is also recommended thataspirin be administered 2 hours before administration of ibuprofen, but notrefocoxib and diclofenac, because of its potential for diminishing the antiplateleteffect of aspirin when given in reverse order (Catella-Lawson et al.).

Hormone Replacement TherapyEstrogen has several favorable effects on vascular physiology: The hormonepromotes endothelial-dependent vasodilation and inhibits inflammation,platelet aggregation, and smooth-muscle hyperplasia. On the basis of results oflarge observational studies, the beneficial role of hormone replacement therapyin preventing or slowing the onset of cardiovascular disease was widelyaccepted. This assumption was first challenged by two trials of secondary pre-vention. The Heart and Estrogen/progestin Replacement Study (HERS) stud-ied the effect of hormone replacement therapy in older postmenopausal womenwith established coronary artery disease and demonstrated an adverse clinicaloutcome in the estrogen–progestin arm during the first 2 years of the trial(Grady et al.), and the ERA trial in a similar sample found no benefit(Herrington et al.).

The Women’s Health Initiative, a randomized controlled trial of estrogenand progesterone, was designed to test the role of hormone replacement ther-apy in the primary prevention of cardiovascular disease, stroke, breast cancer,and osteoporosis. In July 2002, the arm studying continuous estrogen–prog-estin therapy versus placebo was abruptly terminated because of an increasedrisk for invasive breast cancer and a composite index of several conditions(including stroke, pulmonary embolus, and total cardiovascular disease)

Mukherjee D, Nissen SE, Topol EJ. Riskof cardiovascular events associated with selective COX-2 inhibitors. JAMA.2001;286:954-9. PMID: 11509060Catella-Lawson F, Reilly MP, Kapoor SC,Cucchiara AJ, DeMarco S, Tournier B, et al.Cyclooxygenase inhibitors and theantiplatelet effects of aspirin. N Engl J Med.2001;345:1809-17. PMID: 11752357


(Rossouw et al.). This arm of the study included 16,608 healthy post-menopausal women 50 to 79 years old who were followed for a mean of 5.2years (planned duration of 8 years). The arm of the study examining the role ofunopposed estrogen in women with prior hysterectomy was continued becauseno adverse effect was demonstrated at this time point. Therefore, hormonereplacement therapy can no longer be recommended for primary or secondaryprevention of coronary artery disease. It is appropriate only to treat intolerablepostmenopausal symptoms.

Acute Coronary Syndromes

Each year in the United States, there are over 5 million visits to emergencydepartments for evaluation of chest pain. There are roughly 1.7 million hospi-talizations each year for unstable angina and the closely related conditionnon–ST-segment elevation myocardial infarction. In the United States alone,ST-segment elevation myocardial infarction occurs in roughly 1.5 million per-sons and accounts for roughly 0.6 million deaths each year. Data from theFramingham Study indicate that 45% of persons with myocardial infarction(MI) are younger than 65 years of age and 5% are younger than 40 years of age.

With advances in the rapid diagnosis and management of acute ischemicheart disease, the mortality rate from coronary heart disease has decreased by50% over the past three decades. Although the incidence of MI has decreasedonly slightly, the case fatality rate for patients with MI has decreased dramati-cally. In-hospital and out-of-hospital mortality rates for both men and womenwith MI have steadily decreased over the past several decades.

The term acute coronary syndrome (ACS) refers to any component of theconstellation of clinical syndromes caused by acute myocardial ischemia. Itencompasses the spectrum from unstable angina to non–ST-segment elevationMI to ST-segment elevation MI (Figure 4).

15

Rossouw JE, Anderson GL, Prentice RL,LaCroix AZ, Kooperberg C, Stefanick ML,et al. Risks and benefits of estrogen plusprogestin in healthy postmenopausal women:principal results from the Women’s HealthInitiative randomized controlled trial. JAMA.2002;288:321-33. PMID: 12117397

F I G U R E 4 .Nomenclature of acute coronary syndrome(ACS). The spectrum of clinical conditionsranging from UA to NQMI to QwMI isreferred to as ACS.

NQMI = non–Q-wave myocardial infarction; NSTEMI =non–ST-segment elevation myocardial infarction; QwMI =Q-wave myocardial infarction; UA = unstable angina

Reproduced with permission from: Braunwald E. AntmanEM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, et al.ACC/AHA 2002 guideline update for the management ofpatients with unstable angina and non-ST-segment eleva-tion myocardial infarction: a report of the American Collegeof Cardiology/American Heart Association Task Force onPractice Guidelines (Committee on the Management ofPatients with Unstable Angina). 2002. Available at:http://www.acc.org/clinical/guidelines/unstable/unstable.pdf

NSTEMI

Acute Coronary Syndrome

No ST Elevation

Unstable Angina NQMI QwMI

ST Elevation

Myocardial Infarction

Unstable Angina and Non–ST-Segment Elevation Myocardial Infarction

16

ST-segment elevation MI is diagnosed in patients with a clinical presenta-tion consistent with acute MI and electrocardiographic evidence of ST-segmentelevation. The majority of patients with ST-segment elevation MI ultimatelydevelop a Q-wave acute MI, while a minority develop non–Q-wave acute MIon subsequent electrocardiography.

Patients who present with ischemic chest pain (termed possible ACS) butno ST-segment elevation are categorized as having unstable angina or non–ST-segment elevation MI. These two conditions are closely related and have simi-lar pathophysiology and clinical presentations, but they differ in the severity ofthe myocardial ischemia. In non–ST-segment elevation MI, ischemia is severeand results in a detectable release of biomarkers of myocardial injury, most com-monly cardiac troponin I, troponin T, or the MB isoenzyme of creatine phos-phokinase (creatine phosphokinase). In unstable angina, there is no detectableincrease in these enzymes. Biomarkers of myocardial injury may be detected inthe bloodstream hours after the onset of ischemic chest pain. However, at timeof initial presentation, unstable angina and non–ST-segment elevation MI maybe indistinguishable, and principles of risk stratification and management applyto both entities. In most patients with non–ST-segment elevation MI, a Q wavedoes not evolve on repeated electrocardiography, and disease is subsequentlydiagnosed as non–Q-wave acute MI; only a minority of patients with non–ST-segment elevation MI develop a Q wave.

Acute coronary syndrome is characterized by an imbalance betweenmyocardial oxygen supply and demand. This syndrome typically is caused byatherosclerotic coronary artery disease. The pathophysiology of ACS is charac-terized by atherosclerotic plaque rupture, formation of platelet and fibrinthrombi, and release of locally active vasoactive substances. Unstable angina andnon–ST-segment elevation MI are most commonly caused by a nonocclusivethrombus that develops on a disrupted atherosclerotic coronary artery plaque,resulting in reduced myocardial perfusion. Less commonly, unstable angina andnon–ST-segment elevation MI may be caused by severe coronary artery nar-rowing without thrombus. This may occur in patients with restenosis after per-cutaneous coronary intervention or those with progressive atherosclerosis. Rarecauses of unstable angina and non–ST-segment elevation MI include dynamicobstruction from intense coronary vasospasm of an epicardial coronary artery(termed Prinzmetal’s angina) and secondary unstable angina, in which the pre-cipitating condition is extrinsic to the coronary arteries (that is, hypotension,hypoxemia, anemia, tachycardia, or thyrotoxicosis). The most common cause ofST-segment elevation MI is an occlusive thrombus that develops on a dissectedor ulcerated atherosclerotic plaque, resulting in complete epicardial coronaryartery occlusion.


• What is the appropriate treatment of patients with unstable angina or non–ST-segment elevation MI?

• What are the roles of low-molecular-weight heparin and glycoprotein IIb/IIIa receptor inhibitors?

• What adjunctive therapies should be considered for management of unstable angina or non–ST-segment elevation MI?

• When should early invasive coronary angiography be recommended for patients with unstable angina or non–ST-segment elevation MI?


Case 2A 68-year-old postmenopausal woman with history of currentsmoking has had stable angina for 2 years. She takes aspirindaily and sublingual nitroglycerin on occasion. Over the pastday, she has had three episodes of substernal chest discomfortwith associated dyspnea at rest. The first two episodes wererelieved with one sublingual nitroglycerin tablet, but the mostrecent episode was not relieved after three nitroglycerin tablets.She comes to the emergency department with decreased butcontinued chest discomfort. Electrocardiography shows 1-mmST-segment depression in leads V2 to 5. Her troponin I level ismildly elevated at 2.2 ng/mL.

Risk StratificationPatients with unstable angina or non–ST-segment elevation MI most frequentlypresent with rest angina but may also describe patterns of new-onset or increas-ing angina (Table 6). Early risk stratification for patients with chest discomfortfocuses on anginal symptoms, physical findings, 12-lead electrocardiography,and biomarkers of cardiac injury. The following clinical features, which are avail-able from history and physical examination, increase the likelihood that apatient’s chest discomfort represents ACS: chest or left arm pain or discomfort,age 65 years or older, male sex, history of coronary artery disease or diabetes,pulmonary edema, and findings of noncardiac vascular disease. The followingelectrocardiographic and cardiac biomarker findings increase the risk of adversecardiac events in patients with unstable angina or non–ST-segment elevationMI: ST-segment deviation of 0.5 mm or greater or T-wave inversions withsymptoms, and elevated levels of troponin I, troponin T, or creatine phospho-kinase (Table 7). Recent studies reported that serologic markers of inflamma-tion (C-reactive protein) and left ventricular dysfunction (B-type natriureticpeptide) provide unique prognostic information in addition to these clinical fea-tures and cardiac biomarkers (Sabatine et al.; de Lemos et al.). Although C-reactive protein and B-type natriuretic peptide may identify patients withinflammation or left ventricular dysfunction, respectively, these tests are still notindicated in the routine evaluation of patients with ACS.

A simple seven-point risk estimation score has been established for patientswith unstable angina or non–ST-segment elevation MI. The Thrombolysis inMyocardial Infarction (TIMI) risk score is defined as the sum of seven individ-ual prognostic variables (Table 8) (Antman et al.). Patients may be catego-rized as low (TIMI risk score, 0 to 2), intermediate (score, 3 or 4), or high risk(score, 5 to 7) according to the number of variables they fulfill. As the TIMIrisk score increases, more aggressive therapies offer progressively greater bene-fit; these include low-molecular-weight heparin, glycoprotein IIb/IIIa receptorinhibitors, and an invasive management strategy (Figure 5).

17

Sabatine MS, Morrow DA, de Lemos JA,Gibson CM, Murphy SA, Rifai N, et al.Multimarker approach to risk stratification innon-ST elevation acute coronary syndromes:simultaneous assessment of troponin I, C-reactive protein, and B-type natriureticpeptide. Circulation. 2002;105:1760-3.PMID: 11956114de Lemos JA, Morrow DA, Bentley JH,Omland T, Sabatine MS, McCabe CH, et al.The prognostic value of B-type natriureticpeptide in patients with acute coronary syn-dromes. N Engl J Med. 2001;345:1014-21.PMID: 11586953Antman EM, Cohen M, Bernink PJ,McCabe CH, Horacek T, Papuchis G, et al.The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognos-tication and therapeutic decision making.JAMA. 2000;284:835-42. PMID: 10938172

K E Y P O I N T S

• Aspirin, heparin, nitrates, and β-blockersare the foundation of management ofacute coronary syndromes.

• Low-molecular-weight heparin (enox-aparin) is a suitable alternative toheparin for patients with acute coronarysyndrome or ST-segment elevationmyocardial infarction and those under-going early percutaneous coronaryintervention.

• Glycoprotein IIb/IIIa receptor inhibitorsare indicated for high-risk patients withacute coronary syndrome (particularlyST-segment depression or an elevatedcardiac troponin level) and those under-going percutaneous coronary intervention.

• New evidence from randomized trialssupports the addition of clopidogrel andstatins, beginning early in the manage-ment of acute coronary syndromes.

• Intermediate- and high-risk patientswith unstable angina or non–ST-segmentelevation myocardial infarction (ST-segment depression, elevated cardiacbiomarkers, or Thrombolysis inMyocardial Infarction risk score ≥3)benefit from an early invasive approachwith coronary angiography rather thana conservative approach with noninva-sive stress testing to assess risk.

TABLE 6 Principal Presentations of Unstable Angina

Rest angina Angina occurring at rest, usually >20 minutes

New-onset angina New-onset angina which markedly affects ordinary daily activity

Increasing angina Previously diagnosed angina that has become distinctly morefrequent, longer in duration, or lower in threshold

Adapted from: Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, et al. ACC/AHA 2002 guide-line update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: areport of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committeeon the Management of Patients with Unstable Angina). 2002. Available at: http://www.acc.org/clinical/guidelines/unstable/unstable.pdf.


18

Recent randomized trials have established that higher-risk patients withunstable angina or non–ST-segment elevation MI benefit from a strategy ofearly invasive coronary angiography compared with a more conservativeapproach involving risk stratification with predischarge noninvasive stress test-ing (Wallentin et al.; Cannon et al.). The benefits of early coronary angiog-raphy include identification of left main or three-vessel coronary disease, assess-ment of coronary thrombus or plaque ulceration, measurement of left ventric-ular function, and facilitation of early coronary revascularization if indicated. Inthe modern era of interventional cardiology using coronary stenting and glyco-protein IIb/IIIa receptor inhibitors, patients with a TIMI risk score of 3 orgreater, ST-segment depression, or elevated cardiac biomarkers seem to benefitfrom early coronary angiography and revascularization (Figure 6). For thepatient in Case 2, the TIMI risk score is 5, identifying her as a high-risk patientwho would probably benefit from an early invasive approach (Table 8). Hercoronary angiograms (Figure 7 A and B) show a high-grade stenosis in the

Wallentin L, Lagerqvist B, Husted S,Kontny F, Stahle E, Swahn E. Outcome at1 year after an invasive compared with a non-invasive strategy in unstable coronary-arterydisease: the FRISC II invasive randomisedtrial. FRISC II Investigators. Fast revasculari-sation during instability in coronary arterydisease. Lancet. 2000;356:9-16.PMID: 10892758Cannon CP, Weintraub WS, Demopoulos LA,Vicari R, Frey MJ, Lakkis N, et al.Comparison of early invasive and conservativestrategies in patients with unstable coronarysyndromes treated with the glycoproteinIIb/IIIa inhibitor tirofiban. N Engl J Med.2001;344:1879-87. PMID: 11419424

F I G U R E 5 .Impact of the Thrombolysis In MyocardialInfarction (TIMI) risk score on 6-monthadverse cardiac events (death, myocardialinfarction, acute coronary syndrome rehospi-talization) among patients randomized toconservative or invasive management in the TACTICS* TIMI-18 trial.

*TACTICS = Treat angina with Aggrastat and determineCost of Therapy with an Invasive Conservative Strategy

Adapted with permission from: Antman EM, Cohen M,Bernink PJ, McCabe CH, Horacek T, Papuchis G, et al. TheTIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decisionmaking. JAMA. 2000;284:835-42.

TABLE 7 Early Indicators of High-Risk among Patients with Unstable Anginaand Non–ST-Segment Elevation Myocardial Infarction

Clinical presentation Rest angina

Age ≥65 years

Diabetes mellitus

History of CAD, with coronary artery diameter stenosis ≥50%

Need for intravenous nitroglycerin

Physical examination Hypotension

Diaphoresis

Pulmonary edema, S3 gallop

Transient mitral regurgitation

12-lead ECG ST-segment depression or transient elevation

T-wave inversions with chest pain

Cardiac biomarkers Elevated level of troponin I, troponin T, or creatine kinase-MB

Additional markers C-reactive protein, B-type natriuretic peptide

Angiographic findings Intracoronary thrombus

High-grade atherosclerotic CAD

Noninvasive testing Wall-motion abnormalities at rest or stressechocardiography

Reversible perfusion defects on nuclear imaging

CAD = coronary artery disease; ECG = electrocardiography

11.8

20.3

30.6

12.816.1

19.5

0

5

10

15

20

25

30

35

Low (0-2) Intermediate (3-4) High (5-7)

TIMI Risk Score

6-M

onth

Dea

th/M

I/AC

S R

ehos

p (

%)

ConservativeInvasive


19

F I G U R E 6 .Algorithm for the management of patientsadmitted with unstable angina or non–ST-segment elevation myocardial infarction.

CK-MB = creatine kinase-MB; ECG = electrocardiography;GP = glycoprotein; LMWH = low-molecular-weight heparin;LVEF = left ventricular ejection fraction; TIMI = Thrombolysisin Myocardial Infarction; UFH = unfractionated heparin

TABLE 8 The TIMI Risk Score for Patients with Unstable Angina

Prognostic Variables

Age ≥65 years

≥3 CAD traditional risk factors

Documented coronary disease with ≥50% coronary artery diameter stenosis

ST-segment deviation

2 anginal episodes in the past 24 hours

Aspirin use in the past week

Elevated cardiac biomarkers (creatine kinase-MB or troponin)

Risk Score* Recommended Management

Low 0–2 Conservative or invasive

Intermediate 3–4 Invasive

High 5–7 Invasive

CAD = coronary artery disease; TIMI = Thrombolysis in Myocardial Infarction

*The sum of the prognostic variables.

Adapted from: Antman EM, Louwerenburg HW, Baars HF, Wesdorp JC, Hamer B, Bassand JP, et al. Enoxaparin as adjunc-tive antithrombin therapy for ST-elevation myocardial infarction: results of the ENTIRE-Thrombolysis in MyocardialInfarction (TIMI) 23 Trial. Circulation. 2002;105:1642-9.

Aspirinβ-blockersNitrates

UFH or LMWHMonitoring (telemetry and daily ECGs)

Early invasive strategy:TIMI risk scores ≥3ST-segment deviationPositive CK-MG or troponin

Add GP IIb/IIIa inhibitor

Coronary angiography Recurrent symptomsHeart failureSerious arrhythmia

Patient stabilizes

Early conservative strategy:TIMI risk scores <3No ischemia on ECGNegative biomarkers

Stress test

Low riskLVEF >.40

Follow onmedicaltherapy

Not Low riskLVEF ≤.40


20

mid-left anterior descending coronary artery, which was treated with stentingwith adjunctive glycoprotein IIb/IIIa receptor inhibition. Low-risk patientsmay undergo noninvasive exercise or pharmacologic stress testing with echo-cardiographic or nuclear imaging; if testing is positive, coronary angiographyshould be performed before hospital discharge.

ManagementFor the patient in Case 2, the goal of initial therapy should be control of chestpain with nitrates and narcotic analgesics, if necessary, and control of heart rateand blood pressure with a β-blocker, given intravenously and then orally. Sheshould receive a chewable aspirin in the emergency department. Oxygen andanxiolytics should be administered as needed. Anemia and acute infectionshould be excluded as contributing or precipitating factors. Twelve-lead electro-cardiography should be performed and repeated at least daily if the character or intensity of the chest pain changes. Baseline cardiac biomarkers (troponin or creatine phosphokinase) should be measured on admission and then remea-sured at least once more within 6 to 12 hours.

While the patient is still in the emergency department, initiation of additional antithrombotic and antiplatelet therapy should be considered.Unfractionated heparin is beneficial in the management of unstable angina andnon–ST-segment elevation MI. Recent data from randomized clinical trials sup-port the safety and efficacy of the low-molecular-weight heparin enoxaparincompared with unfractionated heparin (Antman et al., 2002). Compared withintravenous unfractionated heparin, the weight-based dosing of enoxaparin (1 mg/kg subcutaneously every 12 hours) has more predictable absorption owingto a low degree of protein binding, offers a more predictable anticoagulanteffect, obviates the need to monitor partial thromboplastin time, has a higheractivity against factor Xa, and has a lower incidence of thrombocytopenia.Enoxaparin should not be given to patients with severe obesity (>150 kg),thrombocytopenia, or a creatinine clearance less than 30 mL/min. Algorithmshave been developed for the seamless integration of care for patients with unsta-ble angina and non–ST-segment elevation MI who require percutaneous coro-nary intervention while receiving treatment with low-molecular-weight heparin

F I G U R E S 7 A A N D 7 B .Coronary angiography in the patient in Case 2.Coronary angiography shows a high-grade stenosis (arrow) in the mid-portion of the left anteriordescending (LAD) coronary artery, with mildly diminished filling of the distal vessel. There were noother significant coronary stenoses. Left ventriculography showed mild anteroapical hypokinesis withan ejection fraction of 45%. B. The patient underwent successful stenting (arrow) of the LAD, withrestoration of normal flow in the distal vessel.

Antman EM, Cohen M, McCabe C,Goodman SG, Murphy SA, Braunwald E.Enoxaparin is superior to unfractionatedheparin for preventing clinical events at 1-year follow-up of TIMI 11B andESSENCE. Eur Heart J. 2002;23:308-14.PMID: 11812067Young JJ, Kereiakes DJ. Low-molecular-weight heparin in percutaneous coronaryintervention: ready for prime time? ACC Curr J Rev. 2002;11:59-64.O’Rourke RA, Hochman JS, Cohen MC,Lucore CL, Popma JJ, Cannon CP. Newapproaches to diagnosis and management ofunstable angina and non-ST-segment eleva-tion myocardial infarction. Arch Intern Med.2001;161:674-82. PMID: 11231699Braunwald E, Antman EM, Beasley JW,Califf RM, Cheitlin MD, Hochman JS, et al. ACC/AHA 2002 guideline update forthe management of patients with unstableangina and non-ST-segment elevationmyocardial infarction: a report of theAmerican College of Cardiology/AmericanHeart Association Task Force on PracticeGuidelines (Committee on the Managementof Patients with Unstable Angina). 2002.Available at: http://www.acc.org/clinical/guidelines/unstable/unstable.pdf.

ST-Segment Elevation Myocardial Infarction

(Young and Kereiakes). Not all low-molecular-weight heparins have per-formed well in clinical trials of ACS; other agents, such as dalteparin, have notbeen shown to be superior to unfractionated heparin.

High-risk patients with unstable angina or non–ST-segment elevation MIshould be considered for treatment with a glycoprotein IIb/IIIa receptorinhibitor (O’Rourke et al.). The small-molecule agents, such as tirofiban andeptifibatide, have been shown to provide benefit compared with heparin alone.Patients who present with ST-segment depression or elevated troponin or cre-atine phosphokinase levels, and those with a TIMI score of 3 or greater, shouldbe considered for glycoprotein IIb/IIIa receptor inhibitor treatment(Braunwald et al.). Recent studies have shown that low-molecular-weightheparin and glycoprotein IIb/IIIa receptor inhibitors can be combined safelyin patients with unstable angina or non–ST-segment elevation MI (Goodmanet al.).

In addition to aspirin (81 to 325 mg/d, given orally), low-molecular-weight heparin, and glycoprotein IIb/IIIa receptor inhibitors, the antiplateletagent clopidogrel appears to offer further benefit to patients with unstableangina or non–ST-segment elevation MI. Clopidogrel (300-mg loading dose,followed by 75 mg/d orally) reduced both early (48 hours) and late (1 year)refractory ischemia, MI, and stroke (Yusuf et al.). In the Clopidogrel inUnstable Angina to prevent Recurrent Events study, patients with unstableangina or non–ST-segment elevation MI received clopidogrel for 9 months. Arecent randomized trial demonstrated that atorvastatin, 80 mg/d, significantlyreduced recurrent ischemia (Schwartz et al.). Administration of this high-dosestatin early in the management of unstable angina or non–ST-segment elevationMI appeared to have a beneficial effect in terms of plaque stabilization. Theincidence of stroke was also significantly reduced over the 4-month studyperiod. It is still unclear whether other statins or lower doses of atorvastatinoffer a similar benefit. However, a recent study showed that atorvastatin maydecrease with the antiplatelet effect of clopidogrel. Simvastatin and lovastatinalso may have a similar drug interaction due to P450 hepatic metabolism.Pravastatin, which does not have this interference, is a reasonable substitute forcombination therapy with clopidogrel and a statin (Lau et al.).

ST-Segment Elevation Myocardial Infarction• What clinical factors identify patients with ST-segment elevation MI who are at

high-risk for adverse events?• What is the best approach to the management of ST-segment elevation MI?• What adjunctive measures should be used?• When should coronary angiography be considered for patients who have received

thrombolytic agents for management of ST-segment elevation MI?

Case 3A 52-year-old man with a history of hyperlipidemia, obesity,and adult-onset diabetes mellitus was brought to the emergencydepartment by ambulance within 60 minutes of onset of severesubsternal chest pain with associated dyspnea and diaphoresis.

Blood pressure is 100/80 mmHg, with a heart rate of80/min. His lung fields are clear to auscultation. Electro-cardiography shows 3-mm ST-segment elevation in leads II, III, and aVF, with no Q waves.

21

Goodman SG, Fitchett D, Armstrong PW,Langer A. The Integrilin and EnoxaparinRandomized Assessment of Acute CoronarySyndrome Treatment (INTERACT) Trial.INTERACT Trial Investigators. In: Programand Abstracts of the American College ofCardiology 51st Annual Meeting, March 17-20, 2002, Atlanta, Georgia. Abstract 405-5.Yusuf S, Zhao F, Mehta SR, Chrolavicius S,Tognoni G, Fox KK. Effects of clopidogrelin addition to aspirin in patients with acutecoronary syndromes without ST-segmentelevation. The Clopidogrel in UnstableAngina to Prevent Recurrent Events TrialInvestigators. N Engl J Med. 2001;345:494-502. PMID: 11519503Schwartz GG, Olsson AG, EzekowitzMD, Ganz P, Oliver MF, Waters D, et al.Effects of atorvastatin on early recurrentischemic events in acute coronary syndromes:the MIRACL study: a randomized controlledtrial. JAMA. 2001;285:1711-8.PMID: 11277825Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp SA, et al.Atorvastatin reduces the ability of clopido-grel to inhibit platelet aggregation: a newdrug-drug interaction. Circulation.2003;107:32-7. PMID: 12515739

K E Y P O I N T S

• Advancing age, anterior-wall myocardialinfarction (MI), and evidence of heartfailure are the three most importantclinical factors that identify high-riskpatients with ST-segment elevation MI.

• Immediate reperfusion therapy witheither percutaneous coronary interven-tion or thrombolysis should be performedas soon as possible after identificationof ST-segment elevation.

• An oral angiotensin-converting enzymeinhibitor should be started within 24hours in patients with anterior MI, signsor symptoms of congestive heart failure,or reduced left ventricular ejection frac-tion. An angiotensin-converting enzymeinhibitor generally should not be pre-scribed for patients with hypotension or hyperkalemia, those with severerenal insufficiency (creatinine level ≥3.0 mg/dL) who are not dialysisdependent, or those with bilateral renal artery stenosis.

• Coronary angiography should be per-formed after thrombolysis in patientswith evidence of failure to reperfuse,recurrent angina, congestive heart fail-ure, or residual myocardial ischemia onnoninvasive stress testing.


22

Early Risk StratificationThe initial history and physical examination performed in the emergencydepartment provides important information for immediate risk stratification ofpatients with ST-segment elevation MI. The most important predictors of mor-tality identified at presentation include age, clinically evident heart failure, dia-betes mellitus, renal failure, and previous MI. The time of presentation is alsoimportant: Patients who present more than 12 hours after the onset of symp-toms are less likely to have successful reperfusion and have a worse prognosis.The initial 12-lead electrocardiogram can identify patients at higher risk foradverse events. Patients with anterior-wall MI, right ventricular MI, andadvanced atrioventricular block are at increased risk. The TIMI risk score inpatients with ST-segment elevation MI is also useful for estimating prognosis byusing variables readily available in the emergency department (Table 9)(Morrow et al.). The 14-point risk score is based on advancing age, evidenceof heart failure, anterior wall infarction, and late time to reperfusion therapy. Asthe score increases, the 30-day risk for death in patients with ST-segment ele-vation MI increases from 0.8% (risk score of 0) to 36% (risk score >8).

ManagementPatients with ST-segment elevation MI should promptly be treated with aspirin,narcotic analgesics, intravenous nitroglycerin, and intravenous β-blockers(Ryan et al.). Suitable candidates should receive immediate reperfusion ther-apy with thrombolysis or percutaneous coronary intervention. The advantagesof thrombolysis include its ease of use, whereas the advantages of primary per-cutaneous coronary intervention include higher vessel patency rates, lower rein-farction and stroke rates, and immediate risk stratification. Treatment outcomesare closely related to achievement of early, complete, and sustained reperfusion.Thrombolysis should be started within 30 minutes of entry to the emergencydepartment; for percutaneous coronary intervention, the infarct-related arteryshould be recanalized within 90 minutes. There are four subgroups in which

Morrow DA, Antman EM, Giugliano RP,Cairns R, Charlesworth A, Murphy SA, et al. A simple risk index for rapid initialtriage of patients with ST-elevation myocardialinfarction: an InTIME II substudy. Lancet.2001;358:1571-5. PMID: 11716882Ryan TJ, Anderson JL, Antman EM,Braniff BA, Brooks NH, Califf RM, et al.ACC/AHA guidelines for the managementof patients with acute myocardial infarction.A report of the American College ofCardiology/American Heart AssociationTask Force on Practice Guidelines(Committee on Management of AcuteMyocardial Infarction). J Am Coll Cardiol.1996;28:1328-428. PMID: 8890834

TABLE 9 The TIMI Risk Score for Patients with ST-Segment Elevation Myocardial Infarction

Prognostic Variables Points Risk Score* 30-Day Mortality Rate (%)

Historical

Age ≥75 years 3 0 0.8

Age 65–74 years 2 1 1.6

Diabetes, hypertension, or angina 1 2 2.2

3 4.4

Physical Examination 4 7.3

Systolic blood pressure <100 mm Hg 3 5 12

Heart rate >100/min 2 6 16

Killip class II–IV 2 7 23

Weight <67 kg (150 lb) 1 8 27

>8 36

Presentation

Anterior ST-segment elevation or 1left bundle-branch block

Time to reperfusion therapy >4 hours 1

Risk score = total points (0–14)

TIMI = Thrombolysis in Myocardial Infarction

*The total of the prognostic variables.

Adapted from: Morrow DA, Antman EM, Giugliano RP, Cairns R, Charlesworth A, Murphy SA, et al. A simple risk index for rapid initial triage of patients with ST-elevation myocardial infarction: an InTIME II substudy. Lancet. 2001;358:1571-5.


percutaneous coronary intervention is preferred because of concerns about thesafety or efficacy of thrombolysis: patients in whom thrombolysis is contraindi-cated (Table 10), those presenting more than 12 hours since the onset of chestpain and who have continued chest pain or ST-segment elevation, those with ahistory of coronary artery bypass graft surgery, and those with cardiogenicshock (pulmonary edema and systolic blood pressure less than 100 mm Hg).

The most important risk of thrombolysis is bleeding, particularly intracra-nial hemorrhage. This complication is more common in patients with a historyof chronic severe hypertension, those who present with severe hypertension,and elderly persons. Contraindications to and cautions about thrombolyticagents are listed in Table 10.

Evidence of successful thrombolysis involves resolution of both chest painand ST-segment elevation. The rapidity with which these resolve is directlyrelated to early patency of the infarct-related artery. Reperfusion arrhythmias,typically manifested as a transient accelerated idioventricular arrhythmia, usuallydo not require additional antiarrhythmic therapy.

In the past 5 years, significant advances have been made in thrombolyticand primary percutaneous coronary intervention strategies. Tissue plasminogenactivator achieves normal coronary flow in the infarct-related artery at 60 min-utes in 50% to 55% of cases. Newer thrombolytic agents, such as tenecteplaseand reteplase, are administered as a single or double bolus, respectively. Pilotcoronary angiographic studies showed that patency rates were improved bycombining full-dose glycoprotein IIb/IIIa receptor inhibitors with half-dosethrombolytic agents. In large clinical trials, this combination therapy reducedreinfarction rates but had no significant effect on mortality (Topol; ASSENT-3Investigators). Diabetic patients and older patients had higher rates of adverse

23

Topol EJ. Reperfusion therapy for acutemyocardial infarction with fibrinolytic therapyor combination reduced fibrinolytic therapyand platelet glycoprotein IIb/IIIa inhibition:the GUSTO V randomised trial. TheGUSTO V Investigators. Lancet. 2001;357:1905-14. PMID: 11425410Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3randomised trial in acute myocardial infarction.Lancet. 2001;358:605-13. PMID: 11530146

TABLE 10 Absolute and Relative Contraindications for the Use ofThrombolytic Agents To Treat ST-Segment Elevation Myocardial Infarction

Absolute Contraindications

Any hemorrhagic stroke

Nonhemorrhagic stroke or cerebrovascular events within the past year

Known intracranial neoplasm

Active internal bleeding, or active peptic ulcer disease (does not include menses)

Suspected aortic dissection

Blood pressure >180/110 mm Hg despite antihypertensive medication

Relative Contraindications

Blood pressure >180/110 mm Hg initially at presentation, but lower with medication

History of chronic severe hypertension

History of intracerebral pathologic condition

History of proliferative diabetic retinopathy

Current uses of anticoagulants in therapeutic doses (INR ≥2.0); known bleeding diathesis

Recent trauma or major surgery (within 4 weeks), or prolonged CPR (>10 minutes)

Recent internal bleeding (within 4 weeks)

Noncompressible vascular punctures

Pregnancy

For streptokinase or anistreplase: previous exposure (within 2 years) or previous allergic reaction

INR = international normalized ratio; CPR = cardiopulmonary resuscitation

Adapted from: Ryan TJ, Anderson JL, Antman EM, Braniff BA, Brooks NH, Califf RM, et al. ACC/AHA guidelines for themanagement of patients with acute myocardial infarction. A report of the American College of Cardiology/AmericanHeart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol. 1996;28:1328-428.


24

events with combination therapy. Use of low-molecular-weight heparin insteadof unfractionated heparin with newer thrombolytic strategies not only improvesease of administration but also is associated with lower rates of recurrentischemic complications (Antman et al.).

The strategy of primary percutaneous coronary intervention has evolvedinto “facilitated percutaneous coronary intervention,” which includes the use ofhalf-dose thrombolytics and/or glycoprotein IIb/IIIa receptor inhibitorsbefore planned immediate percutaneous coronary intervention (Montalescotet al.; Stone et al.). At this time, coronary stenting with adjunctive glycopro-tein IIb/IIIa receptor inhibitors appears to be the optimal immediate reperfu-sion strategy if access to cardiac catheterization facilities is readily available. Thepatient in Case 3 underwent immediate percutaneous coronary intervention.Coronary angiography (Figure 8 A and B) shows thrombotic occlusion of themid right coronary artery, which was treated successfully with coronary stent-ing and adjunctive glycoprotein IIb/IIIa inhibition.

Several recent trials have randomized thrombolytic-eligible patients withST-segment elevation MI to receive thrombolysis with front-loaded tissue plas-minogen activator or primary percutaneous coronary intervention. Both theAtlantic Cardiovascular Patient Outcomes Research Team (CPORT) trial(Aversano et al.) and the Danish Trial in Acute Myocardial Infarction 2(DANAMI) (Andersen et al.) demonstrated the superiority of percutaneouscoronary intervention over thrombolysis. In the CPORT trial, percutaneouscoronary intervention was performed at U.S. hospitals without on-site cardiacsurgery. In the DANAMI study, patients randomized to percutaneous coronaryintervention were transported by ambulance to a hospital with cardiac catheter-ization facilities. Despite these limitations and delays in patient transport, thoseassigned to the percutaneous coronary intervention group had significantlyimproved clinical outcomes and shorter hospital stays. Current standard of carerecommendations for immediate reperfusion therapy for patients with ST-seg-ment elevation MI would favor primary percutaneous coronary interventionover thrombolysis if transfer to an experienced cardiac catheterization center isfeasible within 90 minutes of presentation. Intravenous glycoprotein IIb/IIIainhibitors may be started in the emergency department before transfer for per-cutaneous coronary intervention.

Mechanical Complications after Myocardial InfarctionMechanical complications occur in roughly 0.1% of patients with acute MI, typ-ically around 2 to 7 days after the event. These complications include ventricu-lar septal defect, papillary muscle rupture leading to acute mitral regurgitation,and left ventricular free wall rupture leading to tamponade. Ventricular septaldefect and papillary muscle rupture usually lead to abrupt pulmonary edema orhypotension. Papillary muscle dysfunction without rupture can also causesevere mitral regurgitation after acute MI. Early diagnosis is critical because thesurvival rate 24 hours after a large ventricular septal defect or papillary musclerupture is roughly 25% with medical therapy.

Emergent echocardiography is indicated to help with the early diagnosis.Hemodynamic monitoring with a pulmonary artery catheter is usually neces-sary. Increased oxygen saturation between the right atrium and ventricle is seenwith left-to-right shunting through a ventricular septal defect. Both ventricularseptal defect and papillary muscle rupture may be associated with prominent Vwaves on the pulmonary capillary wedge tracing.

For both disorders, rapid treatment involves nitroprusside or intra-aorticballoon pump (or both). Emergent surgical repair is usually considered fordefinitive therapy; however, the survival rate is still only 50% after repair.

Antman EM, Louwerenburg HW, BaarsHF, Wesdorp JC, Hamer B, Bassand JP,et al. Enoxaparin as adjunctive antithrombintherapy for ST-elevation myocardial infarc-tion: results of the ENTIRE-Thrombolysis inMyocardial Infarction (TIMI) 23 Trial.Circulation. 2002;105:1642-9.PMID: 11940541Montalescot G, Barragan P, Wittenberg O,Ecollan P, Elhadad S, Villain P, et al.Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardialinfarction. N Engl J Med. 2001;344:1895-903.PMID: 11419426Stone GW, Grines CL, Cox DA, Garcia E,Tcheng JE, Griffin JJ, et al. Comparison ofangioplasty with stenting, with or withoutabciximab, in acute myocardial infarction. N Engl J Med. 2002;346:957-66.PMID: 11919304Aversano T, Aversano LT, Passamani E,Knatterud GL, Terrin ML, Williams DO,Forman SA. Thrombolytic therapy vs pri-mary percutaneous coronary intervention formyocardial infarction in patients presentingto hospitals without on-site cardiac surgery: a randomized controlled trial. JAMA.2002;287:1943-51. PMID: 11960536Andersen HR. The Danish MulticenterRandomized Trial on Thrombolytic TherapyVersus Acute Coronary Angioplasty in AcuteMyocardial Infarction. DANAMI-2 StudyGroup. Program and Abstracts of theAmerican College of Cardiology 51st AnnualMeeting, March 17-20, 2002, Atlanta,Georgia. Abstract 421.4


Pericardial tamponade from rupture of the left ventricular free wall usuallyleads to sudden hypotension and death. After heart failure, free-wall rupturerepresents the second most common cause of death for patients who in die inhospitals after an MI. Predisposing factors include advanced age as well as firstMI, probably due to lack of coronary collaterals. Ventricular free-wall ruptureis most commonly seen 1 to 4 days after acute MI but in rare cases occurs upto 3 weeks after MI. The free-wall rupture typically occurs in the junction of theinfarction with normal myocardium and less often within the center of theinfarct. Patients usually present with cardiovascular collapse, tamponade, orpulseless electrical activity. Right-heart catheterization would demonstrate dias-tolic elevation and equalization of pressures from the right atrium, right ventricle,and pulmonary capillary wedge with reduced cardiac output.

Post-MI Risk StratificationMortality rates from trials enrolling patients with ST-segment elevation MIpatients differ according to the type of reperfusion therapy (percutaneous coro-nary intervention versus thrombolysis) and the presence of cardiogenic shock.In the CADILLAC (Controlled Abciximab and Device Investigation to LowerLate Angioplasty Complications) trial, in which patients were randomized toprimary angioplasty or stenting, the 30-day mortality rate was 1.0% to 1.6%. Inthe GUSTO V (Global Use of Strategies To Open Coronary Arteries V) throm-bolytic trial that randomized patients to tissue plasminogen activator alone orhalf-dose tissue plasminogen activator plus abciximab, the 30-day mortality ratewas 5.5% to 6.0%. The 30-day mortality rate was 5% for those who receivedthrombolytic therapy within 4 hours of chest pain and increased to 11% forthose treated more than 6 hours after the onset of chest pain. The 7-day rein-farction rate was 3%. In the SHOCK (SHould we use emergently revascularizeOccluded Coronaries in cardiogenic shocK?) trial, patients were randomizedpatients with acute MI with cardiogenic shock to maximal medical therapy(including pressors, intra-aortic balloon pump, and thrombolysis) or emergentcoronary revascularization; the 30-day mortality rate was 50% (Hochman et al.).The TIMI risk score is a helpful index to gauge the risk for early mortality inpatients presenting with ST-segment elevation MI (Table 9). In summary, post-MI mortality rates are generally low for stable patients who present early forreperfusion therapy but remain high for patients admitted in cardiogenic shock.

After initial reperfusion therapy, additional risk stratification involves assess-ment of left ventricular function, residual myocardial ischemia, and risk of ven-tricular arrhythmias. All survivors of MI should have left ventricular systolicfunction measured. Patients with depressed left ventricular function are atincreased risk for adverse events, and they should be treated aggressively withβ-blockers (if heart failure is compensated) and oral angiotensin-convertingenzyme inhibitors. Angiotensin-converting enzyme inhibitors should be used inpatients with anterior-wall MI, clinical evidence of heart failure, or an fractionof 40% or less. In light of the results of the HOPE (Heart Outcomes PreventionEvaluation) trial, it is reasonable to consider angiotensin-converting enzymeinhibitor therapy for any patient after MI.

Patients who undergo primary percutaneous coronary intervention for ST-segment elevation MI already have immediate risk stratification for nonculpritcoronary disease. Further noninvasive stress testing is indicated only if interme-diate-severity stenosis is present in a nonculprit coronary artery or if myocardialviability testing is required before further coronary revascularization. Once apatient has undergone successful thrombolysis, further evaluation is required toassess for residual myocardial ischemia. Patients with the following featuresshould undergo invasive coronary angiography: recurrent myocardial ischemia,

25

F I G U R E S 8 A A N D 8 B .Coronary angiography in the patient in Case 3.Coronary angiography shows thrombotic occlu-sion of the mid-right coronary artery (RCA). Therewere no other significant coronary stenoses. Leftventriculography showed inferior hypokinesis withan ejection fraction of 40%. B. The patient under-went successful stenting of the RCA with adjunc-tive glycoprotein IIb/IIIa receptor inhibitor use.

Hochman JS, Sleeper LA, Webb JG,Sanborn TA, White HD, Talley JD,et al.Early revascularization in acute myocardialinfarction complicated by cardiogenic shock.SHOCK Investigators. Should We EmergentlyRevascularize Occluded Coronaries forCardiogenic Shock. N Engl J Med.1999;341:625-34. PMID: 10460813

Diagnosis of Coronary Artery Disease

26

hemodynamic instability, ventricular tachycardia, clinical heart failure, ejectionfraction of 40% or less, or post-MI mechanical complications (Scanlon et al.).Low-risk patients with an uncomplicated MI course who do not have theseindications for coronary angiography may undergo predischarge noninvasivesymptom-limited stress testing. The approaches are identical to those describedin the section on chronic coronary artery disease.

Patients with depressed left ventricular systolic function are at higher riskfor subsequent ventricular tachyarrhythmias. The occurrence of asymptomaticnonsustained ventricular tachycardia within 48 hours of MI should not changeusual management consisting of aspirin, β-blockers, ACE inhibitors, and statins.If antiarrhythmic drug therapy is considered for patients after MI, amiodaroneis generally the preferred agent. The finding of asymptomatic nonsustained ventricular tachycardia more than 48 hours after MI or symptomatic ventriculararrhythmias, particularly in patients with an ejection fraction of 35% or less,generally prompts electrophysiologic testing or implantation of an implantablecardioverter-defibrillator. Such studies as Multicenter Automatic DefibrillatorImplantation Trial-I (MADIT-I) and MADIT-II have consistently shown thathigh-risk patients who have had MI typically do better with implantable cardio-verter-defibrillator therapy compared to antiarrhythmic therapy. Patient selection for electrophysiologic testing and implantable cardioverter-defibrilla-tor after MI is described in the section on arrhythmia.

Coronary Artery Disease and Chronic Stable Coronary Artery Disease

In this discussion, coronary artery disease (CAD) refers to atherosclerotic dis-ease of the major epicardial coronary arteries. The first step in the diagnosis ofCAD is to estimate its likelihood by taking into account the patient’s risk fac-tors for CAD and symptoms. The pretest probability of CAD is estimated aslow, intermediate, or high and is important for choosing the right diagnostic approach.

Diagnosis of Coronary Artery Disease• Which stress test is best for the diagnosis of coronary artery disease?• Is electron-beam computed tomography useful for the diagnosis of coronary

artery disease?

Most noninvasive tests for detecting CAD perform best when pretest probabil-ity is intermediate. In patients with low pretest probability, a positive test resultis more likely to be falsely so. In patients with a high pretest probability of dis-ease, a negative test result is most likely to be false. Thus, in patients with a highpretest probability of disease, a test such as coronary angiography is preferableto noninvasive stress testing. In patients with a low pretest probability of dis-ease, a test such as electron-beam computed tomography (CT) for coronary cal-cification may be more appropriate (Greenland et al.; Newman et al.).

Case 4A 40-year-old man presents because during a heated argumentwith his wife, he noted mild anterior chest tightness. He has afamily history of premature CAD and a low-density lipoproteincholesterol level of 160 mg/dL. He rarely exercises and has abody mass index of 28 kg/m2. He does not have diabetes and isa nonsmoker. Physical examination was remarkable for bloodpressure of 150/90 mm Hg, pulse rate 90/min and regular,and a grade II/VI early systolic murmur at the base. A tread-mill stress echocardiographic study was normal.

Scanlon PJ, Faxon DP, Audet AM,Carabello B, Dehmer GJ, Eagle KA, et al.ACC/AHA guidelines for coronary angiog-raphy. A report of the American College ofCardiology/American Heart AssociationTask Force on practice guidelines (Committeeon Coronary Angiography). Developed incollaboration with the Society for CardiacAngiography and Interventions. J Am CollCardiol. 1999;33:1756-824. PMID: 10334456

Greenland P, Smith SC Jr, Grundy SM.Improving coronary heart disease risk assess-ment in asymptomatic people: role of tradi-tional risk factors and noninvasive cardiovas-cular tests. Circulation. 2001;104:1863-7.PMID: 11591627Newman AB, Naydeck BL, Sutton-Tyrrell K, Feldman A, Edmundowicz D,Kuller LH. Coronary artery calcification inolder adults to age 99: prevalence and riskfactors. Circulation. 2001;104:2679-84.PMID: 11723018


For patients with an intermediate likelihood of CAD, stress testing is thepreferred approach (Shavelle et al.). Various techniques are available for stress-ing the cardiovascular system (Table 11); exercise is the preferred method.Most patients prefer treadmill exercise to bicycle and consequently achievehigher workloads with treadmill exercise. For patients who cannot exercise,pharmacologic stress testing can be performed by using with agents that mimicthe catecholamine increases of exercise, such as dobutamine, or agents thatcause coronary artery vasodilation, such as dipyridamole. A method of detect-ing myocardial ischemia is used in conjunction with stress testing to establishthe diagnosis of CAD. The traditional technique for detecting ischemia is elec-trocardiographic monitoring. Currently, however, many patients undergo car-diac imaging studies, such as echocardiography or myocardial perfusion scintig-raphy, during stress testing. The determination of which stress and whichischemia detection method to use is often a source of confusion for the generalist.

Regardless of the technical merits of the various stress testing procedures,access, availability, cost, and perceived quality often simplify the decision insome clinical settings. Risk to the patient is similar with all stress testing meth-ods. The overall risk of a serious cardiac event, such as myocardial infarction ordeath, is approximately 1 in 10,000 stress tests. With careful patient selectionand the availability of highly trained staff to supervise the stress test, this risk canoften be decreased to almost zero.

Although individual factors at particular clinical locations may modify testselection, the following is a general approach based on the strengths and weak-nesses of the various tests relative to pretest probability of disease. First, exer-cise, especially treadmill exercise, is the preferred mode of stress testing as longas the patient can perform well. The patient must be able to exercise sufficientlyto increase the heart rate to 85% or more of the maximum predicted value.Although most patients believe that they can exercise to this level, relatively feware actually able to do so. Second, the resting electrocardiogram must be con-sidered. If it is normal and the patient can exercise well, the overall accuracy ofexercise electrocardiography is about 85%. However, if the patient does notexercise well or has abnormalities on the resting electrocardiogram, the accu-racy decreases to about 50%, rendering the test diagnostically worthless. Thus,in patients who can exercise well and have a normal resting electrocardiogram,treadmill electrocardiography testing is still an efficacious and low-cost initialapproach.

In patients with an abnormal resting electrocardiogram, cardiac imagingmethods must be used. For practical purposes, there are two methods of imag-ing: echocardiography and myocardial perfusion scintigraphy. Although in indi-vidual clinical settings one of these methods may be superior to the other, ingeneral echocardiography has a lower sensitivity but higher specificity thanradionuclide perfusion imaging. Radionuclide perfusion imaging, on the otherhand, has high sensitivity (approaching 95% in some studies) but a somewhatlower specificity than echocardiography. The sensitivity and specificity of bothtechniques also depend on the number of diseased vessels, increasing with moreextensive disease. Radionuclide perfusion imaging is superior for localizingwhich coronary distribution is probably causing the ischemia because on

27

Shavelle DM, Budoff MJ, LaMont DH,Shavelle RM, Kennedy JM, Brundage BH.Exercise testing and electron beam computedtomography in the evaluation of coronaryartery disease. J Am Coll Cardiol. 2000;36:32-8. PMID: 10898409

TABLE 11 Stress Testing Possibilities To Diagnose Coronary Artery Disease

Cardiac Stressor Ischemia Detector

Exercise Electrocardiography

Dobutamine Echocardiography

Dipyridamole/adenosine Radionuclide perfusion


28

echocardiography, abnormal wall motion in one area may affect adjacent areas.Finally, both tests have significant technological limitations. Echocardiographywith stress testing is challenging and requires highly skilled technicians andexperienced physician readers. In general, the proportion of patients with poorechocardiographic images from stress testing is about 5%. This rate can bedecreased to almost zero if contrast echocardiography is used. Radionuclideimaging suffers from photon attenuation due to chest-wall structures, such asbreasts. Unless special attention is paid to attenuation, false-positive studiesoften result. In addition, since radionuclide imaging depends on a difference inperfusion between areas of the heart, the scan can appear normal in patientswith severe three-vessel CAD in which all three coronary vessels are equally dis-eased. This unusual circumstance reinforces the idea that if clinical informationindicates CAD, further invasive testing may be appropriate even if results ofnoninvasive testing are normal.

In head-to-head comparison studies, the relative strengths and weaknessesof the two imaging techniques tend to cancel out, and the overall accuracy inthe clinical arena is similar. Therefore, test selection often depends on patientfactors, physician preference, and institutional factors. For example, in Case 5,stress echocardiography was chosen because the patient had a systolic heartmurmur. Some evidence indicates that stress testing is less accurate in womenand that imaging must always be used in women; however, these studies suf-fered from selection bias, and the evidence is not sufficiently strong to opt foran expensive imaging test as the first choice in all women. However, womenhave a higher likelihood of not being able to exercise adequately, which mustbe considered in test ordering. If electrocardiographic abnormalities are present, imaging must be substituted for electrocardiography with exercisestress testing.

Autopsy studies have shown a direct relationship between calcium in thewalls of coronary arteries and underlying coronary atherosclerosis. This princi-ple was used in conjunction with electron-beam CT to develop a coronaryartery calcium score, which identifies the risk of subsequent cardiac events(Keelan et al.). A higher coronary artery calcium score is associated with anincreased risk of coronary artery disease regardless of the number of conven-tional risk factors present. However, the coronary calcium score does not cor-relate well with coronary angiographic results because of coronary arteryremodeling in the setting of plaque deposition (Bielak et al.). Coronary arter-ies can increase their lumen size to compensate for plaque development.Although this measurement can be useful, calcium scores derived from elec-tron-beam CT do not correlate exactly with clinical events in an individualpatient. For example, a patient may have a very low score yet have cholesteroldeposits in the coronary arteries, increasing the risk for rupture and acutemyocardial infarction. Or a patient may have heavily calcified coronary arteriesyet stable plaques, and myocardial infarction does not ensue. Overall accuracyis about 70%, mainly owing to low specificity (Haberl et al.).

The precise role of electron-beam CT calcium scores is still being defined(O’Rourke et al.). In patients with a low probability of CAD on the basis oftraditional risk factors but who are concerned because of a family history ofpremature CAD, electrom-beam CT may be useful, especially if negative, toreassure the patient. However, it is likely to be more accurate when positive inan elderly asymptomatic patient. Patients with symptoms suggestive of CADand risk factor profiles that make the presence of disease almost certain do notbenefit from a calcium score because it will not affect their management. Inaddition, there is insufficient evidence to recommend using calcium scores toassess the response of CAD to treatment.

Keelan PC, Bielak LF, Ashai K, JamjoumLS, Denktas AE, Rumberger JA, et al.Long-term prognostic value of coronary cal-cification detected by electron-beam com-puted tomography in patients undergoingcoronary angiography. Circulation.2001;104:412-7. PMID: 11468202Bielak LF, Rumberger JA, Sheedy PF2nd, Schwartz RS, Peyser PA. Probabilisticmodel for prediction of angiographicallydefined obstructive coronary artery diseaseusing electron beam computed tomographycalcium score strata. Circulation.2000;102:380-5. PMID: 10908208Haberl R, Becker A, Leber A, Knez A,Becker C, Lang C, et al. Correlation ofcoronary calcification and angiographicallydocumented stenoses in patients with sus-pected coronary artery disease: results of1,764 patients. J Am Coll Cardiol.2001;37:451-7. PMID: 11216962O’Rourke RA, Brundage BH, FroelicherVF, Greenland P, Grundy SM,Hachamovitch R, et al. American Collegeof Cardiology/American Heart AssociationExpert Consensus document on electron-beam computed tomography for the diagno-sis and prognosis of coronary artery disease.Circulation. 2000;102:126-40.PMID: 10880426

Treatment of Coronary Artery Disease

Case 5A 66-year-old man had had multivessel coronary artery bypassgraft surgery for severe angina 5 years ago. In the past month,he has experienced dyspnea on exertion. Since this symptommay indicate an angina equivalent, further evaluation was war-ranted. Dipyridamole radionuclide perfusion imaging is donebecause the patient’s ability to exercise fully was in doubt. Noangina or ischemic electrocardiographic changes were found.The perfusion scintigraphy showed a small area of ischemia inthe inferoapical region. The right coronary artery was bypassed,but distal posterior descending disease was noted on the preop-erative coronary angiogram. It was decided that this was a low-risk situation that was not causing the patient’s symptomsand did not warrant coronary angiography. Other causes fordyspnea were pursued.

If the patient cannot exercise, pharmacologic stress with myocardial imag-ing must be used. Pharmacologic stress does not reliably produce electrocardio-graphic changes even in patients in whom imaging shows evidence of myocar-dial ischemia. Thus, pharmacologic electrocardiographic testing is not recom-mended. Dobutamine echocardiography and dipyridamole or adenosinenuclear perfusion imaging both have similar accuracy in general clinical settings(Smart et al.). Some believe that dipyridamole nuclear perfusion imaging issuperior to dobutamine echocardiography in patients with left bundle-branchblock on resting electrocardiography, although head-to-head data on this topicare sparse. Compared to echocardiography or myocardial perfusion imaging,exercise radionuclide ventriculography does not perform as well and has largelybeen abandoned. Although stress magnetic resonance imaging has been tested,it has not been sufficiently developed to the point where it is a clinical reality.

Treatment of Coronary Artery Disease• Are calcium antagonists contraindicated for the treatment of angina?• Is coronary artery bypass graft surgery ever superior to angioplasty?

The treatment of chronic stable CAD begins with lifestyle modification to con-trol risk factors. A low-fat, low-cholesterol diet, regular exercise, and smokingcessation have all been shown to improve outcomes in patients with CAD.Secondary prevention involves use of aspirin, statin drugs in patients whoselipid level cannot be adequately controlled by diet and exercise, andangiotensin-converting enzyme or receptor blocking drugs in patients withhypertension (Table 12). All three of these approaches have been shown toreduce events in patients with known CAD (Dagenais et al.; White et al.).Aggressive risk factor control, including use of statin drugs, may obviate theneed for revascularization in patients with CAD (MRC/BHF HeartProtection Study).

Symptoms of CAD should also be treated. The most common symptom isangina pectoris, for which three major classes of drugs are useful prophylacti-cally: long-acting nitrates, β-blockers, and calcium antagonists. All three classesof drugs have been shown in double-blind studies to decrease the number ofangina attacks and increase exercise tolerance. β-Blockers prevent angina pec-toris largely by decreasing heart rate and reducing blood pressure, therebyreducing myocardial energy consumption. β-Blockers have a definite role aftermyocardial infarction, in hypertensive patients, and in patients with reduced leftventricular performance. β-Blocker use is encouraged because they have proven

29

Smart SC, Bhatia A, Hellman R, StoiberT, Krasnow A, Collier BD, Sagar KB.Dobutamine-atropine stress echocardiogra-phy and dipyridamole sestamibi scintigraphyfor the detection of coronary artery disease:limitations and concordance. J Am CollCardiol. 2000;36:1265-73.PMID: 11028482

K E Y P O I N T S

• An electron-beam computed tomogra-phy coronary calcium score is most use-ful for refining the assessment of riskfor coronary artery disease in elderlyasymptomatic patients.

• If the diagnosis of coronary artery dis-ease is in question after history, physicalexamination, resting electrocardiog-raphy, and chest radiography, exerciseelectrocardiography is the next step in most patients.

• The initial stress test should use cardiacimaging if the resting electrocardiogramis abnormal, adequate exercise perform-ance is unlikely, or prior revasculariza-tion or known coronary artery disease is present.

Dagenais GR, Yusuf S, Bourassa MG, Yi Q, Bosch J, Lonn EM, et al. Effects of ramipril on coronary events in high-riskpersons: results of the Heart OutcomesPrevention Evaluation Study. Circulation.2001;104:522-6. PMID: 11479247White CW, Gobel FL, Campeau L,Knatterud GL, Forman SA, Forrester JS,et al. Effect of an aggressive lipid-loweringstrategy on progression of atherosclerosis inthe left main coronary artery from patients in the post coronary artery bypass graft trial.Circulation. 2001;104:2660-5.PMID: 11723015MRC/BHF Heart Protection Study of cho-lesterol lowering with simvastatin in 20,536high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22.PMID: 12114036

Treatment of Coronary Artery Disease

30

efficacy and relatively few patients are intolerant of them or have contraindica-tions to their use.

Nitrates and calcium antagonists work largely by dilating the coronaryarteries and increasing myocardial blood flow to the ischemic areas. Althoughnitrates are effective, patients may develop tolerance to them, and special dos-ing regimens are required. To avoid tolerance, patients should spend at least 8hours daily (usually overnight) free of nitrates. Calcium antagonists have fewerside effects than do β-blockers and nitrates and are well tolerated by mostpatients. The most common side effect of calcium antagonists is peripheraledema due to changes in capillary hydrostatic pressure rather than to inductionof heart failure. The newer dihydroperidine calcium antagonists have few neg-ative inotropic effects and can be used in patients with reduced left ventricularperformance. However, observational studies have raised concerns about thelong term safety of calcium channel blockers, especially the short-acting prepa-rations. In addition, these agents do little to arrest the progression of diseaseand have not been shown to increase longevity.

Patients with angina pectoris that is refractory to medical therapy; thosewith high-risk coronary anatomy, such as left main stenosis; and those with sig-nificant coronary lesions and reduced left ventricular performance benefit fromrevascularization. Studies have shown that revascularization is excellent foreliminating angina pectoris, increasing longevity in patients with certainanatomic features, and improving left ventricular performance in appropriatelyselected patients (Gibbons et al.).

For patients with discrete single- or double-vessel CAD, a percutaneousintervention is often preferred because it avoids the morbidity and mortality ofbypass surgery. The main limitation of percutaneous intervention is restenosis,which with plain balloon angioplasty occurs in 30% to 40% of patients. Theadvent of stents has decreased the incidence of restenosis to 15% to 20%, whichexplains why almost all patients currently undergoing percutaneous interven-tion receive a stent. Stent technology is evolving rapidly, and stents coated withantineoplastic agents are now available. These agents inhibit the neointimalhyperplasia that causes in-stent restenosis. Data from the initial studies with 6months to 1 year of follow-up has shown restenosis rates in the range of 5% to10%. If very low rates of restenosis continue with coated stents in the long term,less severe lesions will be stented more often.

In patients with severe multivessel disease, especially diabetic patients orpatients with reduced left ventricular ejection fraction, coronary artery bypassgraft (CABG) surgery is the preferred revascularization technique. In appropri-ately selected patients, such surgery has a 30-day mortality rate in the range of1% to 3% range. Other comorbid conditions, especially renal failure, canincrease the mortality rate. Although diabetic patients with multi-vessel diseasehave better outcomes with CABG surgery than with percutaneous intervention,they perioperative rates of mortality and morbidity rates are somewhat higher(The BARI Investigators). For example, the incidence of postoperativewound infection is higher in diabetic patients.

The average vein graft lasts about 8 years. Patients who carefully controltheir risk factors after surgery can extend the life of the graft to to 12 years ormore. Arterial grafts last much longer than vein grafts and are preferred if tech-nically feasible. The internal thoracic arteries are the preferred conduits, eitheras pedical grafts or as freestanding grafts (Leavitt et al.). Other arteries, such asthe radial, the gastroepiploic, and splenic, have been also used. Some centersbelieve that a total arterial CABG is the preferred technique.

Minimally invasive techniques have been developed for CABG that allowrevascularization through small intercostal incisions by using specially designed

Gibbons RJ, Miller DD, Liu P, Guo P,Brooks MM, Schwaiger M. Similarity ofventricular function in patients alive 5 yearsafter randomization to surgery or angioplastyin the BARI trial. Circulation. 2001;103:1076-82. PMID: 11222469

Seven-year outcome in the BypassAngioplasty Revascularization Investigation(BARI) by treatment and diabetic status. J Am Coll Cardiol. 2000;35:1122-9.PMID: 10758950Leavitt BJ, O’Connor GT, Olmstead EM,Morton JR, Maloney CT, Dacey LJ, et al.Use of the internal mammary artery graftand in-hospital mortality and other adverseoutcomes associated with coronary arterybypass surgery. Circulation. 2001;103:507-12. PMID: 11157714

TABLE 12 Proven SecondaryPrevention Interventions for Patientswith Coronary Artery Disease

Aspirin and angiotensin-convertingenzyme inhibitors

β-Blockers and blood pressure control

Cholesterol lowering and smokingcessation

Diet and diabetes control

Exercise

Management of Coronary Artery Disease

equipment and by using the femoral vessels for cardiopulmonary bypass.However, these techniques lend themselves best to simple operations on theproximal anterior coronary vessels and are more difficult to perform on poste-rior vessels or on multiple vessels (Mehran et al.). Use of several intercostalincisions, although small and cosmetically more appealing than a mid-sternalvertical incision, frequently results in much greater postoperative pain. Giventhe limited access to the heart, the postoperative pain associated with these min-imally invasive techniques, and the increased success of percutaneous interven-tion, these procedures have waned in popularity.

The reported incidence of demonstrable cognitive problems after CABG is10% to 15%; frank neurologic defects occurred in half of the patients, and min-imal cognitive dysfunction occurred in the other half. Concern about this com-plication led to the development of off-pump revascularization techniques,because the effect of the heart–lung pump on coagulation elements in theblood is thought to be a major reason for these neurologic defects. Off-pumprevascularization has become more feasible with technologic advances in coro-nary revascularization techniques, such as a sutureless attachment device thatallows rapid insertion of bypass grafts on the beating heart. Despite the theo-retic attractiveness of these off-pump techniques, they do not completely pre-vent neurologic events. This is probably because disruption of aortic debrisfrom the proximal anastomosis procedure accounts for a significant proportionof central nervous system events. Currently, aorta manipulation during bypassgraft insertion cannot be completely avoided, unless only arterial pedicle graftsare used.

A few patients have angina that is refractory to maximum medical therapyand are not good candidates for revascularization, usually because the risk out-weighs the potential benefit. Few options are available for such patients.Although heart transplantation can be done, these patients are often not goodcandidates for this surgery. Long-term use of narcotic analgesics is not optimalbut is often the only option. Recently, some success with enhanced externalcounterpulsation was reported. This procedure involves foot-to-buttocksequential inflation of compressive cuffs during diastole, with rapid deflation inearly systole. Like intra-aortic balloon pumping, external counterpulsationincreases diastolic aortic or coronary perfusion pressure and reduces afterload,augmenting cardiac output. Studies have shown that after brief periods of coun-terpulsation, angina is relieved, exercise tolerance is increased, and ischemia isreduced for prolonged periods (Urano et al.).

Management of Coronary Artery Disease• Are routine stress tests after revascularization advisable?

Follow-up of patients after revascularization is often shared by the surgeon orcardiologist and the primary care physician until the periprocedure period isover and the surgeon or cardiologist feels comfortable releasing the patient tothe care of the primary care physician. At 3 months after any stressful proce-dure, stress-related neurohormonal changes have usually abated. At this time,cholesterol measurements are again accurate, as are determinations of bloodpressure and heart rate. This is a good time to assess and treat risk factors toprevent future events.

In addition to providing secondary prevention of atherosclerosis, the physi-cian must assess the patient for evidence of restenosis or graft failure. This canusually be accomplished by assessment of the patient’s symptoms, especially ifhe or she had symptoms before revascularization.

31

Mehran R, Dangas G, Stamou SC, PfisterAJ, Dullum MK, Leon MB, Corso PJ.One-year clinical outcome after minimallyinvasive direct coronary artery bypass.Circulation. 2000;102:2799-802.PMID: 11104735

Urano H, Ikeda H, Ueno T, Matsumoto T,Murohara T, Imaizumi T. Enhanced exter-nal counterpulsation improves exercise toler-ance, reduces exercise-induced myocardialischemia and improves left ventricular dias-tolic filling in patients with coronary arterydisease. J Am Coll Cardiol. 2001;37:93-9.PMID: 11153780

K E Y P O I N T S

• Proven secondary prevention strategiesin patients with coronary artery diseaseinclude aspirin, angiotensin-convertingenzyme inhibitors, β-blockers, decreas-ing lipid levels, blood pressure control,smoking cessation, and exercise.

• Calcium antagonists are potent antiang-inal drugs that have few adverse effectscompared with nitrates and β-blockers,but they do not increase longevity inpatients with coronary artery disease.

• Coronary revascularization is excellentfor relieving angina, increasinglongevity in patients with certain high-risk anatomic feature, and improvingleft ventricular function in selectedpatients.

• Randomized studies have shown similarbenefits of percutaneous interventionand coronary artery bypass graft sur-gery, except in diabetic patients, who do better with coronary artery bypassgraft surgery.

Epidemiology

32

The use of routine exercise testing, especially in the first 5 years after revas-cularization, is controversial (Zellweger et al.). There is little scientific evidencethat routine stress testing in the absence of symptoms or other indications pro-vides any definite benefit for its cost early after revascularization. Nonetheless,some physicians perform a yearly stress test in all patients, perhaps to providethe patient a psychological boost and incentive to continue their secondary pre-vention measures. Physicians who do not advocate routine testing often have alow threshold for doing repeated stress testing. Patients with successfullytreated CAD should have follow-up visits every 4 to 12 months, depending onhow recently successful treatment was accomplished.

Heart Failure

Heart failure is a major worldwide public health problem. In the United States,heart failure affects nearly 5 million persons (about 2% of the population).Greater understanding of the pathophysiology of heart failure has improvedprevention and treatment protocols.

Heart failure is a clinical syndrome of cardiac pump dysfunction that man-ifests as systolic or diastolic abnormalities, along with myocardial remodeling(ventricular hypertrophy, chamber dilation, and interstitial fibrosis). Hormonal,cytokine, and neural regulatory function is disturbed, with subsequent circula-tory insufficiency. Patients with heart failure may be asymptomatic or experi-ence fatigue, dyspnea, or fluid retention of fluctuating severity.

EpidemiologyThe prevalence of heart failure is increasing (Table 13). The condition is newlydiagnosed in almost 500,000 patients annually. Almost 300,000 patients peryear die of heart failure, and this figure is increasing. The annual mortality ratein severely decompensated patients is 80% to 90%.

Heart failure is associated with aging. It is estimated that 10% of personsolder than 65 years have heart failure and that approximately 80% of patientshospitalized for decompensated heart failure are older than 65 years of age.

Zellweger MJ, Lewin HC, Lai S, Dubois EA,Friedman JD, Germano G, et al. When tostress patients after coronary artery bypasssurgery? Risk stratification in patients earlyand late post-CABG using stress myocardialperfusion SPECT: implications of appropri-ate clinical strategies J Am Coll Cardiol.2001;37:144-52. PMID: 11153729

K E Y P O I N T S

• Routine stress testing after revascular-ization in asymptomatic patients is notrecommended in the first 5 years.

TABLE 13 The Burden of Heart Failure in North America

Economic, Morbidity, and Mortality Burden

5 million patients diagnosed with symptomatic heart failure

500,000 new cases of symptomatic heart failure diagnosed annually

15 million visits for heart failure annually

6.5 million heart failure hospital days annually

Almost 1 million hospitalizations for heart failure annually

2.6 million patients hospitalized with heart failure as a second-degree diagnosis annually

2% prevalence of heart failure in population

10% of patients older than 65 years with heart failure

80% of hospitalized patients with heart failure older than 65 years of age

33% of patients with heart failure as discharge diagnosis readmitted within 90 days

Heart failure most common Medicare diagnosis-related group

24 billion dollars spent annually on heart failure in United States

5-10% annual mortality rate in mildly symptomatic heart failure

30-40% annual mortality rate in more symptomatic heart failure

20-25% mortality rate at 180 days after heart failure hospitalization

Epidemiology

Heart failure is the most common Medicare diagnosis-related group catego-rization, and more Medicare dollars are spent for diagnosis and treatment ofheart failure than for any other single diagnosis.

33

TABLE 14 World Health Organization: Classification of Heart FailureEtiologies

Dilated cardiomyopathy

Idiopathic

Hypertrophic cardiomyopathy

Idiopathic hypertrophic subaortic stenosis

Hypertrophic obliterative cardiomyopathy

Hypertrophic nonobstructive cardiomyopathy

Restrictive cardiomyopathy

Specific infiltrating diseases

Idiopathic

Arrhythmogenic right ventricular cardiomyopathy

Idiopathic right ventricular outflow tract tachycardia

Arrhythmogenic right ventricular dysplasia

Unclassifiable cardiomyopathies

Atypical presentation: fibroelastosis, systolic dysfunction without dilation,mitochondrial cardiomyopathy

Mixed presentation (dilated/hypertrophic/restrictive): amyloidosis, hypertension

Specific cardiomyopathies

Ischemic

Valvular obstruction/insufficiency

Hypertensive

Inflammatory: myocarditis (lymphocytic, giant cell, autoimmune)

Infectious: Chagas’ disease, HIV, Enterovirus, adenovirus cytomegalovirus

Bacterial and fungal endocarditis

Metabolic

Endocrine: thyrotoxicosis, hypothyroidism, adrenal cortical insufficiency,pheochromocytoma, acromegaly, diabetes mellitus

Familial storage disease/infiltration: hemochromatosis, glycogen storage disease,Hurler’s syndrome, Refsum’s disease, Niemann–Pick disease, Hand-Schuler-Christiandisease, Fabry–Anderson disease, Morquio–Ullrich disease

Electrolyte deficiency syndromes: potassium metabolism disturbances (hypokalemia),magnesium deficiency

Nutritional disorders: kwashiorkor, anemia, beriberi, selenium deficiency, nonspecificmalabsorption, starvation

Amyloid (primary, secondary, familial, hereditary, senile)

Familial Mediterranean fever

General system disease

Rheumatologic disorders: systemic lupus erythematosus, polyarteritis nodosa,rheumatoid arthritis, scleroderma, dermatomyositis

Nonspecific infiltrations and granulomas: sarcoidosis

Leukemia

Muscular dystrophies: Duchenne’s, Becker’s, myotonic

Neuromuscular disorders: Friedreich’s ataxia, Noonan’s syndrome, lentiginosis

Sensitivity and toxic reactions: alcohol, catecholamines (endogenous or exogenous),anthracyclines, irradiation

Peripartum cardiomyopathy (a heterogeneous group)

Information from: 1995 Report World Health Organization/International Society and Federation of Cardiology Task Forceon the Definition of Cardiomyopathies. Circulation. 1996;93:8412.

Etiology

34

EtiologyThe causes of heart failure are varied. Table 14 summarizes the current WorldHealth Organization categorization of diseases that cause heart failure.Structural heart lesions are commonly diagnosed, and arrhythmias are frequent.Specific cardiomyopathies include ischemic heart disease, valvular obstructionand insufficiency causing heart failure, hypertensive heart disease with heart fail-ure, and various inflammatory cardiomyopathies. Often, combinations of dis-eases contribute to underlying heart failure. Idiopathic dilated cardiomyopathyis diagnosed when heart failure with systolic dysfunction is discovered and noother disease is apparent.

A detailed family history is critical because specific genetic disorders areassociated with heart failure. Dilated cardiomyopathy is familial in approxi-mately 20% to 25% of patients. Hypertrophic cardiomyopathies, usually associ-ated with heart failure due to diastolic dysfunction are a distinct entity that aregenetic in origin and have well-defined heritable characteristics and gene muta-tions. Arrhythmogenic right-ventricular cardiomyopathy is uncommon but life-threatening because of unstable ventricular arrhythmias that arise in the rightventricular outflow tract. Fibrotic infiltration of the outflow tract and general-ized right ventricular dysplasia account for substantial right-sided congestiveheart failure in many patients.

Metabolic abnormalities that can cause cardiomyopathy include endo-crinopathies, such as thyrotoxicosis and hypothyroidism; pheochromocytoma;acromegaly; diabetes mellitus; and Addison’s disease. General systemic illnessesalso precipitate heart failure and include a large group of rheumatologic disor-ders such as systemic lupus erythematosus (see Table 14). Systemic musculardystrophies, in particular, Duchenne’s, Becker’s, and myotonic dystrophy arealso associated with cardiomyopathy. Toxic injury to the heart can result fromalcohol, anthracyclines, and irradiation, as well as states in which endogenouscatecholamines are chronically elevated.

Pathophysiology of Heart FailureAfter primary heart injury, a series of molecular biodynamic, cellular membrane,subcellular signaling, and other compensatory events occur that lead to cardiacdysfunction and circulatory inadequacy (Figure 9). Even after elimination ofthe initiating events, the latter forces perpetuate dysfunction and failure.Remodeling of the heart, resulting in abnormal myocyte contraction and relax-ation, causes cardiac dysfunction, resulting in circulatory perturbation (gener-ally decreased vital organ perfusion). Circulatory perturbation results in physio-logic responses that initially preserve organ perfusion but ultimately producethe clinical manifestations of heart failure.

The clinical presentation of heart failure can primarily be categorized intolow cardiac output states (which manifest as weakness, fatigue, malaise, andorgan dysfunction) and congestive conditions (which manifest as systemic vol-ume overload with peripheral, central organ, and pulmonary edema). Althoughsome congestive conditions may be designated as congestive heart failure, notall patients with heart failure have a congestive state.

The molecular biodynamics of heart failure result primarily from produc-tion of more contractile proteins by cardiac myocytes and from the signalingschemes of various membranes and submembranes after an initial injury. Thesemechanisms would restore contractile function in normal circumstances.However, this response in heart failure results in production of a fetal type ofmyocyte contractile protein and less normal interstitial matrix matter, such that

K E Y P O I N T S

• Coronary artery disease and hyperten-sion are the most common causes ofheart failure. Primary myocardial injuryresults in ventricular remodeling (hyper-trophy, chamber dilation, and interstitialfibrosis), which perpetuates the syndrome.

Pathophysiology of Heart Failure

cardiac remodeling with cardiac hypertrophy, chamber enlargement, and wors-ening interstitial fibrosis ensues. The anatomic and morphologic responses tocardiac injury are primarily myocyte hypertrophy, cardiac chamber dilation, andvarying degrees of interstitial fibrosis. Cardiomegaly ensues, in which chambervolumes, cardiac mass, and sphericity of the ventricles and atria are increased.Cellular responses include adrenoreceptor abnormalities, such as down-regula-tion of myocyte surface β-adrenergic receptors. Circulatory abnormalities man-ifest as baroreceptor dysfunction; decreased systemic flow; and activation ofperipheral venous and arterial autoregulatory actions, in which changes in nitricoxide, prostacyclin, and endothelin expression produce local vasoconstrictionand vasodilation. Other physiologic responses include sympathetic nervous sys-tem up-regulation, with increased blood levels of epinephrine and norepineph-rine and activation of the renin–angiotensin–aldosterone systems. The inflam-mation seen in heart failure involves release of interleukins and tumor necrosisfactor, which subsequently contribute further to abnormal cardiac cell function,apoptosis, and interstitial fibrosis. All of these complicated interactions producethe setting for cardiac dysfunction, and many faces of clinical heart failure sub-sequently emerge.

Heart failure may occur with normal left ventricular systolic function. Thisstate is commonly called diastolic dysfunction heart failure or heart failure withpreserved systolic function. These patients have impaired ventricular filling andelevated left-sided filling pressures that increase during exercise, leading to exer-tional dyspnea. The ventricular volume is usually reduced and the ventricularwalls are thick, either because of hypertrophy or an infiltrative process, such asamyloid. The atrial volumes are often increased. Neurohormonal and other bio-chemical responses are less marked.

35

F I G U R E 9 .The facets of heart failure: complexity of the syndrome.

TheHeart Failure

Milieu

AcutePulmonary

Edema/Shock

ClinicalManifestations

PhysiologicResponses

CirculatoryPerturbation

CardiacDysfunction Anatomic/

Morphologic(“Remodeling”)

CellularResponses

MolecularBiodynamic

Injury/Induction

“Failure is the inability to measure up to certain normal standards”Webster’s Dictionary

AsymptomaticChronic

CongestiveHeart Failure

Diagnosis of Heart Failure

36

Diagnosis of Heart FailureDiagnosis algorithms for heart failure have been based largely on experiencegained through large clinical trials (Table 15). These algorithms have beenincorporated into practice guidelines that contain several common factors specific to diagnosis of the syndrome (Table 16). Early diagnosis is stressedbecause therapy has greater benefit when, for example, asymptomatic left ven-tricular systolic dysfunction is discovered and treated. Furthermore, heart fail-ure is not the primary problem in all patients with dyspnea and edema.Therefore, measurement of systolic and diastolic left ventricular function inpatients at risk and in symptomatic patients is critical. Identification of specificcardiac structural abnormalities and determination of the primary cause of cardiac dysfunction are of major importance.

The European Society of Cardiology Guidelines for the Diagnosis andTreatment of Chronic Heart Failure focus attention on the diagnosis of heartfailure (Remme and Swedberg). Figure 10 summarizes the recommendedapproach in persons in whom heart failure is suspected on the basis of certainsymptoms and signs. Symptoms associated with heart failure (such as dyspnea)or physical findings in heart failure (such as peripheral edema) trigger this diag-nostic algorithm. Mild symptoms and early signs should be investigated to iden-tify disease at an early stage. Electrocardiography or chest radiography shouldbe used to assess for cardiac disease.

If heart failure is suspected on the basis of initial assessment, cardiac imag-ing should be done. Echocardiography should be done first because it is widelyavailable; its cost is reasonable; and it can characterize systolic and diastolic ven-tricular function, wall-motion abnormalities, ventricular hypertrophy, valvular

Remme WJ, Swedberg K. Comprehensiveguidelines for the diagnosis and treatment ofchronic heart failure: task force for the diag-nosis and treatment of chronic heart failureof the European Society of Cardiology. Eur JHeart Fail 2002;4:11-22. PMID: 11812661

TABLE 15 Clinical Heart Failure Guidelines

Guideline

Clinical Practice Guideline No. 11. Rockville, MD: U.S. Department of Health andHuman Services, Agency for Healthcare Policy and Research; 1994. Publication 94-0612.

American College of Cardiology/American Heart Association Guidelines for theEvaluation and Management of Heart Failure. Circulation. 1995;92:2764. Revised inCirculation. 2001;104:1996.

World Health Organization Heart Failure Guidelines. J Card Failure. 1996;2:153.

European Society of Heart Failure Guidelines. Eur Heart J. 1997;18:736. Revised in Eur J Heart Failure. 2002;4:11.

ACTION Heart Failure Treatment Guidelines. Am J Cardiol. 1999;83(2A):1.

Heart Failure Society of America Guidelines for the Management of Heart Failure. J Card Failure. 1999;5:358.

TABLE 16 Common Themes of Heart Failure Guidelines: Diagnosis of the Syndrome

Diagnostic Themes

Diagnose syndrome early

Measure left ventricular function (systolic vs. diastolic dysfunction)

Identify specific cardiac structural abnormalities

Determine cause of cardiac dysfunction

Determine whether ischemic heart disease, hypertension, valvular heart disease,arrhythmias, or a metabolic disturbance (e.g., diabetes mellitus or thyroid functiondisorders) are contributing to the problem

Diagnosis of Heart Failure

abnormalities, cardiac hemodynamics, and anatomic relationships. Radio-nuclide angiography can be used to measure ejection fraction but does not pro-vide additional information about structural heart disease. Magnetic resonanceimaging and computed tomography of the heart may be helpful in selectedpatients. A normal echocardiogram (no evidence of systolic dysfunction, dias-tolic dysfunction, or valvular dysfunction) in the setting of test abnormalitiesrules out significant heart failure with great certainty.

As Figure 10 suggests, if the echocardiogram is abnormal, various ancillarytests should be done to determine the etiology, severity, and precipitating fac-tors of the heart failure and the type of cardiac dysfunction. Laboratory testingmay reveal conditions that can lead to or exacerbate heart failure. The initialevaluation of patients with heart failure should include complete blood count,urinalysis, serum electrolytes, and lipid levels, as well as tests of renal and hepaticfunction, chest radiography, and 12-lead electrocardiography. Thyroid functiontests should be performed because hyperthyroidism and hypothyroidism can beprimary or contributory causes of heart failure. The serum ferritin level andtransferrin saturation may help to detect hemochromatosis. Assays for connec-tive tissue diseases and pheochromocytoma should be performed if these diag-noses are suspected. Coronary angiography should be considered in patients inwhom atherosclerotic cardiovascular disease is suspected as a cause of heart fail-

37

Suspected heart failurebecause of symptoms and signs

Assess presence of cardiac disease by ECG,radiograph, or natriuretic peptide levels

(where available)

Normal:heart failure

unlikely

Test abnormal

Test abnormal

Choose therapy

Image by echocardiography (nuclearangiography or MRI where available)

Assess etiology, degree, precipitatingfactors, and type of cardiac dysfunction

Normal:heart failure

unlikely

Additional diagnostic testswhen appropriate

(e.g., coronary angiography)

F I G U R E 1 0 .European Society of Cardiology guidelines for the diagnosis and treatment of chronic heart failure.

ECG = electrocardiography; MRI = magnetic resonance imaging

Peproduced with permission from: Remme WJ, Swedberg K; European Society of Cardiology. Comprehensive guidelines for the diagnosis and treatment of chronic heart failure. Task forcefor the diagnosis and treatment of chronic heart failure of the European Society of Cardiology. Eur J Heart Fail. 2002;4:11-22.

Staging Heart Failure

38

ure. Information from the history, physical examination, and diagnostic testswill guide best therapies.

Natriuretic peptide levels are now recognized as useful for distinguishingdyspnea due to a pulmonary or central process from heart failure. B-type natri-uretic peptide is a 32–amino acid peptide released predominantly from the ven-tricles in response to stretch and increased volume. The specific role for B-typenatriuretic peptide in screening for heart failure is still being defined. However,if the diagnosis of heart failure is uncertain on the basis of the history and phys-ical examination, use of the B-type natriuretic peptide assay can be considered.If the B-type natriuretic peptide level is less than 100 pg/mL, heart failure isless likely.

Staging Heart Failure• What are the clinical stages of heart failure?

Case 6A 54-year-old woman with a 10-year history of hypertensionpresents for routine follow-up. She has no symptoms andreports that her blood pressure is well controlled. The medicalhistory is notable for hypertension and mild osteoarthritis. Thefamily history is notable for breast cancer. She does not smokeor drink alcohol. She takes amlodipine, 10 mg/d; aspirin, 81 mg/d; and vitamin E.

On physical examination, the blood pressure is 130/85 mmHg, heart rate was 82/min, respiratory rate is 14/min, andbody mass index was 26 kg/m2. Electrocardiography shows leftventricular hypertrophy. Her physician did not alter her medi-cation regimen.

On a return visit, she had had symptoms of bronchitis for 3days. Chest radiography shows cardiomegaly. Echocardiographyshows a left ventricular ejection fraction of 40%, left ventricularend-diastolic dimension of 66 mm, mild mitral regurgitation,and mild tricuspid regurgitation. Amlodipine therapy is discon-tinued, and treatment is started with the angiotensin-convertingenzyme inhibitor ramipril, 5 mg/d, and the β-blocker metopro-lol CR/XL, 50 mg/d. The angiotensin-converting enzymeinhibitor and β-blocker therapy is titrated over time. Sheremains free of heart failure symptoms over the next 5 years.

K E Y P O I N T S

• In patients with symptoms or signs thatmay be related to heart failure, electro-cardiography, chest radiography,echocardiography, and serum and bloodlevels of B-type natriuretic peptide areimportant diagnostic and prognostictools. Measurement of left ventricularejection fraction is recommended in allpatients with heart failure.

TABLE 17 American Heart Association/American College of Cardiology Heart Failure Guidelines: Stages of Heart Failure

Stage Description Examples

A Patients at high risk of developing heart failure because Hypertension, diabetes mellitus, coronary heart conditions associated with heart failure are present, but with disease, cardiotoxin exposure, family history of DCM, no overt structural/functional abnormalities of the heart and no past rheumatic fever, hemochromatosisheart failure symptoms or signs

B Patients with overt heart disease that is strongly associated Ventricular hypertrophy, cardiac chamber dilation, with developing heart failure but who have never shown asymptomatic valve disease, prior MI or anginasigns or symptoms of heart failure

C Patients with prior or current symptoms of heart failure Dyspnea, fatigue, fluid retention or other signs and associated with structural heart disease symptoms due to cardiac dysfunction

D Patients with advanced structural heart disease and marked Frequent CHF hospitalizations, hospital bound on symptoms of heart failure at rest despite maximal treatment inotropes, heart transplant candidate, hospice patientand require specialized interventions

CHF=congestive heart failure; DCM=dilated cardiomyopathy; MI=myocardial infarction

Medical Treatment of Heart Failure Due to Systolic Dysfunction

Table 17 presents the new and broader classification scheme for staging heartfailure from the American College of Cardiology (ACC) and the AmericanHeart Association (AHA). Four clinical stages of heart failure (stage A throughD) were defined to reflect the fact that patients can present at different pointsin the course of their illness. This scheme is not intended to replace the NewYork Heart Association functional classification, which grossly quantitates theseverity of symptoms (class I to IV) in patients with stage C or D disease.

Stage A includes persons at high risk for heart failure because of associatedconditions (hypertension, ischemic heart disease, diabetes, or family history ofcardiomyopathy), who have no overt structural or functional heart abnormali-ties and no symptoms of heart failure. Stage B includes patients who have overtstructural heart disease but do not have signs or symptoms of heart failure.Stage C includes patients with prior or current symptoms of heart failure withstructural heart disease, and stage D includes patients with advanced structuralheart disease and marked symptoms of heart failure despite maximal and aggres-sive therapies.

The patient described in Case 6 progressed from stage A or B to stage Cheart failure. There is no way of knowing whether she already had structuralheart disease at the time of her first visit when she was asymptomatic. Even withadequate blood pressure control, patients with hypertension are at higher riskfor heart failure. Angiotensin-converting enzyme inhibitors and β-blockerswould have decreased the likelihood of progression to symptomatic heart fail-ure and death. No consensus has been reached on the best screening methodfor identifying asymptomatic persons who would be characterized as havingstage B disease.


• Can heart failure be prevented?• What are the core therapies and adjunctive treatments of heart failure?

Figure 11 summarizes the ACC/AHA Guidelines for the Evaluation andManagement of Chronic Heart Failure in the Adult and links therapeutic inter-vention to the four stages of heart failure (Hunt et al.).

Core treatments for heart failure include diuretics to achieve euvolemia,angiotensin-converting enzyme inhibitors in all tolerant patients with left-ven-tricular systolic dysfunction, and selected β-blockers in patients with stable com-pensated heart failure (who also have depressed left ventricular ejection frac-tion). Adjunctive medical therapies include electrolyte supplements, digitalis,and aldosterone blockade with spironolactone in certain circumstances (Hoodet al.; Rathore et al.). Preventive measures, including control of systolic anddiastolic hypertension and treatment of lipid disorders, are key for patients withstage A disease. Education about avoidance of high-risk behaviors (cigarettesmoking, excessive alcohol consumption, illicit drug use, and cardiovasculardeconditioning) is essential. New evidence from clinical trials suggests that allpatients with a history of arteriosclerotic disease, diabetes mellitus, or hyper-tension (Arnold et al.) and associated risk factors who can tolerate anangiotensin-converting enzyme inhibitor should receive these agents. Otherimportant considerations are control of heart rate in patients with supraventric-ular tachyarrhythmias, treatment of manifest thyroid disorders, and periodicevaluation for signs and symptoms of congestive heart failure (progression tostage C).

39

K E Y P O I N T S

• Patients who have diseases associatedwith heart failure but no symptoms oridentifiable structural abnormalities(stage A) and those who have structuralor functional abnormalities but nosymptoms or obvious clinical findings(stage B) must be identified.Appropriate intervention can often prevent progression to symptomatic(stage C) or advanced or refractory(stage D) disease.

Hunt SA, Baker DW, Chin MH,Cinquegrani MP, Feldman AM, FrancisGS, et al. ACC/AHA guidelines for theevaluation and management of chronic heart failure in the adult: executive summary.A report of the American College ofCardiology/American Heart AssociationTask Force on Practice Guidelines(Committee to Revise the 1995 Guidelinesfor the Evaluation and Management ofHeart Failure). Circulation 2001;104:2996-3007. PMID: 11739319Hood WB, Dans A, Guyatt GH, Jaeschke R,McMurray JV. Digitalis for treatment ofcongestive heart failure in patients in sinusrhythm. Cochrane Database Syst Rev 2001.Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxinfor the treatment of heart failure. N Engl J Med 2002;347:1403-11. PMID: 12409542Arnold JM, Yusuf S, Young J, Mathew J,Johnstone D, Avezum A, et al. Preventionof heart failure in patients in the HeartOutcomes Prevention Evaluation (HOPE) Study. Circulation. 2003 Mar11;107(9):1284-90. PMID: 12628949


40

Screening patients at high risk for heart failure (stage A) for the develop-ment of asymptomatic left ventricular dysfunction (stage B) is desirable, butroutine echocardiography would be cost prohibitive. Recently, the B-type natri-uretic peptide blood test has been demonstrated to identify patients with Stage Bdisease and may be cost-effective, but further study is needed.

Recommendations for patients with asymptomatic left ventricular systolicdysfunction (stage B disease) include use of angiotensin-converting enzymeinhibitors and β-blockers. All patients with prior myocardial infarction shouldreceive these agents even if the ejection fraction is normal. Furthermore,angiotensin-converting enzyme inhibitors and β-blockers should be used inpatients with reduced left ventricular ejection fraction regardless of whetherthey have experienced prior myocardial infarction. In patients with reducedejection fraction, three β-blockers have been well studied in clinical trials anddemonstrate incontrovertible evidence of efficacy: bisoprolol, carvedilol, andmetoprolol CR/XL. Currently, only metoprolol CR/XL and carvedilol areapproved by the U.S. Food and Drug Administration for use in heart failure.One of the agents recommended in the heart failure guidelines should be pre-scribed, as it is not clear that other β-blockers provide similar benefits in patientswith reduced ejection fraction and target doses have not been defined. Regularevaluation for the development of signs and symptoms of heart failure is important,

F I G U R E 1 1 .American College of Cardiology/American Heart Association guidelines for the diagnosis and treatment of heart failure.

ACE = angiotensin-converting enzyme; HF = heart failure; IV = intravenous; LV = left ventricular; MI = myocardial infarction

Reproduced with permission from: Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldmanmd AM, Francis GS, et al. ACC/AHA Guidelines for the Evaluation and Management of ChronicHeart Failure in the Adult: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration With the International Society for Heart and Lung Transplantation; Endorsed by the HeartFailure Society of America. Circulation. 2001;104:2996-3007.

e.g., Patients with:• Hypertension• Diabetes mellitus• Using cardiotoxins• With family history of cardiomyopathy

• Treat hypertension• Encourage smoking cessation• Treat lipid disorders• Encourage regular exercise• Discourage alcohol intake, illicit drug use• ACE inhibition in appropriate patients

Stage AAt high risk forHF but without

structural heart diseaseor symptoms of HF

e.g., Patients with:• Previous MI• LV systolic dysfunction• Asymptomatic valvular disease

StructuralHeartDisease

Symptomsof HFdevelop

Refractorysymptomsof HF atrest

• All measures under stage A• ACE inhibitors in appropriate patients• β-blockers in appropriate patients

Stage BStructural heart

disease but withoutsymptoms of HF

e.g., Patients with:• Known structural heart disease• Shortness of breath and fatigue, reduced exercise tolerance

• All measures under stage A• Drugs for routine use: - Diuretics - ACE inhibitors - β-blockers - Digitalis• Dietary salt restriction

Stage CStructural heart

disease with prior orcurrent symptoms of HF

e.g., Patients who have symptoms at rest despite maximal medical therapy(e.g., those who arerecurrently hospitalizedor cannot be safelydischarged from hospital without specialized interventions)

• All measures under stages A, B, and C• Mechanical assist devices• Heart transplantation• Continuous (not intermittent) IV inotropic infusions for palliation• Hospice care

Stage DRefractory HF

requiring specializedinterventions

Therapy Therapy Therapy Therapy


as is implementing all measures discussed for patients with stage A disease. Digoxinis not recommended in patients with stage B disease who are in sinus rhythm.

Case 7A 65-year-old man with a history of myocardial infarction andleft ventricular ejection fraction of 20% presents with 2 weeks of worsening shortness of breath at rest and lower-extremityedema despite an increase in his furosemide dose. He has nochest pain but notes orthopnea requiring three pillows andweight gain of 2.3 kg (5 lb). The medical history is notable forcoronary artery bypass grafting surgery 10 years ago andmyocardial infarction 5 years ago and 2 years ago. He has hadsymptoms of heart failure for the past 2 years and has been hos-pitalized for heart failure twice in the past 6 months. At base-line, he can walk only across the room before becoming short ofbreath. His medical regimen was furosemide 120 mg twicedaily; digoxin, 0.125 mg/d; benazepril, 5 mg/d.

On physical examination, blood pressure is 95/43 mm Hg,heart rate is 90/min, and respiratory rate is 24/min. Thejugulovenous pressure is estimated to be 16 cm, and the lungsare clear. Cardiac examination reveals a regular rate and rhythm,normal S1, physiologically split S2, grade III/IV holosystolicmurmur, and an S3. Abdominal examination showedhepatomegaly, and the extremities showed 3+ pitting edema.

The patient is admitted. Chest radiography shows cardio-megaly and pulmonary vascular redistribution. The creatinineconcentration is 1.6 mg/dL and the sodium concentration is 132 meq/L. Treatment with intravenous furosemide and nesiritide is started. Over the next few hours, shortness of breathresolves. More than 2 L is diuresed in the first 24 hours of hospi-talization. The dose of angiotensin-converting enzyme inhibitor isincreased to 10 mg/d. After 48 hours, nesiritide therapy is dis-continued. Treatment with oral furosemide and spironolactone,12.5 mg/d, is begun. A 2-g sodium diet and monitoring of bodyweight daily is prescribed. Treatment with aspirin, 81 mg/d, andsimvastatin, 40 mg/d, is started. Since the patient is no longervolume overloaded, β-blocker therapy with carvedilol, 3.125mg/twice daily, is begun. An implantable cardioverter-defibrilla-tor is inserted, and he is discharged to home 1 day later.

Over a few weeks, the patient’s condition improves, and heis able to walk two blocks. The medication regimen is adjustedto benazepril, 40 mg/d; aspirin, 81 mg/d; carvedilol, 25 mgtwice daily; simvastatin, 40 mg/d; furosemide, 80 mg/d; andspironolactone, 25 mg/d. He continues to do well. On cardio-pulmonary exercise testing, his peak oxygen consumption is18.4 mg/kg/min. During an argument with his wife, he passesout and his implantable cardioverter-defibrillator fires. Ondevice interrogation, he is found to have had a successfully cardioverted episode of ventricular tachycardia. Over the nextyear, the patient’s condition improves enough that he returns to work as a college professor.

In patients with left ventricular dysfunction and current or prior symptoms ofheart failure (stage C disease), measures discussed for patients with stage A or B

41


42

disease should be implemented. Immunization against influenza and pneumo-coccal pneumonia are important, and patients should be encouraged to perform moderate aerobic physical activity except during periods of acutedecompensation. Table 18 lists the core drugs used to treat chronic heartfailure, initial dosing recommendations, and maximum or target doses.Generally, patients with symptomatic left ventricular systolic dysfunction willbe managed with a diuretic, an angiotensin-converting enzyme inhibitor, a β-blocker, and digoxin. Generally, patients with evidence of fluid retention on physical examination are given diuretics until a euvolemic state is reached.Diuretic therapy should probably be continued in most of these patients toprevent recurrence of sodium and water retention. Of note, diuretics do notbeneficially affect mortality, and they may create a metabolic milieu that leadsto increased rates of adverse events. With salt and fluid restriction, patientscan often discontinue diuretic therapy. Even if patients respond favorably to diuresis, treatment with angiotensin-converting enzyme inhibitors and β-blockers should be initiated and maintained, perhaps indefinitely, in all patients who tolerate them.

The patient in Case 7 was stabilized with medications. During his hospi-talization, he was initially treated with nesiritide, an intravenous preparation ofB-type natriuetic peptide, that was recently approved for treatment of acutelydecompensated heart failure. In a decompensated patient who has already beentaking high-dose diuretics, such as this patient, an intravenous infusion of nesir-itide is often helpful. This agent has been shown to lower pulmonary capillary

TABLE 18 Drugs Used to Treat Chronic Heart Failure

Agent Initial Dose Maximum/Target Dose

Loop diuretics*

Bumetanide 0.5-1.0 mg qd or bid 10 mg†

Furosemide 20-40 mg qd or bid 400 mg†

Torsemide 10-20 mg qd or bid 200 mg†

Angiotensin-convertingenzyme inhibitors

Captopril 6.25 mg tid 50 mg tid‡

Enalapril 2.5 mg bid 10 mg bid‡

Fosinopril 5 mg qd 40 mg qd‡

Lisinopril 2.5 mg qd 20 mg qd‡

Quinapril 10 mg bid 40 mg bid‡

Ramipril 1.25 mg qd 10 mg qd‡

β-Blockers

Bisoprolol 1.25 mg qd 10 mg qd‡

Carvedilol 3.125 mg bid 25 mg bid‡

Metoprolol tartrate 6.25 mg bid 75 mg bid‡

(CR/XL-extended release)

Digitalis

Digoxin 0.125 mg qd 0.25 mg qd

bid = twice daily; qd = once daily; tid = three times daily

*Diuretics should be titrated up or down with respect to dose to achieve dry weight. Thiazide agents may be appropriatein mild heart failure, for associated hypertension, or as a second diuretic with loop agents in severe congestive states(loop diuretic–resistant patients).

†Maximum dose

‡Target dose

From: American College of Cardiology/American Heart Association Guidelines for the Evaluation and Management ofHeart Failure. Circulation. 2001;104:1996.


wedge pressure. The most common side effect is hypotension which usuallyresolves with discontinuation of the drug and restarting it at a lower dose. Inan open-label trial comparing nesiritide to dobutamine, there were fewer seri-ous arrhythmias and a trend toward lower readmission rates and mortality(Burger et al.; Silver et al.).

Once the patient was stable and euvolemic, β-blocker therapy was indi-cated. With appropriate adjustment of his heart failure regimen, the patient was able to take target doses in the evidence-based regimen of angiotensin-converting enzyme inhibitors and β-blockers. Because he had coronary arterydisease it was important to use therapies that decrease the risk for atheroscleroticevents (including aspirin and lipid-lowering medication adjusted to achieve alow-density lipoprotein cholesterol level <100 mg/dL, a high-density lipopro-tein cholesterol level >40 mg/dL, and a triglyceride level <150 mg/dL).Several additional pharmacologic strategies have been shown in controlled clin-ical trials to be useful in selected patients with heart failure. In the RandomizedAldactone Evaluation Study (RALES), spironolactone was shown to decreasemorbidity and mortality in patients older than 65 years of age with New YorkHeart Association class III or IV (ACC/AHA stage C or D) chronic conges-tive heart failure (Pitt et al.). Low doses of spironolactone are recommended(12.5 mg/d to 25 mg/d) and serum potassium should be monitored closely.The drug should be used with caution in patients with a serum creatinine con-centration greater than 2.5 mg/dL.

In patients with intolerance to angiotensin-converting enzyme inhibitors,angiotensin-receptor blockers should be administered. One large clinical trialand several smaller ones have suggested that angiotensin receptor blockers areat least equivalent to angiotensin-converting enzyme inhibitors in patients withheart failure who cannot tolerate the latter agents (Lindholm et al.). Use of anangiotensin receptor blocker when a patient is already receiving an angiotensin-converting enzyme inhibitor and a β-blocker may be associated with adverseoutcome, but is being studied in several ongoing clinical trials. Another optionin patients who cannot tolerate angiotensin-converting enzyme inhibitors is thecombination of hydralazine and isosorbide dinitrate. When prescribing diuret-ics, the clinician should choose a dose that will relieve congestion, whereas withangiotensin-converting enzyme inhibitors and β-blockers, the target dosedefined by clinical trials should be attempted. Withdrawal of treatment withdrugs known to adversely affect the clinical outcome of patients (such as nons-teroidal anti-inflammatory drugs, most antiarrhythmic agents, most calciumchannel blocking agents, and the glitazone insulin-sensitizing agents) is oftensufficient to restabilize a significantly congested patient.

Therapeutic interventions for which there is little evidence of efficacy andpossible evidence of harm include long-term intermittent infusion of a posi-tive inotropic drug, use of an angiotensin receptor blocker instead of anangiotensin-converting enzyme inhibitor in patients with heart failure who cantolerate an angiotensin-converting enzyme inhibitor, addition of an angiotensinreceptor blocker before a β-blocker in patients with heart failure who are tak-ing an angiotensin-converting enzyme inhibitor, and use of a calcium channelblocking drug as a primary treatment for heart failure. Nutritional supplements(such as multivitamins, coenzyme Q10, carnitine, taurine, selenium) and hor-monal therapies (growth hormone or thyroid hormone in the absence of defi-ciency states) have no proven efficacy.

Patients with stage D disease involving refractory end-stage heart failureare more challenging to treat. These patients generally have profound fatigue,weakness, and dyspnea with associated fluid retention, which preclude even theminimal exertion required for activities of daily living. Patients with advanced

43

Burger AJ, Elkayam U, Neibaur MT,Haught H, Ghali J, Horton DP, et al.Comparison of the occurrence of ventriculararrhythmias in patients with acutely decom-pensated congestive heart failure receivingdobutamine versus nesiritide therapy. Am JCardiol. 2001;88:35-9. PMID: 11423055Silver MA, Horton DP, Ghali JK,Elkayam U. Effect of nesiritide versus dobut-amine on short-term outcomes in the treat-ment of patients with acutely decompensatedheart failure. J Am Coll Cardiol. 2002;39:798-803. PMID: 11869844Pitt B, Zannad F, Remme WJ, Cody R,Castaigne A, Perez A, Palensky J, Wittes J.The effect of spironolactone on morbidityand mortality in patients with severe heartfailure. Randomized Aldactone EvaluationStudy Investigators. N Engl J Med.1999;341:709-17. PMID: 10471456Lindholm LH, Ibsen H, Dahlof B,Devereux RB, Beevers G, de Faire U, et al.Cardiovascular morbidity and mortality inpatients with diabetes in the LosartanIntervention For Endpoint reduction inhypertension study (LIFE): a randomisedtrial against atenolol. Lancet. 2002;359:1004-10. PMID: 11937179

Medical Treatment of Heart Failure with Preserved Systolic Dysfunction

44

heart failure often deteriorate because of salt and water retention resulting fromdietary or medication noncompliance. These patients should be treated withaggressive salt and fluid restriction and all of the measures listed for patients instages A, B, and C heart failure. β-Blockers may worsen the congestive state inpatients with stage D disease. Nonetheless, recent evidence supports use ofthese agents to reduce morbidity and mortality when advanced heart failure ispresent, but the patients who are most likely to benefit from upward titrationare generally not significantly congested. Another potentially beneficial thera-peutic strategy is inpatient titration of medication directed by invasive hemo-dynamic monitoring. Although routine intermittent infusion of positive inotro-pic agents is not recommended, continuous infusion of these agents may berequired for palliation of symptoms in patients with severe end-stage disease.Nesiritide (B-type natriuretic peptide) in the outpatient setting is being evalu-ated in clinical trials.

Eventually, patients may require referral for cardiac transplantation evalua-tion or for other procedures. Table 19 summarizes when to consider referral toa heart failure specialist or heart transplantation center.

Medical Treatment of Heart Failure with Preserved Systolic DysfunctionTreatment of patients with symptoms of congestive heart failure but ejectionfractions that are considered normal or near-normal are often said to have heartfailure due to diastolic dysfunction. The best management strategies for thesepatients have not yet been defined. Most experts, however, stress the impor-tance of controlling systolic and diastolic hypertension in accordance with pub-lished guidelines. In patients with atrial fibrillation, control of the ventricularrate should be a goal. Diuretics should be used to control pulmonary conges-tion and peripheral edema. Patients with heart failure due to diastolic dysfunc-tion and ischemic heart disease also benefit greatly from coronary revascular-ization. Some emphasize restoration of normal sinus rhythm in patients withatrial fibrillation, even though this was not associated with improved outcomesin patients in the Atrial Fibrillation Follow-up Investigation of RhythmManagement (AFFIRM) trial. Although use of digitalis was generally discour-aged in patients with diastolic dysfunction, a subset of patients in the DigitalisInvestigation Group trial with normal systolic function were treated and heartfailure hospitalizations were reduced (Digitalis Investigation Group). Thus,digoxin therapy should be considered when moderate symptoms of congestiveheart failure are present.

K E Y P O I N T S

• Tailored therapeutic protocols importantfor heart failure include multiple differ-ent drug classes, and are based on theprogression from insidious (stage A orB) to symptomatic (stage C) or advancedor refractory disease (stage D).

• Therapy for heart failure aims to pre-vent as well as treat cardiac dysfunctionand its manifestations.

• Detecting and eliminating treatable dis-eases, such as ischemic heart disease,hypertension, and valvular heart dis-ease, are critical to improving symptomsand attenuating morbidity and mortality.

• Diuretics should be used to create aeuvolemic state and relieve symptomsassociated with congestion, but they do not favorably effect mortality.

• When left-ventricular systolic dysfunc-tion is present, angiotensin-convertingenzyme (ACE) inhibitors in all tolerantpatients and certain β-blockers in stablepatients with mild to moderate tosevere symptoms reduce mortality and morbidity.

• Ancillary medications include digitalispreparations in patients with sympto-matic congestive heart failure andspironolactone in selected patients. Thedigoxin level should be measured andthe dose adjusted to maintain a levelless than 0.7 ng/mL.

• Angiotensin-receptor blocking drugs areeffective when an ACE inhibitor cannotbe tolerated, but these drugs should notbe substituted in patients who tolerateACE inhibitors. They should not beadded to therapy with ACE inhibitors,particularly in conjunction with a β-blocker.

• Therapy for heart failure with poten-tially detrimental drugs or those ofquestionable benefit should be stopped.

The effect of digoxin on mortality and mor-bidity in patients with heart failure. DigitalisInvestigation Group. N Engl J Med1997;336:525-33. PMID: 9036306

TABLE 19 When to Refer Patients to Heart Failure Specialists or for HeartTransplant Consideration

Consider Patient Referral

Frequent hospital or emergency department admissions for heart failuredecompensation

Difficulty in determining patient’s volume or systemic organ perfusion status

Complex heart failure with renal insufficiency, hepatic congestion, severe pulmonaryhypertension, systemic hypoperfusion, or congenital abnormalities

Problems emerge with up-titration of complex polypharmacy therapeutic protocols

Biventricular pacing or defibrillator insertion being considered

Patient is severely ill from heart failure but is of reasonable age with adequatepreservation of systemic organ function such that heart transplantation might befeasible and acceptable

Other Therapeutic Considerations

Randomized clinical trials of angiotensin-converting enzyme inhibitors, β-blockers, and calcium channel blockers have not been performed in patientswith heart failure and preserved systolic function. Recommendations are basedon observational studies and expert opinion and should thus be considered abit tenuous (Table 20). Because patients with diastolic dysfunction frequentlyhave hypertension, coronary artery disease, or diabetes, use of angiotensin-converting enzyme inhibitors is recommended. Data from observational studiesshow that use of angiotensin-converting enzyme inhibitors is associated withreduced mortality. Use of β-blockers has also been associated with improvedoutcomes. Calcium channel blockers have not been studied in this setting anddo not improve outcome in systolic dysfunction heart failure; thus, their useshould be reserved for patients with hypertension that is not controlled withangiotensin-converting enzyme inhibitors and β-blockers. Angiotensin receptorantagonists are being studied in this patient population.

Other Therapeutic ConsiderationsPatients with chronic heart failure are at increased risk of thromboembolicevents due to stasis of blood in dilated hypokinetic cardiac chambers andperipheral blood vessels as well as increased activity of procoagulant factors. Therisk of thromboembolization in clinically stable patients has been low (1% to 3%per year), even in patients with very depressed ejection fraction and echocardio-graphic evidence of intracardiac thrombi. In the absence of definitive trials, it is not clear that anticoagulants should be prescribed to patients with heart failure who are in sinus rhythm unless they have experienced embolic events. Inthe absence of contraindications, anticoagulation is recommended in patientswith heart failure and paroxysmal or sustained atrial fibrillation. Although atrialfibrillation increases the risk of embolic events, the outcome associated withrestoring and maintaining sinus rhythm was uncertain until recently. It was longrecognized that class I antiarrhythmic agents can have cardiodepressant andproarrhythmic effects in patients with heart failure, increasing the risk of sudden death. The Atrial Fibrillation Follow-up Investigation of RhythmManagement (AFFIRM) trial showed that the strategy of rate control and anti-coagulation was similar to rhythm control in patients with atrial fibrillation(although this trial included relatively few patients with moderate or severeheart failure) (Wyse et al.).

When an antiarrhythmic agent is indicated, amiodarone is usually well tol-erated and has a low incidence of proarrhythmic events despite prolongation ofthe QT interval. Patients with heart failure who are treated with this agentshould be monitored for excessive bradycardia, especially in association with use of a β-blocker, and for thyroid and hepatic toxicity (which are well-knownside effects).

45

K E Y P O I N T S

• In symptomatic congestive heart failurewith preserved or relatively preservedsystolic left ventricular function (so-called diastolic heart failure), treatmentguidelines are less well established.There is general agreement on aggres-sive blood pressure control, diuretics tocreate a euvolemic state, and use of ACE inhibitors and β-blockers.

Wyse DG, Waldo AL, DiMarco JP,Domanski MJ, Rosenberg Y, Schron EB,et al. A comparison of rate control andrhythm control in patients with atrial fibrilla-tion. N Engl J Med. 2002;347:1825-33.PMID: 12466506

TABLE 20 Treating Heart Failure Due to Diastolic Dysfunction

Considerations

Control systolic and diastolic hypertension and consider use of β-blockers andangiotensin-converting enzyme inhibitors

Prescribe diuretics and digoxin to minimize symptoms

Consider coronary revascularization in patients with symptomatic or demonstrableischemia that is thought to have an adverse effect on diastolic function

Control ventricular rate in patients with atrial fibrillation and consider restoration ofsinus rhythm

Nonpharmacologic Therapies for Heart Failure

46

Nonpharmacologic Therapies for Heart FailureStandard approaches to heart failure should also include recommendations forroutine nonpharmacologic interventions. Appropriate dietary recommenda-tions include salt and fluid restriction in patients with volume overload and adiet low in animal fat in patients with arteriosclerosis. Elimination of alcoholseems appropriate in patients with cardiomyopathy but normal coronary arter-ies. Aerobic exercise is increasing in importance as part of treatment of patientswith heart failure, but its effect on mortality remains undetermined.

Surgical or procedural therapies to consider include coronary revascular-ization (coronary artery bypass graft surgery or percutaneous interventions),repair or replacement of faulty heart valves, ventricular remodeling aftermyocardial infarction, biventricular pacing, and implantation of cardioverter-defibrillators. Ventricular assist devices and heart transplantation can be consid-ered in highly selected patients (Goldstein et al.; Hosenpud et al.).

Novel surgical approaches to patients with heart failure are becomingincreasingly important. Revascularization strategies in patients with sympto-matic or demonstrable ischemia should be considered in the presence of docu-mented viable myocardium, although the effect on survival is not yet fullydefined. The choice between percutaneous coronary intervention (angioplastywith or without stenting) and coronary bypass surgery is largely based on tech-nical and anatomic considerations. An emerging surgical approach combinescoronary artery bypass surgery with infarct exclusion. Removing the scarred tis-sue from a failing left ventricle and favorably reshaping the heart, addressesischemia and may improve the mechanical abnormalities associated with detri-mental heart remodeling. Patients with significant mitral or tricuspid regurgita-tion may benefit from valve repair or replacement that eliminates the associatedvolume overload. Consensus on these approaches is beginning to emerge.Randomized controlled trials of these surgical interventions are probably notfeasible, but accumulated experience provide more definitive information onwhich patients are likely to benefit from them.

Approximately 20% of patients with heart failure have a wide QRS complex(>120 ms) due to an interventricular conduction delay, most commonly a leftbundle-branch block. This condition leads to a dyssynchronous contractionpattern within the left ventricle and has been associated with worse prognosisin patients with heart failure. Simultaneous activation of the right and left ven-tricles with biventricular pacing in patients with marked QRS prolongation hasbeen shown to improve quality of life, symptoms of heart failure, and exercisevariables and is associated with remodeling of the heart (decreased cardiac vol-ume and increased ejection fraction). Biventricular pacing systems have beenapproved for use in patients who have refractory symptoms of heart failuredespite optimized medical therapy (ACC/AHA stage C or D disease and NewYork Heart Association functional class III or IV), with an ejection fraction lessthan 35% and a QRS duration greater than 120 ms. Implantation of thesedevices requires an experienced electrophysiologist, as the success of the proce-dure is sometimes compromised by constraints posed by the coronary sinus andleft lateral coronary venous anatomy. The effect of cardiac resynchronizationwith biventricular pacing on mortality is being evaluated (Abraham).

Malignant ventricular arrhythmias are common in the setting of heart fail-ure. Prevention of sudden cardiac death in patients with heart failure is impor-tant. Most antiarrhythmic drugs are contraindicated in heart failure, and use ofamiodarone alone for prevention of sudden death is controversial; therefore, animplantable cardioverter-defibrillator, alone or in combination with amiodaronetherapy, is recommended for patients with heart failure who have a history of

Goldstein DJ, Oz MC, Rose EA.Implantable left ventricular assist devices. N Engl J Med 1998;339:1522-33.PMID: 9819452Hosenpud JD, Bennett LE, Keck BM,Boucek MM, Novick RJ. The Registry of the International Society for Heart andLung Transplantation: seventeenth officialreport—2000. J Heart Lung Transplant2000;19:909-31. PMID: 11044685

Abraham WT. Rationale and design of arandomized clinical trial to assess the safetyand efficacy of cardiac resynchronizationtherapy in patients with advanced heart fail-ure: the Multicenter InSync RandomizedClinical Evaluation (MIRACLE). J Card Fail.2000;6:369-80. PMID: 11145762

Prognosis

ventricular fibrillation or hemodynamically destabilizing ventricular tachy-cardia. Data from the Multicenter Automatic Defibrillator Implantation Trial II(MADIT-II) suggest that mortality rate can be significantly reduced in patientswho have had myocardial infarction and have an ejection fraction less than orequal to 30% despite presence or absence of arrhythmias (Moss et al.). TheACC/AHA guidelines recommend prophylactic placement of an implantablecardioverter-defibrillator in patients with ischemic cardiomyopathy and left ven-tricular ejection fraction less than or equal to 30%, as long as they do not havestage D heart failure or medical illness that would otherwise greatly limit survival.

PrognosisMuch information has been accrued to predict adverse outcomes in patientswith heart failure. The presence and persistence of jugular venous distensionand S3 gallop carry a poor prognosis. Adverse electrocardiographic findingsinclude wide QRS complexes; low limb-lead voltage; extensive Q-wave forma-tion; and arrhythmias, including atrial fibrillation and ventricular tachycardia.Radiographic evidence of severe cardiomegaly and persistent pulmonary venouscongestion despite medical therapy are ominous signs. Laboratory findingsassociated with poor prognosis include hyponatremia, azotemia, and hepaticfunction abnormalities and prolonged prothrombin time in the absence of anti-coagulation.

Levels of B-type natriuretic peptide have prognostic value in patients withheart failure. The following ranges for B-type natriuretic peptide levels havebeen generally associated with the following heart failure syndromes: less than100 pg/mL, no significant heart failure; 100 to 250 pg/mL, significant leftventricular dysfunction but compensated congestion; 250 to 500 pg/mL, con-gestive heart failure with both diastolic and systolic dysfunction; 500 to 1000pg/mL, decompensated congestive state; greater than 1000 pg/mL, high-riskpatients with substantial congestive heart failure. Pilot trials suggest that adjust-ment of medical therapy for heart failure on the basis of B-type natriuretic peptide levels plus clinical assessment produced superior outcomes compared to therapy guided by clinical assessment alone (Maisel).

Echocardiographic variables that suggest an adverse outcome include lowejection fraction (particularly <20%). Large ventricular volumes and significantdiastolic dysfunction are also associated with adverse outcome.

Cardiopulmonary exercise testing, which provides an objective measure-ment of peak oxygen consumption during exercise, is the most useful tool fordefining heart failure disability and determining prognosis and is recommendedin patients being considered for heart transplantation. In the ACC/AHAguidelines, this test receives a class IIa recommendation to determine whetherheart failure is the cause of a patient’s exercise limitation. Patients who do notreach anaerobic threshold (a respiratory exchange ratio <1.0) are probably lim-ited by factors in addition to cardiac abnormalities; these factors may includepulmonary disease, anemia, obesity, and cardiovascular deconditioning. PeakVO2 is determined by using formulas based on age and sex. Some heart failurespecialists believe that a peak VO2 in the setting of a respiratory exchange ratiogreater than 1.10 and less than 14 mL O2/kg/min is associated with such apoor prognosis the findng characterizes patients best referred for cardiac trans-plantation.

47

K E Y P O I N T S

• Surgical therapies in carefully selectedpatients can dramatically relieve symp-toms. Patients with coronary or valvularheart disease amenable to operativeintervention should be referred forappropriate surgeries.

• Ancillary electrophysiologic and surgicaltreatment strategies for heart failureare available.

Moss AJ, Daubert J, Zareba W. MADIT-II:clinical implications. Card ElectrophysiolRev. 2002;6:463-5. PMID: 12438829

Maisel A. B-type natriuretic peptide in thediagnosis and management of congestiveheart failure. Cardiol Clin. 2001;19:557-71.PMID: 11715177

When To Consider Cardiac Transplantation and Use of Ventricular Assist Devices

48

When To Consider Cardiac Transplantation and Use of Ventricular Assist DevicesCardiac transplantation can be lifesaving in selected patients with end-stageheart failure. Donor organ availability limits to the number of transplants toapproximately 2500 yearly in the U.S. Therefore, alternative strategies andproper patient selection are important. Even in patients with severe systolic leftventricular dysfunction, the 3- to 5-year survival rate with optimal medical ther-apy is about 80%. With contemporary immunosuppressive therapies, the half-life of a transplanted heart is about 10 years. Thus, even after a patient isaccepted and listed for transplantation, every attempt should be made to opti-mize therapy. Age is only a relative contraindication, and patients in their 60sand early 70s have substantially benefited from heart transplantation. Diabeteswas once thought to be a contraindication to heart transplantation but is nolonger considered absolutely exclusionary, as long as renal function is preservedand the patient does not have substantial retinopathy, neuropathy, or peripheralvascular disease. Determination of candidacy for cardiac transplantation is bestmade by an experienced heart transplantation center.

Left ventricular assist devices have improved dramatically over the past twodecades. They are primarily used to bridge patients with cardiogenic shock totransplantation while awaiting a suitable donor organ. The greatest challenge inselecting patients for ventricular assist device stems from the need to ensurereversibility of renal failure, hepatic insufficiency, and severe pulmonary hyper-tension after device insertion. Several intracorporeal pulsatile and extracorporealpulsatile devices are available. The device is selected on the basis of the size ofthe patient and acuity of the situation. General contraindications to ventricularassist device insertion include septicemia and profound coagulopathy. Oncerenal or hepatic failure and pulmonary hypertension are irreversible, deviceplacement may be futile.

A recent clinical trial in patients with end-stage heart failure who were noteligible for transplantation demonstrated that an implantable pulsatile left ven-tricular assist device system increased days alive out of the hospital comparedwith maximal medical therapy with chronic continuous infusion of an inotrope.The morbidity rate associated with the device was high, primarily related toinfection and neurologic events. Mechanical reliability of the device was alsoproblematic. With technological improvements, left ventricular assist devicesmay become a reasonable alternative to transplantation in carefully selected patients.

In patients with very advanced heart failure who are not candidates fortransplantation, end-of-life care issues must be considered. It is important toeducate the patient and family or other caregivers about reasonable expectationsregarding morbidity and mortality in advanced heart failure. Hospice serviceshave proven helpful in patients dying of heart failure. Compassionate care ofpatients with advanced heart failure may require frequent administration of par-enteral agents, such as diuretics, and positive inotropic drugs as well as judicioususe of anxiolytics, soporifics, and potent analgesics.

Arrhythmias

Significant advances have occurred in the recognition and management ofsupraventricular arrhythmias and acute management of atrial fibrillation andstroke prevention. Indications for pacemaker implantation for bradyarrhythmiasand new guidelines for acute treatment of cardiac arrest have also been devel-oped and published.

Supraventricular Arrhythmias

Supraventricular Arrhythmias• How do supraventricular arrhythmias manifest?• What are the common supraventricular arrhythmias?• What is the mechanism of atrioventricular nodal reentrant tachycardia and atrio-

ventricular reentrant tachycardia?• Which drugs are useful in the management of supraventricular arrhythmias?• Which patients should be offered catheter ablation?

By definition, supraventricular arrhythmias are any abnormal rhythm arisingfrom above the ventricle. They can occur as sustained, intermittent, or paroxys-mal arrhythmias.

Premature Atrial ContractionsPremature atrial contractions are a common form of benign supraventriculararrhythmia and usually does not require treatment. They are estimated to occurin 78% of healthy male aviators (Folarin et al.). Typically, they occur sporadi-cally and may be present for hours at a time. Often, people will experience asymptomatic period, are symptom-free for months or years, and then experi-ence a recurrence. Evaluation of the patient with frequent premature atrial con-tractions should focus on excluding an underlying pathologic cause for theectopy. Causes may include any lesion that results in atrial enlargement or pres-sure elevation, such as hypertension or valvular heart disease. Endogenous (forexample, stress) or exogenous (for example, caffeine) stimulants may lead tofrequent premature atrial contractions. In some patients, premature atrial con-tractions may trigger atrial fibrillation.

Treatment may include management of underlying pathology. If patientsremain symptomatic despite reassurance and desire therapy, β-blockers and cal-cium channel blockers can be used. It is rarely necessary to use antiarrhythmicsto treat premature atrial contractions. Patients who have noted an associationbetween palpitations and exogenous stimulants, such as caffeine, should beadvised to avoid these agents.

Paroxysmal Reentrant Supraventricular Tachycardia

Case 8A 32-year-old woman presents to the emergency departmentwith palpitations, dizziness, and feeling as though she mightfaint. She states that this is the first time she has experiencedsuch symptoms. In her efforts to make a work deadline, she hasbeen drinking five to seven cups of coffee daily. Her symptomsbegan abruptly as she bent to tie her shoes.

Physical examination shows a blood pressure of 100/65mm Hg and a pulse rate of 180/min. Electrocardiographyshows a narrow complex rhythm without apparent P waves.

Paroxysmal reentrant supraventricular arrhythmias are characterized by abruptonset and regularity. Offset may appear to be gradual because the patient mayconvert from the arrhythmia to sinus tachycardia, which then gradually slows.For reentry to occur, these arrhythmias require two tissues that have discrepantconduction velocities and refractory periods. One pathway must block in onedirection while the impulse can progress through the other. Both pathwaysmust have conductive properties that permit the rhythm to persist.

The most common paroxysmal reentrant supraventricular arrhythmia isatrioventricular nodal reentrant tachycardia (AVNRT), which involves reentrywithin atrioventricular nodal tissue. AVNRT is usually a regular, narrow com-

49

K E Y P O I N T S

• Premature atrial contractions are com-mon, benign, and usually do not requiretreatment.

• Evaluation of the patient with frequentpremature atrial contractions shouldfocus on excluding an underlying patho-logic cause for the ectopy; causes mayinclude any lesion that results in atrialenlargement or pressure elevation,stress, or ingestion of stimulants.

• Paroxysmal reentrant supraventriculararrhythmias are characterized by abruptonset and regularity; the most commonparoxysmal reentrant supraventriculararrhythmia is atrioventricular nodalreentrant tachycardia (AVNRT).

• Vagal maneuvers can terminate tachy-cardia; medical therapy may be appro-priate in patients with recurrentepisodes who cannot interrupt theirtachycardia by vagal maneuvers.

• In the Wolff-Parkinson-White syndrome,atrial fibrillation can be treated withdrugs that block conduction in theaccessory pathway; useful oral drugsinclude class Ia, Ic, and III agents.

• Curative catheter ablation is recom-mended in patients with Wolff-Parkinson-White syndrome when symp-tomatic tachycardia is drug resistant orwhen the patient is drug intolerant ordoes not desire long-term drug therapy.

• Atrial tachycardia can manifest as anintermittent or persistent arrhythmia;the mechanism can be reentry, trig-gered, or automatic. Reentry is the mostcommon mechanism of arrhythmia.

• Persistent atrial tachycardia can cause atachycardia-mediated cardiomyopathy.

Folarin VA, Fitzsimmons PJ, Kruyer WB.Holter monitor findings in asymptomaticmale military aviators without structuralheart disease. Aviat Space Environ Med.2001;72:836-8. PMID: 11565820


50

plex tachycardia of 160 to 180 beats/min. The retrograde P wave is typicallyburied within the QRS complex but may occur shortly before or after it. In theabsence of structural heart disease, AVNRT is a benign arrhythmia. Typical pre-senting symptoms are palpitations and shortness of breath. Infrequently syn-cope occurs. Case 8 describes a typical first onset of AVNRT.

Vagal maneuvers, such as a Valsalva maneuver, immersion of the face orforearm in ice water, or carotid massage, can terminate tachycardia. Acute phar-macologic termination of tachycardia can usually be achieved with adenosine.Medical therapy may be appropriate in patients with recurrent episodes whocannot interrupt their tachycardia by vagal maneuvers. Atrioventricular nodalblocking agents, such as β-blockers and calcium channel blockers, are ofteneffective in preventing recurrence of AVNRT.

Antiarrhythmics, including class IC and III agents, can be effective in pre-venting AVNRT. However, their utility is limited by side effects and potentialfor proarrhythmia. Patients with refractory AVNRT or those who do not toler-ate or do not wish to take medication should be offered curative catheter abla-tion (Zipes et al.). Conservative management would be most appropriate forthe patient described in Case 8. After treatment of the initial episode, furthermedical or ablative therapy should be intiated only if the arrhythmia recurs.

Preexcitation SyndromesPreexcitation is related to the presence of an accessory pathway that can con-duct the impulse from the atrium to the ventricle by a route that bypasses theatrioventricular node. Accessory pathways straddle the atrioventricular grooveon the mitral or tricuspid annuli. Most patients with an accessory pathway willhave manifest preexcitation (a short PR interval and delta waves on electrocar-diography), making the diagnosis of Wolff-Parkinson-White syndrome readilyapparent. However, a smaller percentage have a concealed pathway capable ofonly retrograde conduction (from ventricle to atrium). In this case, the surfaceelectrocardiogram is normal.

The most common arrhythmia in the Wolff-Parkinson-White syndrome isatrioventricular reentrant tachycardia, in which the pathway serves as one limband the atrioventricular node as the second. Most atrioventricular reentranttachycardia is narrow complex, since antegrade conduction is through the atri-oventricular node and retrograde through the accessory pathway (orthodromicreentry). In some, the circuit is reversed (antidromic), with antegrade conduc-tion through the accessory pathway and retrograde through the atrioventricu-lar node. In these, the tachycardia is wide complex.

The exact percentage of patients with Wolff-Parkinson-White syndromewho have atrial fibrillation is hard to determine but has been estimated to be ashigh as 8% (Goudevenos et al.). Atrial fibrillation becomes concerning inpatients whose accessory pathway is capable of rapid anterograde conduction,which can degenerate to ventricular fibrillation. The overall incidence of suddendeath in patients with the Wolff-Parkinson-White syndrome is estimated to be0.15%, and most cases are probably related to degeneration of rapid atrial fib-rillation (Munger et al.). In some patients with the Wolff-Parkinson-White syn-drome and atrial fibrillation, the ventricular response rate is slower and the elec-trocardiogram shows QRS morphologies that vary in width. This phenomenonis due to varying degrees of fusion as the impulse conducts simultaneouslythrough the atrioventricular node and the accessory pathway. Patients in thiscategory generally have a better prognosis.

The acute management of arrhythmias in Wolff-Parkinson-White syn-drome depends on the mechanism. Adenosine is effective in terminating thenarrow complex orthodromic reentry. However, drugs that block the atrioven-

Zipes DP, DiMarco JP, Gillette PC,Jackman WM, Myerburg RJ, RahimtoolaSH, et al. Guidelines for clinical intracardiacelectrophysiological and catheter ablationprocedures. A report of the AmericanCollege of Cardiology/American HeartAssociation Task Force on PracticeGuidelines (Committee on ClinicalIntracardiac Electrophysiologic and CatheterAblation Procedures), developed in collabo-ration with the North American Society ofPacing and Electrophysiology. J Am CollCardiol. 1995;26:555-73. PMID: 7608464Goudevenos JA, Katsouras CS, Graekas G,Argiri O, Giogiakas V, Sideris DA. Ventri-cular pre-excitation in the general popula-tion: a study on the mode of presentationand clinical course. Heart. 2000;83:29-34.PMID: 10618331Munger TM, Packer DL, Hammill SC,Feldman BJ, Bailey KR, Ballard DJ, et al.A population study of the natural history ofWolff-Parkinson-White syndrome in OlmstedCounty, Minnesota, 1953-1989. Circulation.1993;87:866-73. PMID: 8443907


tricular node should be avoided in patients whose arrhythmia is wide complex(that is, preexcited). Atrioventricular node blocking agents will not block theaccessory pathway and may enhance conduction via the bypass track, potentiallyrendering the arrhythmia unstable.

Any unstable patient should be acutely cardioverted regardless the mecha-nism of the arrhythmia. In the setting of Wolff-Parkinson-White syndrome,atrial fibrillation can be treated with drugs that block conduction in the acces-sory pathway; such agents include ibutilide, procainamide, propafenone, flecainide, and amiodarone. Patients rarely present with sustained antidromicAVNRT (down the accessory pathway and up the atrioventricular node). Thisrhythm will appear wide, and the morphology the QRS complex will be fullypreexcited. These patients should be handled the same way as the patient withatrial fibrillation. Atrioventricular nodal blocking agents should be avoided.

Oral agents useful in treatment of Wolff-Parkinson-White syndromeincludes class Ia, Ic and III agents. For patients with orthodromic AVNRT (nar-row complex), an antiarrhythmic agent plus a β-blocker can be used. No long-term studies of drug efficacy have been done. However, the class Ic drug flecainide has been reported to have a success rate of over 80% in the acute set-ting. For patients with Wolff-Parkinson-White syndrome who present with stableatrial fibrillation, management guidelines are similar to those in other groups.

The American College of Cardiology/American Heart Association(ACC/AHA) guidelines recommend curative catheter ablation in patients withWolff-Parkinson-White syndrome when symptomatic tachycardia is drug resist-ant or when the patient is drug intolerant or does not desire long-term drugtherapy. This recommendation is independent of the type of associatedarrhythmia (atrial fibrillation or atrioventricular reentry) or the mode of con-duction (orthodromic or antidromic). Given the benign nature of asympto-matic Wolff-Parkinson-White syndrome, patients who are incidentally discov-ered to have preexcitation should not undergo electrophysiologic testing orreceive treatment.

Atrial TachycardiaAtrial tachycardia can manifest as an intermittent or persistent arrhythmia. The mechanism of atrial tachycardia can be reentry, triggered, or automatic.Triggered arrhythmias are dependent on the occurrence of the previous beatand arise from afterdepolarizations (oscillations in membrane potential after anaction potential). If the afterdepolarizations reach adequate amplitude, abnor-mal beats occur. Automatic rhythms are generally associated with altered mem-brane function, which permits spontaneous depolarizations. Reentry is the mostcommon mechanism of arrhythmia.

Atrial tachycardia can arise from almost any region of the right or leftatrium. Atrial tachycardias are more common in children than in adults. If atrialtachycardia persists for long enough, a tachycardia-mediated cardiomyopathycan occur. This is a reversible cause of heart failure, but ventricular function maytake several months to normalize after cessation of the arrhythmia. Atrial tachy-cardias are in general resistant to drug treatment (Kowey). Control of heartrate may be achieved with atrioventricular node blocking agents. However,patients with atrial tachycardia that is drug resistant and patients who are drugintolerant or do not desire long-term drug therapy should be considered forablation of the atrial focus. In addition to the atrioventricular node blockingagents, such as calcium channel blockers and β-blockers, type Ia, Ic, and IIantiarrhythmics can be used to attempt suppression of atrial tachycardias. Thelong-term efficacy of drugs in suppression of atrial tachycardia is probably nomore than 50%.

51

Kowey PR. Pharmacological effects ofantiarrhythmic drugs. Review and update.Arch Intern Med. 1998;158:325-32.PMID: 9487229

Atrial Fibrillation and Atrial Flutter

52

Atrial Fibrillation and Atrial Flutter• What are the incidence and prevalence of atrial fibrillation?• What are the major sequelae of atrial fibrillation?• What are the risk factors for stroke in atrial fibrillation?• What are the treatment options for patients with atrial fibrillation?

Incidence and ClassificationAtrial fibrillation is the most common sustained atrial arrhythmia. Atrial fibril-lation is associated with a loss of sinus node function as the primary pacemakerof the heart. There is uncoordinated atrial activation, which results in deterio-ration of atrial mechanical function. The electrocardiogram is characterized byloss of sinus P waves, and gross irregularity of the ventricular response is usuallypresent. The fibrillatory waves may be of variable amplitude and are often seenon electrocardiography.

Atrial flutter is sometimes seen with atrial fibrillation, particularly inpatients taking drug therapy. It is characterized by more regular atrial activity.Typical atrial flutter creates a saw-tooth pattern on electrocardiography. A largemacro reentrant counterclockwise circuit contained largely in the right atriumcreates this pattern. The ventricular response in flutter is generally more regu-lar than in atrial fibrillation owing to a 2:1, 3:1, or greater atrial-to-ventricularconductive pattern. In terms of risk assessment and anticoagulation, patientswith flutter should be handled the same as those with atrial fibrillation.Sustained atrial flutter is less common than atrial fibrillation, and the former willtypically over time give way to the latter.

The prevalence of atrial fibrillation increases with age, affecting less than 1%of people younger than 60 years of age and greater than 6% of those older than80 years of age (Furberg et al.). The age-adjusted prevalence is higher in menthan in women and higher in white persons than in black persons.

Atrial fibrillation is commonly associated with cardiovascular disease; anidentifiable structural lesion is absent in less than 12% of all patients with atrialfibrillation. The term lone atrial fibrillation generally applies to people youngerthan 60 years of age who do not have clinical or echocardiographic evidence ofcardiopulmonary disease and who do not have hypertension. Subclinical hyper-thyroidism is a concern in elderly patients with atrial fibrillation. Similarly, exces-sive thyroid hormone replacement can result in atrial fibrillation. It is thereforeimportant to measure thyroid-stimulating hormone in elderly patients who pre-sent with atrial fibrillation but have no other signs of hyperthyroidism.

Various classifications for atrial fibrillation have been proposed. The schemerecommended in the ACC/AHA/ESC Guidelines is as follows (Fuster et al.).The first episode of atrial fibrillation should be evaluated to determine if thiswas the correct diagnosis, whether the episode was symptomatic, and whetherit was self-limited. By definition, if a patient has had two or more episodes, atrialfibrillation is considered recurrent. If the abnormal rhythm terminates sponta-neously, recurrent atrial fibrillation is paroxysmal. If the recurrent arrhythmia issustained, atrial fibrillation is designated persistent. Persistent atrial fibrillationmay become permanent if cardioversion or drug therapy is not attempted.

Stroke Risk and Mortality

Case 9A 78-year-old man presents for a routine annual physical exami-nation. He notes mild dyspnea on exertion over the past severalmonths but has continued his usual activities. He has a history

K E Y P O I N T S

• The term lone atrial fibrillation gener-ally applies to people younger than 60years of age without clinical or echocar-diographic evidence of cardiopulmonarydisease and hypertension. Persistentatrial fibrillation may become perma-nent if cardioversion or drug therapy isnot attempted.

• Because excessive thyroid hormonereplacement can result in atrial fibrilla-tion, it is important to measure thyroid-stimulating hormone in elderly patientswho present with atrial fibrillation buthave no other signs of hyperthyroidism.

• Risk factors for stroke in patients withatrial fibrillation include a history ofprior stroke, history of myocardialinfarction, history of hypertension, ageover 65 years, and diabetes.

• After restoration of sinus rhythm, inpatients with atrial fibrillation, long-term antiarrhythmic therapy may not beneeded, but short-term therapy mayprevent early recurrences.

• If recurrences of paroxysmal atrial fibril-lation are brief or minimally sympto-matic, avoidance of long-term therapywith antiarrhythmic drugs is reasonable.

• Atrial or atrioventricular synchronouspacing may reduce the incidence ofatrial fibrillation in patients with brady-cardia-dependent or vagally mediatedatrial fibrillation.

• The criteria for patient selection forcatheter-based radiofrequency ablationare not yet well established and pul-monary venous obstruction is a reportedcomplication.

Furberg CD, Psaty BM, Manolio TA,Gardin JM, Smith VE, Rautaharju PM.Prevalence of atrial fibrillation in elderly sub-jects (the Cardiovascular Health Study). AmJ Cardiol. 1994;74:236-41. PMID: 8037127Fuster V, Ryden LE, Asinger RW,Cannom DS, Crijns HJ, Frye RL, et al.ACC/AHA/ESC guidelines for the manage-ment of patients with atrial fibrillation: exec-utive summary. A Report of the AmericanCollege of Cardiology/ American HeartAssociation Task Force on PracticeGuidelines and the European Society ofCardiology Committee for PracticeGuidelines and Policy Conferences(Committee to Develop Guidelines for theManagement of Patients With AtrialFibrillation): developed in CollaborationWith the North American Society of Pacingand Electrophysiology. J Am Coll Cardiol.2001;38:1231-66. PMID: 11583910


of hypertension that is well controlled with a diuretic alone.Physical examination and electrocardiography are consistentwith atrial fibrillation, with a ventricular rate of 110/min.There are no other changes on electrocardiography, andechocardiography shows an ejection fraction of 50% with leftatrial enlargement and mild aortic sclerosis. He has no historyof stroke or ulcer disease.

The major concern in atrial fibrillation is the potential for thromboembolism,in particular, stroke. The stroke rate in patients with nonrheumatic atrial fibril-lation is about 5% per year (Wolf et al.). This rate is two to seven times that ofpeople without atrial fibrillation. In the Manitoba Follow-up Study (Krahn et al.),atrial fibrillation doubled the risk of stroke. Risk factors for stroke in patientswith atrial fibrillation include a history of stroke, myocardial infarction, hyper-tension, age over 65 years, and diabetes. Echocardiographic evidence of leftventricular dysfunction and left atrial enlargement have also been shown to berisk factors for stroke (Echocardiographic predictors of stroke.). Use of war-farin can significantly mitigate the risk for stroke.

The patient in Case 9 has multiple risk factors for stroke and should beanticoagulated. Aspirin (325 mg/d) alone can be used in patients younger than60 years of age who have lone atrial fibrillation or underlying heart disease, aslong as there is no heart failure or hypertension and the left ventricular ejectionfraction is greater than 35%. For patients 60 years of age or older without riskfactors, aspirin therapy (325 mg/d) is adequate. In all other patients with atrialfibrillation, warfarin therapy should be initiated unless there is a specific contra-indication. The target international normalized ratio for most patients is 2.0 to3.0. However, if the patient has rheumatic heart disease, a prosthetic valve, priorthromboembolism, or persistent intra-atrial thrombus on transesophogealechocardiography, a target international normalized ratio of 2.5 to 3.5 may beappropriate.

Another concern in atrial fibrillation is the potential for rate-related cardiomyopathy. Maintaining rate control can obviate this (Shinbane et al.).In the Atrial Fibrillation Follow-up Investigation in Rhythm Management(AFFIRM) trial, rate control was defined as a resting pulse rate 80/min or lessand 110/min or less after a 6-minute walk. These guidelines are appropriate forclinical use.

Although studies have shown that the mortality rate of patients with atrialfibrillation is about double that of patients in normal sinus rhythm, this is largelydue to the presence of underlying heart disease. The AFFIRM trial did notreport causes of death.

Acute Management of Atrial FibrillationThe acute management of patients presenting with either atrial flutter or atrialfibrillation depends on associated symptoms, hemodynamic stability, and theaccuracy with which onset can be determined. The risk of thromboembolismwarrants anticoagulation if atrial fibrillation has been present for more than 48hours or if the time of onset is uncertain. It may not be clear when the episodebegan or whether it is the patient’s first episode of atrial fibrillation, since somepatients have minimal or no symptoms of the arrhythmia. A hemodynamicallyunstable patient with a rapid rate who does not respond to initial therapies withrate control and other supportive measures must be acutely cardioverted evenbefore anticoagulation is established, In the hemodynamically stable patient,there is time to decide whether the primary approach will be rate control orrhythm control.

53

Wolf PA, Abbott RD, Kannel WB. Atrialfibrillation as an independent risk factor forstroke: the Framingham Study. Stroke.1991;22:983-8. PMID: 1866765Krahn AD, Manfreda J, Tate RB,Mathewson FA, Cuddy TE. The naturalhistory of atrial fibrillation: incidence, riskfactors, and prognosis in the ManitobaFollow-Up Study. Am J Med. 1995;98:476-84. PMID: 7733127Echocardiographic predictors of stroke inpatients with atrial fibrillation: a prospectivestudy of 1066 patients from 3 clinical trials.Arch Intern Med. 1998;158:1316-20.PMID: 9645825Shinbane JS, Wood MA, Jensen DN,Ellenbogen KA, Fitzpatrick AP,Scheinman MM. Tachycardia-induced car-diomyopathy: a review of animal models andclinical studies. J Am Coll Cardiol.1997;29:709-15. PMID: 9091514


54

After controlling the heart rate with an atrioventricular node blocker, aperiod of observation is warranted, as many episodes are self-limited. In thesepatients, antiarrhythmic drugs to prevent atrial fibrillation are generally notneeded unless the patient experiences or has experienced severe symptoms(such as hypotension, myocardial ischemia, or heart failure). The decisionregarding long-term anticoagulation depends on the risk assessment for stroke.

In patients with persistent atrial fibrillation, one may attempt to restoresinus rhythm with or without pretreatment with an antiarrhythmic agent. Thesooner this is done, the greater the likelihood of success. If cardioversion is tobe attempted in these patients, waiting days rather than weeks or months isappropriate. However, the risk of thromboembolism must be minimized.Studies using transesophageal echocardiography in patients with atrial fibrilla-tion of more than 48 hours’ duration showed that the incidence of thrombusin the left atrial appendage is approximately 15%. The Assessment ofCardioversion Using Transesophageal Echocardiography (ACUTE) trial inves-tigators randomized more than 1200 patients to either a transesophagealechocardiography-guided approach (immediate anticoagulation with heparinfollowed by transesophageal echocardiography and cardioversion and 4 weeksof warfarin therapy) or a conventional approach (3 weeks of therapeutic anti-coagulation followed by cardioversion and 4 weeks of warfarin therapy). Thegroups did not differ in the rate of embolic events. However, the patients ran-domized to transesopahgeal echocardiography had a shorter duration of atrialfibrillation, a higher success rate of cardioversion, and a lower rate of bleedingepisodes. This trial suggests that this approach is reasonable and safe.

After restoration of sinus rhythm, long-term antiarrhythmic therapy maynot be needed, but short-term therapy may prevent early recurrences. Inpatients with atrial fibrillation for longer than 3 months, early recurrence iscommon after cardioversion. In these patients, antiarrhythmic medication canbe started before cardioversion and after adequate anticoagulation to reduce thelikelihood of recurrence. The antiarrhythmic should be given for a brief periodafter sinus rhythm has been restored (for example, 1 month). Figure 12 pro-vides an algorithm for management of new-onset atrial fibrillation proposed bythe ACC/AHA/ESC Guidelines.

In some patients (such as asymptomatic elderly patients), it is reasonable tomonitor progression to permanent atrial fibrillation while paying close attentionto anticoagulation and rate control. Therapy with an atrioventricular nodeblocking agent in addition to anticoagulation would be appropriate for thepatient described in Case 9.

Long-Term Management of Atrial FibrillationIf recurrences of paroxysmal atrial fibrillation are brief or minimally sympto-matic, avoidance of long-term therapy with antiarrhythmic drugs is reasonable.Moreover, the results of the AFFIRM trial (Wyse et al.) suggest that rhythmcontrol is reasonable even when atrial fibrillation is recurrent and persistent ifsymptoms are acceptable. In this study, 4060 patients with atrial fibrillationwere randomized to rate control plus anticoagulation (2027 patients) orrhythm control (attempts to maintain sinus rhythm; 2033 patients). In bothapproaches, the use of anticoagulant drugs was recommended. At 5 years of follow-up, there were 310 deaths (21.3%) in the rate control group and 356deaths (23.8%) in the rhythm control group (hazard ratio, 1.15; P = 0.08). Thetwo groups did not significantly differ for the secondary end point of ischemicstroke (5.5% in the rate control vs. 7.1%; in the rhythm control group). Themajority of strokes occurred in patients in whom warfarin therapy was discon-tinued or the international normalized ratio was subtherapeutic. More hospi-

Wyse DG, Waldo AL, DiMarco JP,Domanski MJ, Rosenberg Y, Schron EB,et al. A comparison of rate control andrhythm control in patients with atrial fibrilla-tion. N Engl J Med. 2002;347:1825-33.PMID: 12466506


talizations and adverse drug reactions occurred in the rhythm control arm. Thisstudy implies that rhythm control offers no survival advantage over rate controland, consequently, rate control with appropriate anticoagulation is an accept-able alternative, particularly if patients tolerate the rhythm well. The mean ageof patients in this study was approximately 70 years, the incidence of hyperten-sion was 70%, and the left ventricular ejection fraction was abnormal in approx-imately 25% of patients. This study further emphasizes that all high-riskpatients, regardless of whether they appear to maintain sinus rhythm, shouldcontinue therapeutic anticoagulation. Figure 13 shows a therapeutic guide forrate control in persistent or permanent atrial fibrillation.

In contrast, if symptoms are troublesome and not improved with adequaterate control, antiarrhythmic therapy may be desirable. Several antiarrhythmicdrugs may be effective, and drug selection is based on safety. Figure 14 showsan algorithm for management proposed by the ACC/AHA/ESC guidelines.

New TherapiesA small subset of patients has bradycardia-dependent or vagally mediated atrialfibrillation. Two randomized trials have demonstrated a potential benefit ofatrial or atrioventricular synchronous pacing to reduce the incidence of atrialfibrillation in these patients compared with pacing the right ventricle alone(Andersen et al., 1997; Andersen et al., 1994).

55

F I G U R E 1 2 .Pharmacologic management of patients withnewly discovered atrial fibrillation.

AF = atrial fibrillation; HF = heart failure

Reproduced with permission from: ACC/AHA/ESCGuidelines for the Management of Patients with AtrialFibrillation. J Am Coll Cardiol. 2001;38:1231-66.

Andersen HR, Nielsen JC, Thomsen PE,Thuesen L, Mortensen PT, Vesterlund T,Pedersen AK. Long-term follow-up ofpatients from a randomised trial of atrial versus ventricular pacing for sick-sinus syndrome. Lancet.1997. 25;350:1210-6.PMID: 9652562Andersen HR, Thuesen L, Bagger JP,Vesterlund T, Thomsen PE. Prospectiverandomised trial of atrial versus ventricularpacing in sick-sinus syndrome. Lancet.1994;344:1523-8. PMID: 7983951

NEWLY DISCOVEREDAF

Paroxysmal Persistent

No therapy neededunless severe

symptoms (e.g.,hypotension, HF,angina pectoris) Accept

permanent AFRate control andanticoagulation

as needed

Anticoagulationand rate control

as needed

Considerantiarrhythmicdrug therapy

Long-termantiarrhythmicdrug therapyunnecessary

Cardioversion

Anticoagulationas needed


56

The U.S. Food and Drug Administration recently approved an implantableatrial defibrillator for management of patients with recurrent persistent atrialfibrillation. This device permits the patient to trigger cardioversion at home.These devices are only useful in a selected group of highly motivated patientswho experience intolerable symptoms during atrial fibrillation and wish to avoidhospitalization. These patients must be receive long-term anticoagulation. Thistherapy is not appropriate for patients with short episodes of self-terminatingatrial fibrillation or those with chronic atrial fibrillation.

F I G U R E 1 3 .Antiarrhythmic drug therapy to maintain sinus rhythm in patients with recurrent paroxysmal or persistent atrial fibrillation.Drugs are listed alphabetically and not in order of suggested use. *For adrenergic atrial fibrillation, β-blockers or sotalol are the initial drugs of choice.†Consider nonpharmacologic options to maintain sinus rhythm if drug failure occurs.

CAD = coronary artery disease; HF = heart failure; LVH = left ventricular hypertrophy

Reproduced with permission from: ACC/AHA/ECS Guidelines for the Management of Patients with Atrial Fibrillation. J Am Coll Cardiol. 2001;38:1231-66.

DisopyramideProcainamide

Quinidine

Consider nonpharmacologicaloptions

Disopyramide, Procainamide, Quinidine

AmiodaroneDofetilide

Sotalol

FlecainidePropafenone

LVH greater thanor equal to 1.4 cm

AmiodaroneDofetilide

DisopyramideProcainamide

QuinidineAmiodarone

Yes No

SotalolAmiodaroneDofetilide

HF CAD

Yes†No (or minimal*)

Hypertension

Heart disease?

FlecainidePropafenone

Sotalol

Amiodarone, Dofetilide


Traditionally, atrioventricular node ablation and pacemaker implantationhas been offered to patients with uncontrollable ventricular rates or severe drugintolerance. In these patients, the atria continue to fibrillate and the ventricle ispaced. Thus, long-term anticoagulation is indicated. Newer treatments for atrialfibrillation also involve catheter-based radiofrequency ablation. One of thesetechniques arose from the recognition that atrial fibrillation may be triggeredby premature atrial contraction arising within atrial muscle that tracks into thepulmonary veins. The pulmonary veins are approached through an atrial sep-tostomy, and radiofrequency is used to isolate them. Although this technique isgaining more widespread acceptance, the criteria for patient selection are notyet well established and pulmonary venous obstruction is a reported complica-tion. Linear lesions in the right and left atria isolate electrical areas and may pre-vent propagation of the arrhythmia. The surgical technique is called the mazeprocedure. Recently, catheter-based radiofrequency creation of linear lesionsmimics those created surgically but results have been marginal. In contrast, thesurgical technique is most effective, with over 90% of patients achieving sinusrhythm. The success rate must, however, be weighed against the risks of sur-gery, and this procedure is generally reserved for patients with very sympto-matic atrial fibrillation in whom multiple therapies have failed. Often this pro-cedure is performed in conjunction with another cardiac procedure, such asvalve replacement or coronary bypass.

Catheter ablation of typical atrial flutter is feasible, with good long-termsuccess rates. Newer types of mapping systems used in the electrophysiologylaboratories have improved our ability to treat this arrhythmia with ablation.

57

F I G U R E 1 4 .Pharmacologic management of patients withrecurrent persistent or permanent atrial fib-rillation (AF). *Initiate drug therapy beforecardioversion to reduce the likelihood ofearly recurrence of AF.

Reproduced with permission from: ACC/AHA/ECSGuidelines for the Management of Patients with AtrialFibrillation. J Am Coll Cardiol. 2001;38:1231-66.

Minimal orno symptoms

Anticoagulationand rate control*

as needed

Disablingsymptoms in AF

Anticoagulationand rate control

Antiarrhythmicdrug therapy*

Electricalcardioversion as

needed

RECURRENTPERSISTENT

AF

PERMANENTAF

Anticoagulationand rate control*

as needed

Continueanticoagulation as

needed and therapy tomaintain sinus rhythm*

Bradyarrhythmias

58

Bradyarrhythmias• What are common indications for pacemaker implantation?• What are the two types of second-degree atrioventricular block?• What are the indications for pacing in patients with congenital complete heart block?• What patients benefit from rate-responsive pacing?

Permanent pacemakers may be indicated in patients with sinus node dysfunc-tion, in patients with complete heart block, after catheter ablation of the atrio-ventricular node or after cardiac surgery when atrioventricular block persists.

Sinus Node DysfunctionSinus node dysfunction is frequently the primary diagnosis listed for implanta-tion of a permanent pacemaker. However, although symptoms of bradycardiamay be relieved, pacing may not necessarily improve survival. Sinus node dys-function can present as a wide spectrum of dysrhythmias. Persistent slow heartrates or the inability to accelerate the heart rate appropriately are common.Many patients will, however, present with a tachy–brady syndrome.

Permanent pacemakers are indicated in patients with sinus node dysfunc-tion who have documented symptomatic bradycardia, which may include sinuspauses that produce symptoms. Pacing should also be implemented in patientswith symptomatic iatrogenic bradycardia in whom treatment with the impli-cated drug cannot be stopped. Pacing is also indicated in patients with sinusnode dysfunction who have symptomatic chronotropic incompetence associ-ated with exercise intolerance (Gregoratos et al.).

Atrioventricular Nodal BlockAtrioventricular block is classified as first-, second-, or third-degree (complete)block. The level of atrioventricular block is defined anatomically as supra-, intra,or infra-His. First-degree block is present when there is as abnormal prolonga-tion of the PR interval. There are two types of second-degree atrioventricularblock. Type I, or Wenkebach, manifests as progressive prolongation of the PRinterval before a blocked beat. In general, the QRS interval will be narrow. Intype II second-degree block, there is no progressive prolongation of PR inter-val before the blocked beat. Type II block is usually associated with a wide QRScomplex. Advanced atrioventricular block is said to be present when two ormore consecutive P-waves fail to conduct. Third-degree atrioventricular blockis defined as the complete absence of conduction of atrial impulses to the ven-tricle and is also called complete heart block.

Symptoms vary in patients with atrioventricular block from an asympto-matic state to severe bradycardia-related symptoms. The latter patients maydevelop severe ventricular arrhythmias as a result of the bradycardia. Studieshave shown that permanent pacing improves survival in patients with completeheart block, especially if syncope has occurred. No survival data are available,but some patients with prolonged first-degree atrioventricular block might benefit from pacing.

Pacing is indicated in patients with complete heart block regardless of theanatomic level of block if the symptomatic bradycardia is presumed to be dueto atrioventricular block. Pacing is also indicated in cases of iatrogenic atri-oventricular block in which treatment with the implicated medication cannot bestopped. In asymptomatic patients, pacing is indicated for documented asystolelasting 3.0 seconds or longer or with ventricular escape rates less than 40/minwhile awake. Pacemakers must also be implanted after catheter ablation of theatrioventricular node or after cardiac surgery when atrioventricular block per-sists. Some patients with neuromuscular diseases develop heart block that can

K E Y P O I N T S

• Sinus node dysfunction is frequently theprimary diagnosis listed for implanta-tion of a permanent pacemaker.Although pacing may relieve symptomsof bradycardia, it may not necessarilyimprove survival.

• Permanent pacemakers are indicated inpatients with sinus node dysfunctionwho have documented symptomaticbradycardia, those with symptomaticiatrogenic bradycardia in whom treat-ment with the implicated drug cannotbe stopped, and those with sinus nodedysfunction who have symptomaticchronotropic incompetence associatedwith exercise intolerance.

• Pacing is indicated in patients with com-plete heart block if the symptomaticbradycardia is presumed to be due toatrioventricular block and in cases ofiatrogenic atrioventricular block inwhich treatment with the implicatedmedication cannot be stopped.

• Pacemakers must also be implantedafter catheter ablation of the atrioven-tricular node or after cardiac surgerywhen atrioventricular block persists.

• Pacing is indicated in patients with con-genital complete heart block who havea wide QRS escape rhythm or ventricu-lar dysfunction, those at risk for abradycardia-dependent long QT intervaland resultant arrhythmias, and infantswith congenital complete heart blockwho has a ventricular rate less than 50 to 55/min or less than 70/min in thesetting of congenital heart disease.

• Rate-responsive pacing is particularlyuseful in patients who are chrono-tropically incompetent.

• Resynchronization therapy is indicatedin patients with class II to IV heart fail-ure and significant prolongation of the QRS interval.

Gregoratos G, Cheitlin MD, Conill A,Epstein AE, Fellows C, Ferguson TB Jr,et al. ACC/AHA guidelines for implantationof cardiac pacemakers and antiarrhythmiadevices: a report of the American College of Cardiology/American Heart AssociationTask Force on Practice Guidelines (Committeeon Pacemaker Implantation). J Am CollCardiol. 1998;31:1175-209.PMID: 9562026

Bradyarrhythmias

lead to sudden death. These patients should have pacemakers implanted ifsymptomatic second-degree atrioventricular block is present, regardless of thetype or site of block.

Congenital Heart BlockThe indications for permanent pacing in young patients with congenital com-plete atrioventricular block have evolved through greater understanding of thenatural history of the disease. Recent studies have shown that implantation of apacemaker may improve long-term survival, and serious symptoms, such as syn-cope, may be avoidable in patients with congenital complete atrioventricularblock. Several criteria must be considered in asymptomatic patients with con-genital complete atrioventricular block before implanting a pacemaker. In gen-eral, pacing is indicated in patients with congenital complete heart block whohave a wide QRS escape rhythm or ventricular dysfunction. Pacing is also indi-cated in those at risk for a bradycardia-dependent long QT interval and result-ant arrhythmias. Pacing should be considered in an infant with congenital com-plete heart block who has a ventricular rate less than 50 to 55 beats per minuteor less than 70/min in the setting of congenital heart disease. Specific rateguidelines for adults with congenital complete heart block do not exist; how-ever, the above concerns about bradycardia dependent-arrhythmias and ven-tricular dysfunction prompt many physicians to implant devices even in theabsence of symptoms.

Pacemakers—What’s New; and the Role of Physiologic PacingPhysiologic pacing is achieved by pacing the right atrium and right ventricle tomaintain atrioventricular synchrony. Several trials have randomized patients tophysiologic pacing or ventricular pacing. The largest of these trials is theCanadian Trial of Physiologic Pacing (CTOPP) trial. Among the 2568 ran-domized patients, no significant difference was observed in the primary endpoint of stroke or cardiovascular death or in all-cause mortality and 6-minutewalk distance. One subset of patients who had low unpaced heart rates(<60/min) appeared to experience a lower mortality rate if physiologic pacingwas used (Tang et al.). The results of the Pacemaker Selection in the Elderly(PASE) trial were similar, with a borderline significant benefit for physiologicpacing in patients with the sick sinus syndrome (Lamas et al.) In the PASEtrial, approximately 25% of patients randomized to ventricular pacing crossedover to dual-chamber pacing because of symptoms due to the pacemaker syn-drome. Symptoms may include dyspnea, syncope, throat tightness, and exerciseintolerance. Physical examination reveals cannon A waves as the atrium con-tracts against a closed atrioventricular valve.

Most current pacemakers have a rate-responsive feature that permits theheart rate to accelerate in response to exercise. A variety of incorporated sensorspermit this feature. The most common is a piezoelectric crystal or anaccelerometer that detects motion, vibration, pressure, or acceleration. Othersincorporate sensors that measure minute ventilation, and some combine thetwo methods. Rate-responsive pacing is particularly useful in patients who arechronotropically incompetent. Pacemakers incorporating this feature beenshown to improve quality of life.

Another relatively new feature is mode switching. Pacemakers with this fea-ture have dual-chamber sensing and pacing. If an atrial tachyarrhythmia, suchas atrial fibrillation, occurs, the unit switches to a ventricular pacing mode toavoid inappropriate tracking of the atrial arrhythmia.

Developments in lead technology have permitted greater longevity ofleads. This advance is important, particularly for younger patients who face sev-

59

Tang AS, Roberts RS, Kerr C, Gillis AM,Green MS, Talajic M, et al. Relationshipbetween pacemaker dependency and theeffect of pacing mode on cardiovascular out-comes. Circulation. 2001;103:3081-5.PMID: 11425772Lamas GA, Orav EJ, Stambler BS,Ellenbogen KA, Sgarbossa EB, Huang SK,et al. Quality of life and clinical outcomes inelderly patients treated with ventricular pac-ing as compared with dual-chamber pacing.Pacemaker Selection in the ElderlyInvestigators. N Engl J Med. 1998;338:1097-104. PMID: 9545357

Bigger JT Jr, Fleiss JL, Rolnitzky LM.Prevalence, characteristics and significance ofventricular tachycardia detected by 24-hourcontinuous electrocardiographic recordingsin the late hospital phase of acute myocardialinfarction. Am J Cardiol. 1986;58:1151-60.PMID: 3788801Echt DS, Liebson PR, Mitchell LB, PetersRW, Obias-Manno D, Barker AH, et al.Mortality and morbidity in patients receivingencainide, flecainide, or placebo. The CardiacArrhythmia Suppression Trial. N Engl JMed. 1991;324:781-8. PMID: 1900101

Ventricular Ectopy

60

eral pacemaker revisions in their lifetime. A newer single-pass lead is availablethat incorporates poles for sensing (although not pacing) the atrium on thesame lead as the ventricular sensing and pacing electrode. This system, which isindicated in patients with atrioventricular block and intact sinus node function,permits maintenance of an atrioventricular sequential rhythm with the use of asingle lead.

One of the most recent important developments in pacing is the biventric-ular pacemaker, which is used to resynchronize contraction of the left ventriclein patients with ventricular systolic dysfunction and interventricular conductiondelay. The left ventricle is paced with a lead that is placed through the coronarysinus to a lateral epicardial vein. This form of pacing, called resynchronizationtherapy, is indicated in patients with class II to IV heart failure and significantprolongation of the QRS interval.

Ventricular Ectopy• Under what circumstances do premature ventricular contractions have prognostic

importance?• Does premature ventricular contractions suppression improve survival?• Under what circumstances does nonsustained ventricular tachycardia have prognostic

importance?• How is risk reduced in patients with the long QT syndrome?

Premature Ventricular ContractionsPremature ventricular contractions are abnormal heart beats that arise from theright or left ventricle. Similar to premature atrial contractions, they are gener-ally benign. Premature ventricular contractions were found on 24-hour ambu-latory recordings in about 51% of healthy male military aviators. Although premature ventricular contractions may be more frequent in patients with heartdisease, they have minimal prognostic significance if the ejection fraction is preserved. However, among patients with depressed ejection fractions aftermyocardial infarction, frequent premature ventricular contractions are associ-ated with increased mortality (Bigger et al.). Nevertheless, suppression of premature ventricular contractions does not improve outcome, and therapy inthese patients is more appropriately directed toward the underlying heart con-dition (Echt et al.). Because of the implications of frequent premature ventric-ular contractions in post–myocardial infarction patients with depressed ejectionfractions, structural heart disease should be sought in patients presenting withcomplex premature ventricular contractions. Also, frequent premature ventric-ular contractions may be a harbinger of ventricular tachycardia in these patients,and appropriate monitoring should be instituted.

Regardless of their significance, symptomatic premature ventricular con-tractions can be treated with β-blockers. Symptoms of frequent or repetitiveventricular ectopy may include palpitations, fatigue, and near syncope.Antiarrhythmics play little role in the management of premature ventricularcontractions.

Ventricular TachycardiaIn a structurally normal heart, ventricular tachycardia carries little prognosticsignificance. Often, ventricular tachycardia in the structurally normal heart iscatecholamine dependent. These arrhythmias can be triggered or automatic.They often arise from the right ventricular outflow tract. Short runs may be well

K E Y P O I N T S

• Premature ventricular contractions areabnormal heart beats that arise fromthe right or left ventricle; they are gen-erally benign.

• Although premature ventricular contrac-tions may be more frequent in patientswith heart disease, they have minimalprognostic significance if the ejectionfraction is preserved.

• Because of the implications of frequentpremature ventricular contractions inpost–myocardial infarction patients withdepressed ejection fractions, structuralheart disease should be sought inpatients presenting with complex pre-mature ventricular contractions.

• Regardless of their significance, sympto-matic premature ventricular contrac-tions can be treated with β-blockers.Symptoms of frequent or repetitive ven-tricular ectopy may include palpitations,fatigue, and near syncope.Antiarrhythmics play little role in themanagement of premature ventricularcontractions.

• In a structurally normal heart, ventricu-lar tachycardia carries little prognosticsignificance. If the patient has clinicallysignificant symptoms or if the ventricu-lar tachycardia is of longer duration,treatment with a β-blocker or calciumchannel blocker may be useful. For fre-quent short runs or sustained ventricu-lar tachycardia, catheter ablation can behelpful.

• Patients with coronary disease, nonsus-tained ventricular tachycardia, and leftventricular dysfunction have anincreased risk for sudden cardiac death.

Ventricular Ectopy

tolerated and thus not require treatment. If the patient has clinically significantsymptoms or if the ventricular tachycardia is of longer duration, treatment witha β-blocker or calcium channel blocker may be useful. For frequent short runsor sustained ventricular tachycardia, catheter ablation can be helpful.

Ischemic Heart DiseaseThe association between ventricular arrhythmias and mortality after myocardialinfarction is well recognized. Patients with coronary disease, nonsustained ven-tricular tachycardia, and left ventricular dysfunction have an increased risk forsudden cardiac death. Many trials have attempted to predict which patients areat highest risk for sudden death so that only patients with indicators of high riskcan be treated.

Two randomized prospective trials, the Multicenter UnsustainedTachycardia Trial (MUSTT) and the Multicenter Automatic DefibrillatorImplantation Trial (MADIT), used electrophysiologic testing for risk stratifica-tion in patients with left ventricular dysfunction and coronary artery disease. InMADIT, patients with inducible sustained ventricular tachycardia were ran-domized to receive implantable cardioverter-defibrillators (ICDs) or “conven-tional” therapy (Moss et al.). In MUSTT, inducible patients were randomizedto receive no specific antiarrhythmic treatment or electrophysiologically guidedtherapy. Both trials showed a benefit of ICD implantation. The overall mortal-ity rate was reduced by approximately 50% with ICD therapy.

The MUSTT also showed that patients received no survival benefit withelectrophysiologically guided drug treatment. However, patients in MUSTTwith inducible sustained ventricular tachycardia had a worse prognosis thanpatients in whom sustained ventricular tachycardia could not be induced(Buxton et al.). A substudy of MUSTT showed that inducible sustained ven-tricular tachycardia could not be predicted on the basis of characteristics of non-sustained ventricular tachycardia.

The recently completed Multicenter Automatic Defibrillator ImplantationTrial II (MADIT II) was designed to evaluate the effect of prophylactic ICDtherapy on survival in patients with previous myocardial infarction and left ven-tricular dysfunction. Patients had chronic coronary artery disease with priormyocardial infarction. Their ejection fractions were 30% or less, and there wasno baseline requirement for nonsustained ventricular tachycardia or elecro-physiologic testing. The data safety and monitoring board terminated this studyprematurely when the ICD group showed a 31% reduction in mortality rate.Together, these three studies support the use of ICDs in patients with coronaryartery disease and depressed ejection fraction who are at risk for sudden death.

Congenital and Acquired Long QT SyndromesThe congenital long QT syndromes are composed of a spectrum of electro-physiologic disorders. In general, it is an electrical disease without an associatedstructural abnormality. Patients with the long QT syndrome are at risk formalignant ventricular arrhythmias, particularly polymorphic ventricular tachycardia.Several genetic mutations affect potassium currents and sodium channels.

If the arrhythmia is controlled, the long-term prognosis is good.Prevention of arrhythmias is often accomplished by long-term treatment withβ-blockers, permanent pacing, or left cervicothoracic sympathectomy. Patientswho have survived cardiac arrest and those who have had recurrent syncope orsustained ventricular tachycardia despite drug therapy should receive an ICD(class IIb recommendation). Other patients with the long QT syndrome whoshould be considered for primary ICD implantation are those who present withaborted sudden death and those with a strong family history of sudden death.

61

K E Y P O I N T S ( C O N T ' D )

• Randomized studies support the use ofimplantable cardioverter-defibrillators(ICDs) in patients with coronary arterydisease and depressed ejection fractionwho are at risk for sudden death.

• Patients with the long QT syndrome areat risk for malignant ventricular arrhyth-mias, particularly polymorphic ventricu-lar tachycardia.

• If the arrhythmia is controlled, the long-term prognosis is good. Prevention ofarrhythmias is often accomplished bylong-term treatment with β-blockers,permanent pacing, or left cervicotho-racic sympathectomy. Patients who havesurvived cardiac arrest and those whohave had recurrent syncope or sustainedventricular tachycardia despite drugtherapy should receive an ICD (class IIbrecommendation).

• Several drugs can prolong the QT inter-val and place patients at risk for tor-sades de pointes due to acquired longQT syndrome. Risk factors for acquiredlong QT syndrome include female sex,hypokalemia, and hypomagnesemia.

Moss AJ, Hall WJ, Cannom DS, DaubertJP, Higgins SL, Klein H, et al. Improvedsurvival with an implanted defibrillator inpatients with coronary disease at high risk for ventricular arrhythmia. MulticenterAutomatic Defibrillator Implantation TrialInvestigators. N Engl J Med.1996;335:1933-40. PMID: 8960472Buxton AE, Lee KL, Fisher JD, JosephsonME, Prystowsky EN, Hafley G. A random-ized study of the prevention of sudden deathin patients with coronary artery disease.Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med.1999;341:1882-90. PMID: 10601507

Sudden Death

62

Several drugs can prolong the QT interval and place patients at risk for tor-sades de pointes due to acquired long QT syndrome. The list of drugs impli-cated in QT prolongation and risk for torsades de pointes is extensive andincludes antiarrhythmics (classes Ia and III) and some antihistamines. Risk fac-tors for acquired long QT syndrome include female sex, hypokalemia, andhypomagnesemia. An extensive list of offending agents can be found athttp://www.torsades.org/druglist.cfm.

Sudden Death• What is the incidence of cardiac arrest?• What arrhythmias are associated with sudden death?• What are strategies for enhancing survival of cardiac arrest?• What are strategies to prevent cardiac arrest?• What are strategies to prevent recurrent cardiac arrest?

Epidemiology, Risk Factors, and EtiologiesSudden death is a major health problem, with an incidence of 300,000 to400,000 persons annually in the United States. Of these patients, only 2% to15% survive to hospitalization, and half die before discharge. The most com-mon underlying disorder is ischemic heart disease. In a study of Holter tapes ofambulatory patients who died while wearing Holter devices, the causativearrhythmia was ventricular tachycardia in 62%, ventricular fibrillation in 8%, tor-sades de pointes in 13%, and bradycardia in 17% (Bayes de Luna et al.).

Acute Treatment of Cardiac ArrestThe key to survival of a cardiac arrest is rapid treatment, with early institutionof cardiopulmonary resusciation and quick arrival of medical personnel. Theavailability of automatic external defibrillators has increased access to emergencyservices, but mortality rates from cardiac arrest remains high. Figure 15 showsthe new Advanced Cardiac Life Support universal guidelines.

Prevention of Sudden Cardiac DeathGiven the high mortality rate associated with cardiac arrest, much effort hasgone into determining who is at risk for sudden death so that primary preven-tion may be instituted. In addition to the device studies discussed above, twostudies assessed the role of primary drug prevention of sudden death. TheCanadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT)assessed the effect of amiodarone on risk for sudden death in post–myocardialinfarction patients with frequent premature ventricular contractions (Cairns et al.).The European Myocardial Infarct Amiodarone Trial (EMIAT) assessed theeffect of amiodarone on the mortality rate in post–myocardial infarctionpatients with decreased left ventricular function, regardless of ventriculararrhythmias (Julian et al.). Both showed a reduction in arrhythmic death butno reduction in overall mortality rate.

The evidence is strong for the superiority of ICDs as primary prevention inpatients with coronary artery disease in which the ejection fraction is depressed.Data relevant to severe dilated cardiomyopathy are yet to come. The SuddenCardiac Death Heart Failure Trial is designed to determine whether ICDimplantation or amiodarone therapy will decrease the mortality rate in patientswith coronary artery disease or nonischemic cardiomyopathy who are in NewYork Heart Association functional class II or III and have an ejection fractionless than 35%.

K E Y P O I N T S

• In sudden death, the most commonunderlying disorder is ischemic heartdisease.

• The key to survival of a cardiac arrest israpid treatment, with early institution ofcardiopulmonary resuscitation and quickarrival of medical personnel.

• The evidence is strong for the superior-ity of ICDs as primary prevention inpatients with coronary artery disease inwhich the ejection fraction is depressed.

• Patients with an isolated episode ofventricular fibrillation who have under-gone revascularization or who havemoderately preserved left ventricularfunction are not likely to benefit fromICD therapy compared with amiodaronetherapy.

• In the absence of structural heart dis-ease, syncope, near syncope, and tran-sient lightheadedness are generallybenign.

• History and physical examination alonecan identify the probable cause of syn-cope in about 50% of cases; electro-physiologic testing can be considered inpatients with structural or ischemicheart disease.

• Neurocardiogenic syncope is a commoncause of syncope in the absence of acardiac arrhythmia or structural cardiacdisease. The tilt-table test may be usedto define different underlying mecha-nisms for neurocardiogenic syncope.

• Cardiac causes of syncope include brady-arrhythmias or tachyarrhythmias, pul-monary embolism, pulmonary hyperten-sion, acute myocardial infarction, car-diac tamponade, or obstruction to leftventricular outflow (hypertrophic cardio-myopathy or aortic stenosis).

• Invasive electrophysiologic studiesshould be considered in patients at riskfor or with cardiac disease to detectarrhythmias as a possible cause of syncope.

Bayes de Luna A, Coumel P, Leclercq JF.Ambulatory sudden cardiac death: mecha-nisms of production of fatal arrhythmia onthe basis of data from 157 cases. Am HeartJ. 1989;117:151-9. PMID: 2911968Cairns JA, Connolly SJ, Roberts R, Gent M. Randomised trial of outcome aftermyocardial infarction in patients with fre-quent or repetitive ventricular prematuredepolarisations: CAMIAT. CanadianAmiodarone Myocardial InfarctionArrhythmia Trial Investigators. Lancet.1997;349:675-82. PMID: 9078198

Sudden Death

Secondary PreventionSurvivors of cardiac arrest remain at risk for a recurrent event. Cardiac arrest notassociated with an acute myocardial infarction has a 1-year recurrence rate ofapproximately 30%. In patients with associated ischemia, revascularization withcoronary artery bypass graft surgery has been shown to reduce the recurrenceof cardiac arrest.

Recent studies have examined the utility of cardiodefibrillators in survivorsof cardiac arrest and in patients with an episode of hemodynamically unstableand sustained ventricular tachycardia. Three of these studies are compared inTable 21. Overall, the risk for death was reduced by 28%, due almost entirelyto the observed 50% reduction in arrhythmic death. In each of these three studies,the greatest benefit was seen in patients with low ejection fractions. In contrast,patients with an isolated episode of ventricular fibrillation who have undergonerevascularization or who have moderately preserved left ventricular function arenot likely to benefit from ICD therapy compared with amiodarone therapy(Connolly et al.).

Currently, class I indications for ICD implantation include the following:• Cardiac arrest due to ventricular fibrillation or ventricular

tachycardia not due to a transient or reversible cause.• Spontaneous sustained ventricular tachycardia.• Syncope of undetermined origin with clinically relevant, hemo-

dynamically significant sustained ventricular tachycardia or ven-tricular fibrillation induced on an electrophysiologic study whendrug therapy is ineffective, not tolerated, or not preferred.

• Nonsustained ventricular tachycardia with coronary disease, priormyocardial infarction, left ventricular dysfunction, and inducibleventricular fibrillation or sustained ventricular tachycardia on electrophysiologic study that is not suppressible by therapy with a class I antiarrhythmic drug.

Workup of SyncopeSyncope is defined as a transient loss of consciousness. About 30% of the pop-ulation is expected to experience syncope at some point. In the absence ofstructural heart disease, syncope, near-syncope, and transient lightheadedness

63

Julian DG, Camm AJ, Frangin G, JanseMJ, Munoz A, Schwartz PJ, Simon P.Randomised trial of effect of amiodarone onmortality in patients with left-ventricular dys-function after recent myocardial infarction:EMIAT. European Myocardial InfarctAmiodarone Trial Investigators. Lancet.1997;349:667-74. PMID: 9078197Connolly SJ, Hallstrom AP, Cappato R,Schron EB, Kuck KH, Zipes DP, et al.Meta-analysis of the implantable cardioverterdefibrillator secondary prevention trials.AVID, CASH and CIDS studies.Antiarrhythmics vs Implantable Defibrillatorstudy. Cardiac Arrest Study Hamburg.Canadian Implantable Defibrillator Study.Eur Heart J. 2000;21:2071-8.PMID: 11102258

TABLE 21 Comparison of Implantable Cardioverter-Defibrillator Trials Aimed at Primary Prevention of Sudden Death

Aspect of Study CASH AVID CIDS

Protocol ICD vs. conventional ICD vs. amiodarone ICD vs. amiodaronetherapy (mainly or sotalolamiodarone and metprolol)

Patient characteristics Survivors of VF or Survivors of VF; VT Resuscitated VF, VT, or sustained VT with syncope; VT unmonitored syncope

with EF ≤ 40%

Mean ejection fraction 46% 32% 33%

Improvement in survival Not significant Significant Not significantwith ICD

Take-home points May have been negative Strongly supports ICD 20% relative risk reduction in all-secondary to long cause mortality and 33% reduction recruitment arrhythmic mortality with ICD

Reduction did not reach statisticalsignificance, lends support for ICD.

AVID = Antiarrhythmics Versus Implantable Defibrillators; CASH = Cardiac Arrest Study Hamburg; CIDS = Canadian Implantable Defibrillator Study; EF = ejection fraction; ICD = implantablecardioverter-defibrillator; VF = ventricular fibrillation; VT = ventricular tachycardia

Evaluation of a Murmur

are generally benign, however, the recurrence rate is high (30%). A careful his-tory and physical are critical in the evaluation of syncope and can help distin-guish patients with benign syncope from those likely to have a malignant cause.History and physical examination alone can identify the probable cause of syncope in about 50% of cases. Other tests that may be useful in the investiga-tion of syncope include electrocardiography and echocardiography. Electro-physiologic testing can be considered in patients with structural or ischemicheart disease. Neurocardiogenic syncope is a common cause of syncope in theabsence of a cardiac arrhythmia or structural cardiac disease. The tilt-table testmay be used to define different underlying mechanisms for neurocardiogenicsyncope (Goldschlager et al.).

Before the advent of head-up tilt-testing, a large prospective study showedthat approximately 50% of patients had a definable cause of syncope, half ofwhich were cardiovascular. In the remaining 50%, the cause remained obscure(Kapoor et al.). Subsequent studies using head-up tilt-testing diagnosed neurocardiogenic syncoope in patients without other definite etiologies. Cardiaccauses of syncope include bradyarrhythmias or tachyarrhythmias, pulmonaryembolism, pulmonary hypertension, acute MI, cardiac tamponade, or obstruc-tion to left ventricular outflow (hypertrophic cardiomyopathy or aortic stenosis).Electrocardiography alone will rarely reveal the cause of syncope unless there isevidence of heart block or acute MI. A 24-hour Holter monitor may show“footprints” of likely causes of syncope but will not be definitive unless syncopeoccurs during the monitoring period. Various intermittent or implantablerecorders may be used for prolonged monitoring to detect the cause of syncope.

Invasive electrophysiologic studies should be considered in patients at riskfor or with cardiac disease to detect arrhythmias as a possible cause of syncope.Whereas the prognosis of syncope is benign in patients without heart disease,syncope in the presence of cardiovascular disease carries a 30% mortality rate at1 year.

Valvular Heart Disease

A heart murmur on physical examination is not uncommon. Some murmursindicate underlying structural abnormalities of valvular, congenital, or other etiology, whereas others are innocent murmurs not indicative of underlyingpathology. Although the proportion of pathologic and innocent murmurs variesby the group studied, a large proportion of murmurs are innocent. Because amurmur may be a significant clue (or the only sign) suggesting underlying dis-ease, it is important to distinguish pathologic from innocent murmurs.

Evaluation of a Murmur• Are all murmurs a sign of cardiac pathology?• What murmurs should prompt further evaluation?

Table 22 summarizes the typical characteristics of murmurs that are encoun-tered in adults.

The decision to evaluate a murmur further is based on the characteristicsof the murmur and the presence of symptoms (Figure 16). In general, twotypes of murmurs do not require additional evaluation: murmurs that are notindicative of an underlying abnormality, and murmurs that can be ascribed to abenign underlying condition that requires neither specific therapy nor follow-up. Examples of the former type include innocent systolic flow murmurs andthe continuous murmurs of a venous hum or mammary soufflé. The most com-

65

Goldschlager N, Epstein AE, Grubb BP,Olshansky B, Prystowsky E, Roberts WC,et al. Etiologic considerations in the patientwith syncope and an apparently normalheart. Arch Intern Med. 2003;163:151-62.PMID: 12546605Kapoor WN, Karpf M, Wieand S,Peterson JR, Levey GS. A prospective evaluation and follow-up of patients withsyncope. N Engl J Med. 1983;309:197-204.PMID: 6866032

Evaluation of a Murmur

66

mon example of the latter type is a murmur of aortic sclerosis in an elderlypatient. Innocent flow murmurs typically are soft, mid-systolic murmurs with-out significant radiation. The murmur of aortic sclerosis is differentiated fromthat of aortic stenosis by its characteristics (less harsh than aortic stenosis, peak-ing in the first half of systole, and not encompassing S2), the absence of changesin the contour of peripheral pulses, and the absence of symptoms. The presenceof symptoms in conjunction with a systolic murmur or the presence of any dias-tolic murmur should initiate further evaluation with echocardiographic imaging.

K E Y P O I N T S

• A murmur may be innocent or mayreflect an underlying cardiac pathology.

• The characteristics of the murmur andthe presence of symptoms determinewhether echocardiographic imaging is required.

• A diastolic murmur is never normal.

TABLE 22 Characteristics of Cardiac Murmurs

Effect of AssociatedType Timing Quality Location Radiation Maneuvers Findings

Systolic

Innocent flow Mid-systolic Soft; crescendo– Base Variable; None Nonemurmur decrescendo usually none

Aortic sclerosis Early- to mid- Crescendo– Base (right None Decrease with Nonesystolic decrescendo 2nd ICS) handgrip or

standing

Aortic stenosis Mid- to late- Harsh; crescendo– Base (right Carotids; Decrease with Diminished A2;systolic decrescendo 2nd ICS) sometimes apex handgrip or pulses delayed

standing and diminished

Hypertrophic Variable systolic Late-peaking Base Carotids Decrease with Pulses bifidobstructive handgrip; increase cardiomyopathy with standing

Mitral Usually pan- Blowing; Apex Variable; axilla Increase with Left ventricularregurgitation systolic holosystolic if central jet handgrip enlargement

Tricuspid Usually pan- Blowing; Lower left Lower right Increase with Prominent V-regurgitation systolic holosystolic sternal border sternal border inspiration wave in neck;

hepaticpulsation

Pulmonic stenosis Mid- to late- Crescendo– Left 2nd ICS Left sternal Increase with Widely split S2systolic decrescendo border inspiration

Ventricular Pan-systolic High-pitched, Left sternal Precordium Palpable thrillseptal defect peaking in border

mid-systole

Diastolic

Aortic Pan-diastolic or High-pitched; Left sternal Variable; none Loudest at end- Enlarged apical regurgitation early diastolic decrescendo border or apex expiration with impulse; wide

patient leaning pulse pressureforward

Mitral stenosis Variable; early Decrescendo; low- Apex None (usually Loudest with Possiblediastole or pan- pitched rumble localized to patient in left opening snapdiastolic; small area) lateral decubitus presystolic positionaccentuation if sinus rhythm

Pulmonic Pan-diastolic or Decrescendo Left 2nd–3rd ICS Left sternal None Right ventricularregurgitation early diastolic border heave

Tricuspid stenosis Early diastolic or Decrescendo; Left lower None Increase with Possible pan-diastolic; low-pitched sternal border inspiration opening snappresystolic rumbleaccentuation if sinus rhythm

Continuous

Patent ductus Continuous Machinery-like Left 2nd– Backarteriosus 3rd ICS

ICS = intercostal space

Aortic Stenosis

Aortic Stenosis• How is severe aortic stenosis determined?• Does anything affect the progression of aortic stenosis?• Do asymptomatic patients with severe aortic stenosis have an adverse prognosis?• What are the indications for aortic valve replacement?• How are patients with severe stenosis and secondary ventricular systolic dysfunction

differentiated from those with primary cardiomyopathy and mild or moderate stenosis?

Aortic stenosis in adults is predominantly caused by calcific degeneration.Rheumatic aortic stenosis typically is accompanied by aortic regurgitation andinvolvement of the mitral valve. Congenital aortic stenosis is seen in childrenand in younger adults. The normal area of the aortic valve in adults is 3.0 to 4.0cm2. Symptoms usually are not present unless aortic stenosis is severe, typicallydefined as a valve area less than 1.0 cm2 and mean transvalvular gradient greaterthan 50 mm Hg. Two important considerations apply to the assessment of aorticstenosis severity. First, gradients depend on flow and may be low despite severestenosis in the setting of left ventricular systolic dysfunction. Second, valve areashould be considered in relation to patient size: Whereas a 1.0 cm2 valve areamay not reflect severe stenosis in a small patient, it may be associated withhemodynamic significance and symptoms in a larger person. Adjusting the calculatedaortic valve area by body surface area is the most widely used method to accountfor patient size. An aortic valve area of 0.45 cm2/m2 is considered severe.

Evidence is accumulating that aortic stenosis is related to other atheroscle-rotic vascular lesions in its association with cardiac risk factors, especially low-density lipoprotein cholesterol level (Pohle et al.). Retrospective data demon-strate an inverse correlation between statin therapy and progression of aorticstenosis; although large, prospective trials to test efficacy of therapy are not yet reported.

67

Pohle K, Maffert R, Ropers D, Moshage W,Stilianakis N, Daniel WG, Achenbach S.Progression of aortic valve calcification: association with coronary atherosclerosis and cardiovascular risk factors. Circulation.2001;104:1927-32. PMID: 11602496

F I G U R E 1 6 .Suggested approach to the evaluation of a cardiac murmur.

Murmur

Systolic Diastolic

No Symptoms Cardiac Symptoms

Murmur Grade <3/6

Murmur Grade ≥3/6 orHolosystolic, ejectionclick

OBSERVATION ECHOCARDIOGRAPHY

Aortic Stenosis

68

Aortic stenosis has a long latent period in which stenosis gradually worsenswithout symptoms or an adverse prognosis. Angina, heart failure, or syncopesuggests progression to hemodynamic instability and a poor prognosis withoutintervention. Aortic valve replacement is indicated in almost all patients withsymptomatic aortic stenosis. Advanced age is not a contraindication to surgery,although comorbid diseases and left ventricular systolic dysfunction increasesurgical risk. Balloon valvotomy can be used in young patients with noncalcificaortic stenosis. Among older adults, substantial procedure-related risk andrestenosis within 1 year limit balloon valvotomy to a temporizing role in symp-tomatic patients who are not surgical candidates.

Asymptomatic patients with severe aortic stenosis have a good prognosis.The rate of progression to symptoms is variable. Although there are reports ofsudden cardiac death among asymptomatic patients, death appears to be pre-ceded by the onset of symptoms (Rosenhek et al.). Aortic valve replacementmay be reasonable in some asymptomatic patients if there is evidence of left ven-tricular systolic dysfunction, marked left ventricular hypertrophy, moderate orgreater valve calcification coupled with a rapid increase in aortic jet velocity, ora hypotensive response on exercise testing. The recommended frequency ofechocardiographic testing in the patient with asymptomatic aortic stenosis isbased on severity: every 5 years in mild aortic stenosis, even 2 years in moder-ate aortic stenosis, and yearly in severe aortic stenosis. The latter is recom-mended primarily to detect the development of asymptomatic left ventriculardysfunction.

Although exercise testing is contraindicated in the symptomatic patientwith severe aortic stenosis, a carefully supervised exercise test in the asympto-matic patient may provide clinically useful information. Severely reduced exer-cise tolerance may be demonstrated in patients without symptoms. In addition,an adverse hemodynamic response to exercise with a decrease in blood pressuremay be an indication for surgical intervention, according to recent guidelines.

Patients with severe aortic stenosis and secondary left ventricular systolicdysfunction can be difficult to distinguish from those with primary cardiomy-opathy and mild or moderate stenosis. In both cases, valve motion is diminished(because of stenosis in the former and low flow in the latter) and aortic valvegradients are not high. Doppler echocardiography during dobutamine infusionis useful to differentiate and guide therapy in such patients. Contractile reservewith a sharp increase in gradients suggests significant stenosis, whereas stablegradients during increased flow suggest less severe stenosis. Aortic valve replace-ment is associated with better long-term survival compared with medical ther-apy if there is severe stenosis with contractile reserve; conversely, valve replace-ment is associated with reduced survival compared with medical therapy inpatients without contractile reserve (Monin et al.).

There is an added risk for noncardiac surgery in a patient with severe aor-tic stenosis. When elective surgery is required in a patient with severe sympto-matic stenosis, aortic valve replacement should be performed before noncardiacsurgery, as the mortality rate in these patients may be as high as 10%.Occasionally, percutaneous balloon valvuloplasty may be considered when thepatient is not a candidate for aortic valve replacement. If the patient is asymp-tomatic, surgery can be performed with close intraoperative monitoring, withonly slightly increased risk.

Rosenhek R, Binder T, Porenta G, Lang I,Christ G, Schemper M, et al. Predictors of outcome in severe, asymptomatic aorticstenosis. N Engl J Med. 2000;343:611-7.PMID: 10965007Monin JL, Monchi M, Gest V, Duval-Moulin AM, Dubois-Rande JL, Gueret P.Aortic stenosis with severe left ventriculardysfunction and low transvalvular pressuregradients: risk stratification by low-dosedobutamine echocardiography. J Am CollCardiol. 2001;37:2101-7. PMID: 11419894

K E Y P O I N T S

• Aortic valve gradients are affected byflow; valve area should be assessed inthe context of patient size.

• Progression of aortic stenosis is relatedto cardiac risk factors.

• Asymptomatic patients with severe aortic stenosis have a good prognosis.

• Aortic valve replacement should be con-sidered in patients with symptomaticsevere aortic stenosis and in someasymptomatic patients with severestenosis and left ventricular dysfunc-tion, marked left ventricular hypertro-phy, hypotension on exercise testing, ormoderate or greater valve calcificationand a rapid increase in aortic jet velocity.

• Dobutamine echocardiography helpsidentify patients with severe stenosisand secondary left ventricular systolicdysfunction. Severe stenosis with contractile reserve suggests a morefavorable prognosis with surgery.

Mitral Stenosis

Mitral Stenosis• What medical therapy is available for mitral stenosis?• Which patients with mitral stenosis require anticoagulation?• What are the options and indications for intervention in mitral stenosis?• How are pregnant women who require intervention best treated?

Nearly all mitral stenosis in adults is due to previous rheumatic heart disease.Congenital mitral stenosis may be seen in children and adolescents. The normalmitral valve area is 4.0 to 5.0 cm2; moderate and severe stenosis are defined asa valve area of 1.0 to 1.5 cm2 and less than 1.0 cm2, respectively. Symptoms typ-ically do not occur until stenosis is moderate or severe. Because of the increasein heart rate associated with a shorter diastolic filling period, physical exercise,emotional stress, fever, pregnancy, and atrial fibrillation all exacerbate symptomsof mitral stenosis.

Medical therapy for mitral stenosis is limited to antibiotic prophylaxisagainst infective endocarditis and rheumatic fever, salt restriction or diuretics(or both), and negative chronotropic agents to prolong the diastolic fillingperiod. Rheumatic fever prophylaxis should be given for at least 10 years afterthe last episode or until 40 years of age. Indefinite or lifelong prophylaxis isindicated in patients with frequent streptococcal exposure (teachers, for exam-ple). Long-term anticoagulation is indicated for those with chronic or paroxys-mal atrial fibrillation or a prior thromboembolic event. Mechanical interven-tions include percutaneous balloon mitral valvotomy, open and closed commis-surotomy, and mitral valve replacement. Relative merits of the procedures aresummarized in Table 23.

Intervention for mitral stenosis is indicated earlier among patients who arecandidates for percutaneous balloon mitral valvotomy. Echocardiographic valvecharacteristics that predict the success of percutaneous balloon mitral valvotomyinclude the extent and severity of leaflet thickening, leaflet calcification, loss ofleaflet pliability, and subvalvular involvement. Significant (3+ or 4+) mitralregurgitation or a left atrial thrombus are contraindications. Percutaneous bal-loon mitral valvotomy should be considered in symptomatic patients with mod-erate or severe stenosis and favorable valve morphology; in asymptomaticpatients with favorable valve morphology and evidence of pulmonary hyper-tension; and in patients with a nonpliable, calcified valve but New York Heart

69

TABLE 23 Comparison of Interventions in Mitral Stenosis

Intervention Advantages Disadvantages Patient Selection

Percutaneous Percutaneous approach; Requires favorable valve Pliable, non-calcified balloon mitral equivalent hemodynamic anatomy; absence of significant valve, ≤2+ mitral regurgitation, valvotomy results to open commissurotomy mitral regurgitation or left no other cardiac

in selected patients atrial thrombus intervention required

Closed Avoids cardiac arrest and Less reproducible hemodynamic Only used in developing commissurotomy cardiopulmonary bypass results than with percutaneous countries

balloon or open commissurotomy

Open Good hemodynamic results in Major surgical procedure with Relatively pliable, noncalcified commissurotomy selected patients; mitral cardiopulmonary bypass valve, any amount of mitral

regurgitation can be treated; regurgitation, other cardiac feasible to perform additional intervention requiredsurgical procedures

Mitral valve Feasible for valves with heavy Major surgical procedure with Calcified, nonpliable valves not replacement valvular and subvalvular cardiopulmonary bypass; suitable for percutaneous

sclerosis, calcification, with or morbidity, mortality, balloon valvotomy or open without mitral regurgitation anticoagulation associated commissurotomy

with valve prosthesis

Chronic Mitral and Aortic Regurgitation

70

Association class III or IV symptoms who are at high risk for surgery. Unlikeaortic valvotomy, restenosis occurs relatively slowly among appropriatelyselected patients after percutaneous balloon mitral valvotomy. Echo-cardiographic characteristics of valve morphology are predictors of restenosis(Wang et al.). In pregnant women requiring therapy for mitral stenosis, per-cutaneous balloon mitral valvotomy has a high success rate and is associatedwith fewer fetal complications compared with open commissurotomy (deSouza et al.).

In patients with asymptomatic mitral stenosis, yearly echocardiography isnot recommended. Echocardiography should be performed promptly whenthere is a change in symptoms. The presence of mild to moderate pulmonaryhypertension (pulmonary artery systolic pressure >40 mm Hg) may be an indi-cation for more frequent follow-up.

Chronic Mitral and Aortic Regurgitation• What medical therapy is available for severe aortic or mitral regurgitation?• What are the indications for surgical intervention?• What are the respective advantages of mitral valve repair and replacement?

Mitral regurgitation is caused by abnormalities of the mitral leaflets (organicmitral regurgitation, including myxomatous degeneration, rheumatic valve disease, and infective endocarditis) or is secondary to dilation of or geometricchanges affecting the left ventricle (dilated cardiomyopathy or prior myocardialinfarction). Aortic regurgitation is caused by abnormalities of the aortic cusps(including infective endocarditis, rheumatic valve disease, and calcific degener-ation) or is secondary to dilation or dissection of the ascending aorta.

Both aortic and mitral regurgitation are conditions of chronic left ventric-ular volume overload. Forward cardiac output is preserved by compensatoryleft ventricular chamber dilation with eccentric hypertrophy, but at the expenseof increased wall stress. Afterload is increased in chronic severe aortic regurgi-tation but is normal or decreased in chronic mitral regurgitation. In bothlesions, symptoms occur late and typically after the onset of irreversible left ven-tricular systolic dysfunction. Therefore, intervention should ideally precede theonset of symptoms.

Medical therapy for both aortic and mitral regurgitation should includeprophylaxis against infective endocarditis. Patients with chronic severe aorticregurgitation and systolic hypertension benefit from vasodilator therapy with anangiotensin-converting enzyme inhibitor or a calcium channel blocker.Vasodilator therapy may delay the onset of heart failure or need for surgery butis not a substitute for surgical intervention.

In mitral regurgitation, the role of afterload reduction depends on thechronicity of the lesion and on the mechanism of mitral regurgitation (organicor functional). Although vasodilators improve hemodynamics in patients withacute mitral regurgitation, their role in chronic severe organic mitral regurgita-tion has not been adequately studied. Thus, in asymptomatic patients who donot have an indication for surgical intervention, routine use of afterload reduc-tion is not recommended. If there is coexistent hypertension, vasodilator therapyshould be used in lieu of alternative therapy, such as a β-blocker. In contrast,afterload reducers are indicated in patients with functional mitral regurgitationcomplicating underlying cardiomyopathy of ischemic or nonischemic etiology.

Recommendations for serial echocardiography in asymptomatic patientswith aortic or mitral regurgitation are based on lesion severity: only in the pres-ence of new symptoms or a change on examination in mild regurgitation, yearlyin moderate regurgitation, and every 6 to 12 months in severe regurgitation. In

K E Y P O I N T S

• Medical therapy for mitral stenosisincludes antibiotic prophylaxis, heartrate control, and salt restriction ordiuretics (or both).

• Anticoagulation is indicated for atrialfibrillation or prior thromboembolicevent.

• Intervention options include percuta-neous balloon mitral valvotomy, opencommissurotomy, and mitral valvereplacement.

• Echocardiographic variables predict thelikelihood of success and of restenosiswith percutaneous balloon mitral valvotomy.

• In pregnant women, percutaneous bal-loon mitral valvotomy is associated withfewer fetal complications comparedwith open commissurotomy.

Wang A, Krasuski RA, Warner JJ, Pieper K,Kisslo KB, Bashore TM, Harrison JK.Serial echocardiographic evaluation ofrestenosis after successful percutaneous mitral commissurotomy. J Am Coll Cardiol.2002;39:328-34. PMID: 11788227de Souza JA, Martinez EE Jr, Ambrose JA,Alves CM, Born D, Buffolo E, Carvalho AC.Percutaneous balloon mitral valvuloplasty incomparison with open mitral valve commis-surotomy for mitral stenosis during preg-nancy. J Am Coll Cardiol. 2001;37:900-3.PMID: 11693768

Acute Valvular Regurgitation

severe regurgitation, the shorter interval between echocardiograms is recom-mended when the ventricular dimensions begin to approach those that wouldwarrant surgery.

Surgical intervention for aortic regurgitation is usually aortic valve replace-ment, although aortic valve reconstructive procedures may be feasible in aselected group of young patients with congenital, noncalcific disease. Surgery isindicated in symptomatic patients, those with left ventricular systolic dysfunc-tion and asymptomatic patients with severe aortic regurgitation and marked leftventricular dilation (end-systolic diameter >50 to 55 mm or end-diastolic diam-eter >70 to 75 mm, although patient size should be considered).

Surgical intervention for mitral regurgitation includes mitral valve repairand mitral valve replacement with or without chordal preservation (Table 24).Survival is superior after mitral valve repair compared with replacement, anddurability is equivalent (Mohty et al.). Surgery should be considered forpatients with severe mitral regurgitation and symptoms and in asymptomaticpatients with atrial fibrillation, pulmonary hypertension, or evidence of left ven-tricular systolic dysfunction (ejection fraction ≤60% or end-systolic diameter≥45 mm). Intervention should be considered earlier if successful mitral valverepair is likely. Ischemic mitral regurgitation (caused by alteration of left ven-tricular geometry after myocardial infarction) is associated with a poor progno-sis and is not adequately treated with revascularization alone (Aklog et al.).

The anorectic drugs fenfluramine (alone or in combination with phenter-mine) and dexfenfluramine have been associated with acquired mitral and aortic valve regurgitation among patients exposed for longer than 6 months, withhigher risk among those exposed for more than 2 years. Regurgitation appearsto regress in the first year after discontinuation of exposure (Mast et al.,Weissman et al.).

Acute Valvular Regurgitation• What are the causes of acute severe aortic or mitral regurgitation?• How are these conditions diagnosed?• What treatments are useful in patients with acute severe aortic or mitral regurgitation?

Acute severe aortic regurgitation is caused by infective endocarditis, ascendingaortic dissection, or trauma. Because the left ventricle has not had time to com-pensate with chamber dilation and eccentric hypertrophy, left ventricular dias-tolic pressure increases. Despite reflex tachycardia, stroke volume and forwardcardiac output decrease, with resulting pulmonary edema and cardiogenicshock. Many of the physical findings in chronic aortic regurgitation are absent:There is no increase in pulse pressure, and the diastolic murmur is soft and ofshort duration. Diagnosis is made by transthoracic or transesophageal echocar-diography. Medical therapy includes nitroprusside and inotropic agents. Intra-aortic balloon counterpulsation is contraindicated. Increasing the heart rate byusing chronotropic agents or temporary pacing decreases the diastolic periodand lessens the severity of regurgitation. Emergent aortic valve replacement isrequired for patients with cardiogenic shock.

Acute severe mitral regurgitation is caused by valve destruction complicat-ing infective endocarditis, papillary muscle rupture complicating acute myo-cardial infarction, or chordal rupture complicating myxomatous degeneration.Similar to acute severe aortic regurgitation, the absence of compensatory leftventricular dilation and eccentric hypertrophy associated with chronic regurgi-tation result in a decrease in forward stroke volume and cardiac output. Theabrupt increase in left atrial volume is not accommodated by the normal-sizedleft atrium, resulting in pulmonary edema. In acute severe mitral regurgitation,

71

K E Y P O I N T S

• Vasodilator therapy is useful in asymp-tomatic patients with severe aorticregurgitation and systolic hypertension.

• Indications for aortic valve replacementin chronic severe aortic regurgitationinclude symptoms, left ventricular sys-tolic dysfunction, or significant left ventricular dilation.

• Indications for surgery in chronic severemitral regurgitation include symptoms,left ventricular systolic dysfunction,atrial fibrillation, or pulmonary hypertension.

• Intervention for chronic severe mitralregurgitation should be considered earlier if successful mitral valve repair is likely.

• Ischemic mitral regurgitation is not ade-quately treated with revascularizationalone.

• Aortic and mitral regurgitation appearto regress in the first year after discon-tinuation of exposure to the anorecticdrugs fenfluramine and dexfenfluramine.

Mohty D, Orszulak TA, Schaff HV,Avierinos JF, Tajik JA, Enriquez-Sarano M.Very long-term survival and durability ofmitral valve repair for mitral valve prolapse.Circulation. 2001;104(Suppl 1):I1-I7.PMID: 11568020Aklog L, Filsoufi F, Flores KQ, Chen RH,Cohn LH, Nathan NS, et al. Does coro-nary artery bypass grafting alone correctmoderate ischemic mitral regurgitation?Circulation. 2001;104(Suppl 1):I68-75.PMID: 11568033Mast ST, Jollis JG, Ryan T, Anstrom KJ,Crary JL. The progression of fenfluramine-associated valvular heart disease assessed byechocardiography. Ann Intern Med.2001;134:261-6. PMID: 11182835Weissman NJ, Panza JA, Tighe JF,Gwynne JT. Natural history of valvularregurgitation 1 year after discontinuation of dexfenfluramine therapy. A randomized,double-blind, placebo-controlled trial. Ann Intern Med. 2001;134:267-73.PMID: 11182836

Mitral Valve Prolapse

72

the murmur may not be holosystolic, and the apical impulse is not hyper-dynamic. Diagnosis is made by transthoracic or transesophageal echocardiogra-phy. Medical therapy includes nitroprusside with or without inotropic agents.Intra-aortic balloon counterpulsation increases forward cardiac output and canbe a useful temporizing measure. Urgent or emergent surgical intervention maybe required.

Mitral Valve Prolapse• What is mitral valve prolapse?• What is the prognosis of patients with mitral valve prolapse?

Mitral valve prolapse is defined by systolic billowing of one or both mitralleaflets into the left atrium. Although rheumatic and ischemic diseases can leadto mitral valve prolapse, the term is typically used to describe primary myxo-matous degeneration of the valve. True mitral valve prolapse should be differ-entiated from pseudoprolapse caused by dehydration or annular distortion.Mitral valve prolapse due to myxomatous degeneration is accompanied byleaflet thickening or some amount of mitral regurgitation (or both). The highprevalence of mitral valve prolapse reported in the past among asymptomaticyoung women likely reflects inappropriate diagnoses based on echocardio-graphic imaging.

Most patients with mitral valve prolapse have a good prognosis. Patientswith significant leaflet thickening are predisposed to premature degeneration ofthe valve and mitral regurgitation. The risk of infective endocarditis is increased,and antibiotic prophylaxis is warranted if there is leaflet thickening on echocar-diography or auscultory or echocardiographic evidence of mitral regurgitation.Palpitations and atypical chest pain occur as part of the mitral valve prolapsesyndrome. Palpitations caused by nonsustained atrial or ventricular tachyar-rhythmias often respond to therapy with a β-adrenergic antagonist. There is alow (<1% per year) incidence of sudden death associated with mitral valve pro-lapse. Using the current standards for diagnosis, risk for embolic or cryptogenicneurologic events does not seem to be increased among patients with mitralvalve prolapse.

Prosthetic Valves• What are the relative merits of different valve prostheses?• How should anticoagulation be managed in patients with a mechanical prosthesis?• What criteria should be considered in the selection of a valve prosthesis?

K E Y P O I N T S

• Patients with acute severe aortic ormitral regurgitation are symptomaticand may present with cardiogenicshock.

• Many physical findings associated withchronic severe regurgitation are notpresent in patients with acute severeregurgitation.

• Diagnosis is made with transthoracic ortransesophageal echocardiography.

• Nitroprusside with or without inotropicagents may improve hemodynamics.

• Intra-aortic balloon counterpulsation isuseful in patients with acute severemitral regurgitation but is contraindicatedin patients with aortic regurgitation.

• Urgent or emergent surgical interven-tion is usually indicated in acute mitralor aortic regurgitation.

K E Y P O I N T S

• Most patients with mitral valve prolapsehave a good prognosis.

• Patients with myxomatous disease areat risk for premature valve degenera-tion with mitral regurgitation.

• Endocarditis prophylaxis should be usedin patients with mitral regurgitation orleaflet thickening.

TABLE 24 Comparison of Interventions in Mitral Regurgitation

Intervention Advantages Disadvantages Patient Selection

Mitral valve repair Preserves MV apparatus and Technically more demanding; Most patients with myxomatous chords; preserves LV function; not feasible for all valves degeneration, ischemic MR; some avoids prosthesis-related patients with infective complications and anticoagulation endocarditis, rheumatic disease

Mitral valve Relative preservation of LV Prosthesis-related complications, Most unrepairable valvesreplacement with function; feasible in most patients anticoagulationchordal preservation

Mitral valve Feasible in any patient LV systolic dysfunction; prosthesis- Patients with rheumatic disease replacement without related complications; and unrepairable valves, severe chordal preservation anticoagulation subvalvular sclerosis, calcification

LV = left ventricle; MR = mitral regurgitation; MV = mitral valve

Prosthetic Valves

Heart valve prostheses can be divided into three main groups: mechanical pros-theses (caged ball, tilting disk, and bileaflet valves), stented bioprostheses(porcine xenograft or constructed bovine pericardial valves), and stentless bio-logic valves (autograft, allograft, or stentless xenograft valves). The features ofeach type are summarized in Table 25.

Bioprosthetic valves are more durable in older compared with youngerpatients and in the aortic compared with the mitral position. Thromboembolicrisk is lower for tissue than for mechanical prostheses and lower for the sameprosthesis type in the aortic compared with the mitral position. Mechanicalprostheses have the advantage of increased durability, whereas bioprostheseshave a lower thromboembolic potential and obviate the need for long-termanticoagulation. However, freedom from valve-related adverse events is similarat 11 years among patients having undergone mechanical and tissue valvereplacement (Hammermeister et al.). More patients with a tissue prosthesissuffer structural failure and require reoperation, whereas more patients with amechanical prosthesis suffer a thromboembolic or serious hemorrhagic event.Valve replacement with a stentless bioprosthesis is more technically demanding,although hemodynamics and durability are better than with stented biopros-theses (Pibarot and Dumesnil).

Patients with a prosthetic valve require prophylaxis against endocarditis.Recommendations for anticoagulation therapy are summarized in Table 26. Atthe time of writing, no data support the use of low-molecular-weight heparinas a substitute for warfarin or intravenous heparin. During noncardiac or den-tal surgery, anticoagulation for a prosthetic valve should be interrupted for theminimum feasible interval. Among patients at high risk for thrombosis orthromboembolism, intravenous heparin should be administered after the inter-national normalized ratio falls below 2.0, and again within 24 hours after sur-gery until warfarin treatment is reinitiated and the international normalizedratio is 2.0 or greater.

Mechanical valve dysfunction is due to thrombosis or pannus formation, orto fracture or dislodging of part of the occluder mechanism or its housing.Bioprosthetic dysfunction typically occurs with progressive calcification of the prosthesis, often complicated by cusp fracture and acute regurgitation.Diagnosis is based on a change in clinical status or physical examination, and issupported by transthoracic or transesophageal echocardiographic imaging.

The choice of prosthesis should take into consideration the patient’s age,comorbid conditions, lifestyle, and desires. Traditional recommendations werethat tissue valve replacement should be reserved for patients older than 65 to70 years of age because valve durability would suffice relative to the older

73

Hammermeister K, Sethi GK, HendersonWG, Grover FL, Oprian C, RahimtoolaSH. Outcomes 15 years after valve replace-ment with a mechanical versus a biopros-thetic valve: final report of the VeteransAffairs randomized trial. J Am Coll Cardiol.2000;36:1152-8. PMID: 11028464Pibarot P, Dumesnil JG. Hemodynamicand clinical impact of prosthesis-patient mis-match in the aortic valve position and itsprevention. J Am Coll Cardiol. 2000;36:1131-41. PMID: 11028462

TABLE 25 Comparison of Valve Prostheses

Prosthesis Construction Examples Advantages Disadvantages

Mechanical Prosthetic materials Caged-ball, tilting disk, Durability; good Thromboembolic risk; bileaflet hemodynamics in requires long-term

current generation anticoagulation

Stented bioprosthetic Strut-mounted Porcine xenograft, Lower thromboembolic Limited durability, tissue (porcine or bovine) constructed bovine risk than mechanical; especially in younger

pericardium no long-term patients; suboptimal anticoagulation hemodynamics with requirement smaller valve sizes

Stentless bioprosthetic Stentless tissue Autograft, allograft, Hemodynamics, Technically more (human or animal) stentless xenograft durability better demanding implantation;

than stented limited availability of bioprostheses allografts

Acute Pericarditis

74

patient’s shorter life expectancy. However, improved durability of second- andthird-generation stented bioprostheses, anticalcification therapies used withsome stentless and third-generation stented bioprostheses, and decreasing themortality rate associated with reoperation procedures have prompted a shifttoward greater use of bioprostheses in progressively younger patients. Becauseclinical outcomes for prosthetic valves are measured over years and decades andbecause prosthesis designs continue to evolve, patients and physicians mustmake choices about which prosthesis to use without outcome data from large,randomized trials.

Pericardial Disease, Restrictive Cardiomyopathy,and Hypertrophic Cardiomyopathy

The major pericardial diseases are acute pericarditis, recurrent pericarditis, peri-cardial effusion, and constrictive pericarditis. Restrictive cardiomyopathy is arare disorder of diastolic filling caused by myocardial fibrosis or infiltration.Hypertrophic cardiomyopathy is a genetic disease of the cardiac sarcomere.

Acute Pericarditis• What is the first-line therapy for acute pericarditis?• What is the role of corticosteroids in the treatment of acute pericarditis?

Acute pericarditis is inflammation or irritation of the pericardium (and often theepicardium) that is usually painful. Acute pericarditis has many etiologies, butmost often arises in the context of presumed viral upper respiratory tract infec-tion. Patients often present with a low-grade febrile illness and chest pain. Thechest pain is often position related or pleuritic in nature. Associated symptomsmay include diaphoresis, tachycardia, and tachypnea (because deep breaths arepainful). The hallmark feature on physical examination is a three-componentfriction rub. However, the absence of the friction rub does not exclude thediagnosis. An elevated erythrocyte sedimentation rate and characteristic electro-

K E Y P O I N T S

• Mechanical valves are more durablethan bioprosthetic valves but requirelong-term anticoagulation therapybecause of greater thromboembolic risk.

• Freedom from adverse valve-relatedevents at 11 years is similar for mechan-ical and bioprosthetic valves.

• Continuing advances in prosthesisdesign force patients and physicians tomake choices without outcome datafrom large, randomized trials.

TABLE 26 Recommendations for Anticoagulation in Patients with aProsthetic Heart Valve

Type of Prosthesis Warfarin, INR Aspirin, mg

Mechanical

First 3 months after replacement 2.5–3.5 80–100

>3 months after replacement

Aortic valve 2.0–3.0

Aortic valve + risk factors* 2.5–3.5 80–100

Mitral valve (with or without risk factors) 2.5–3.5 80–100

Tissue

First 3 months after replacement 2.5–3.5 80–100

>3 months after replacement

Aortic valve None 80–100

Aortic valve + risk factors* 2.0–3.0 80–100

Mitral valve None 80–100

Mitral valve + risk factors* 2.5–3.5 80–100

INR = international normalized ratio

*Atrial fibrillation, left ventricular systolic dysfunction, previous thromboembolic event, or hypercoagulable state.

Recurrent Pericarditis

cardiographic finding of diffuse ST elevation and PR depression support theclinical diagnosis. About 50% of patients with acute pericarditis have an effusionon echocardiography; however, this feature cannot be used for clinical diagno-sis. The primary role of echocardiography is to detect pericardial effusion inpatients with elevated jugular venous pressure or signs and symptoms of con-gestive heart failure. Other tests that may useful to guide the clinical manage-ment include cardiac biomarkers in patients with increased risk for coronaryartery disease or autoimmune evaluation in patients with recurrent pericarditis.

The first-line therapy for acute pericarditis is a nonsteroidal anti-inflamma-tory agent in relatively high doses for 2 to 4 weeks. Steroids are effective inrelieving symptoms, but they should be avoided because pericarditis tends torecur whenever the steroid dose is decreased.

Recurrent Pericarditis• When is pericarditis more likely to recur?• What is the role of colchicine in the treatment of recurrent pericarditis?

Recurrent pericarditis is manifested by return of symptoms and signs of inflam-mation (elevated erythrocyte sedimentation rate) within days to weeks after dis-continuing the anti-inflammatory drug used to treat the initial episode of acutepericarditis. It tends to occur more often when corticosteroids are used in themanagement of acute pericarditis or when systemic inflammation is ongoing.Examples of the latter situation include rheumatologic disorders, Dressler’s syn-drome (pleuropericarditis after acute myocardial infarction), or the post-peri-cardiotomy syndrome. Recurrent pericarditis usually responds to high-doseaspirin, salicylate, or other nonsteroidal anti-inflammatory drugs. In recurrentpericarditis, these agents should be used for at least 1 month, with slow taper-ing of the dose thereafter. Nonrandomized, observational studies indicate thatthe addition of colchicine (1 mg/d, in divided doses) can aid in the initial man-agement of recurrent pericarditis (Adler et al.). The need for a loading dose of2 to 3 mg/d is unproven. Long-term maintenance therapy with colchicine (0.5mg once or twice daily) has also been observed to prevent subsequent recur-rence (Oakley).

Pericardial Effusion• What is needed to make the diagnosis of pericardial tamponade?• When should therapeutic pericardiocentesis be performed?

Pericardial effusions have the same etiology as acute pericarditis. Most peri-cardial effusions do not result in cardiac tamponade or clinical symptoms.Hemodynamic consequences are related to the rapidity of fluid accumulationrather than the absolute volume of fluid. Low voltage identified on 12-leadelectrocardiography (with or without electrical alternans) or an enlarged cardiacsilhouette can suggest effusion. Echocardiography is the preferred imagingtechnique in most cases, but computed tomography and magnetic resonanceimaging can also readily demonstrate pericardial effusion.

Cardiac tamponade occurs when pericardial effusion restricts diastolic leftor right ventricular filling. Patients have signs and symptoms of reduced cardiacoutput, including tachycardia, breathlessness, elevated jugular venous pressure,hypotension, and exaggerated pulsus paradoxus. The echocardiogram can con-firm the clinical suspicion of effusion and can even show signs of preclinicalhemodynamic compromise, the classic echocardiographic finding of pericardialtamponade. Pericardiocentesis is the treatment for clinical cardiac tamponade.

75

K E Y P O I N T S

• Nonsteroidal anti-inflammatory drugsare the therapy of choice for acute pericarditis.

• Corticosteroids should be avoided in the treatment of acute or recurrentpericarditis.

Adler Y, Finkelstein Y, Guindo J,Rodriguez de la Serna A, Shoenfeld Y,Bayes-Genis A, et al. Colchicine treatmentfor recurrent pericarditis. A decade of experience. Circulation. 1998;97:2183-5.PMID: 9626180Oakley CM. Myocarditis, pericarditis and other pericardial diseases Heart.2000;84:449-54. PMID: 10995424

K E Y P O I N T S

• The use of corticosteroids in the treat-ment of acute pericarditis can lead torecurrent pericarditis when the dose isdecreased.

• The addition of colchicine, 1 mg/d, to anonsteroidal anti-inflammatory drugregimen can facilitate the treatment ofrecurrent pericarditis.

Constrictive Pericarditis

76

Classically, pericardiocentesis has been performed using a subxyphoid blindapproach. In current practice, echocardiography can help identify sites for peri-cardiocentesis and should be used as a routine part of the procedure. A peri-cardial drainage catheter is often left in place until there is no further accumu-lation of pericardial fluid. In rare cases, resection of the pericardium may benecessary for chronic, recurrent effusions (Tsang et al.).

Constrictive Pericarditis• What is needed to diagnose constrictive pericarditis?

Constrictive pericarditis is a contraction of the pericardium, often due tochronic inflammation, that prevents the heart from filling completely. The con-dition is manifest by signs and symptoms of overt right-heart failure (venouscongestion) and poor cardiac output that are out of proportion to the degreeof left ventricular dysfunction or valvular heart disease that may be present.Peripheral edema, ascites, jugular venous distention, fatigue, and dyspnea maybe seen. Currently, the main differential diagnosis is restrictive cardiomyopathy(Hancock). The etiology of constrictive pericarditis is similar to that of theother pericardial processes, with the addition of a history of radiation therapyto the chest (often used to treat breast cancer or Hodgkin’s lymphoma).Differentiating restrictive cardiomyopathy from constrictive pericarditis can bevery challenging and often requires a full spectrum of diagnostic techniques,both noninvasive and invasive. Complicating the diagnostic evaluation is therelatively frequent coexistence of these two conditions, especially in the case ofradiation-induced disease.

Pericardial calcification on chest radiography is highly suggestive of con-strictive pericarditis but is present in fewer than 50% of patients with this diag-nosis. Echocardiography is the primary diagnostic tool for the diagnosis of con-strictive pericarditis, with well-described morphologic and Doppler character-istics. Newer Doppler echocardiography techniques, such as Doppler tissueimaging, have been helpful in differentiating constriction from restriction.Computed tomography and magnetic resonance imaging can readily detect thepresence of pericardial thickening; however, constriction can be seen with nor-mal pericardial thickness in approximately 10% of patients. Finally, cardiaccatheterization with simultaneous pressure recordings from the right and left ven-tricles demonstrating equalization of the diastolic pressures may be required toconfirm constriction. Complete pericardiectomy is the treatment of choice forconstrictive pericarditis. Although some patients with mild symptoms may bemanaged with careful use of diuretics, the operative mortality rate is significant ifpericardiectomy is delayed until advanced symptoms (New York Heart Associationclass III or IV) are present. While the majority of patients will improve after peri-cardectomy, the clinical recovery is often delayed for months and there may becontinued evidence of diastolic abnormalties on echocardiography (Senni et al.).The worst outcome after pericardectomy, including the highest mortality rate andthe least improvement, is seen in radiation-associated disease.

Restrictive Cardiomyopathy• When should restrictive cardiomyopathy be suspected?• What are the factors that influence prognosis in restrictive cardiomyopathy?

Restrictive cardiomyopathy is in the differential diagnosis of any patient pre-senting with signs and symptoms of congestive heart failure. Generally, patientshave nondilated and nonhypertrophied ventricles with preserved systolic function.

K E Y P O I N T S

• Cardiac tamponade is a clinical, bedsidediagnosis and is effectively treated withpericardiocentesis of the presence oftamponade is confirmed by detection of an effusion, usually on echocardiog-raphy and supported by additionalDoppler-echocardiographic signs.

• Pericardiocentesis is ideally performedin a controlled setting, such as the cardiac catheterization laboratory, byphysicians with experience in this tech-nique. Guidance with echocardiographycan reduce associated complications.

Tsang TS, Seward JB, Barnes ME, BaileyKR, Sinak LJ, Urban LH, Hayes SN.Outcomes of primary and secondary treat-ment of pericardial effusion in patients withmalignancy. Mayo Clin Proc. 2000;75:248-53. PMID: 10725950Hancock EW. Differential diagnosis ofrestrictive cardiomyopathy and constrictivepericarditis. Heart. 2001;86:343-9.PMID: 11514495Senni M, Redfield MM, Ling LH,Danielson GK, Tajik AJ, Oh JK. Left ven-tricular systolic and diastolic function afterpericardiectomy in patients with constrictivepericarditis: Doppler echocardiographic find-ings and correlation with clinical status. J AmColl Cardiol. 1999;33:1182-8.PMID: 10193714

K E Y P O I N T S

• Constrictive pericarditis should be sus-pected in any patient with profoundsigns and symptoms of right-heart fail-ure that are out of proportion to anyventricular or valvular abnormalities.Differentiating constrictive pericarditisfrom restrictive cardiomyopathy oftenrequires a full spectrum of noninvasiveand invasive tests, including simultane-ous right and left heart catheterization.

• Up to 10% of patients with pericardialconstriction have no demonstrable peri-cardial thickening on computed tomog-raphy or magnetic resonance imaging.

• While the majority of patients willimprove clinically following completepericardectomy, recovery may bedelayed for months.

• In radiation-associated pericardial dis-ease, there may be coexistent restrictivecardiomyopathy, and the prognosis evenwith pericardectomy is poor.

Hypertrophic Cardiomyopathy

Some infiltrative diseases, such as cardiac amyloidosis, result in secondary restric-tive cardiomyopathy, but with increased left ventricular wall thickness. Additionalechocardiographic features include significant biatrial enlargement and Doppler evi-dence of advanced diastolic dysfunction. If the diagnosis of restrictive cardiomyopa-thy versus constrictive pericarditis remains uncertain after invasive and noninvasiveevaluations, right-heart biopsy may be indicated to detect infiltrative diseases, such asamyloid cardiomyopathy and hemochromatosis.

Treatment of restrictive cardiomyopathy is also difficult. Careful control of fluidbalance is crucial. Patients often present with indications of fluid excess but requirerelatively high preload to maintain cardiac output. Treatment of any underlying orcoexistent diseases that affect diastolic function (for example, hypertension, diabetes,or ischemic heart disease) is also essential. The prognosis of patients with restrictivecardiomyopathy is poor and influenced by the cause of the restrictive cardiomy-opathy, advancing age, worsening functional classification, and left atrial size(Ammash et al.).

In amyloid cardiomyopathy, use of digitalis and calcium channel blockersshould be avoided because binding of these agents to the amyloid protein mayincrease the risk of toxicity. Patients are unlikely to benefit from therapy with β-blockers. Conduction abnormalities often preclude their use. Moreover, becausestroke volume is reduced and relatively fixed, so reduction in heart rate may be asso-ciated with a significant decrease in cardiac output. In cardiomyopathy associatedwith primary amyloid, treatment with melphalan and prednisone may prolong sur-vival. In patients with familial amyloidosis associated with abnormal transthyretin,disease regression has been reported with liver transplantation. Cardiac transplanta-tion alone is not indicated because amyloid may accumulate in the graft, with even-tual development of restrictive cardiomyopathy.

Hypertrophic Cardiomyopathy• What is the genetic basis of hypertrophic cardiomyopathy, and how does it influence

screening?• What is the best strategy to assess for risk of sudden death in hypertrophic cardio-

myopathy?• How should hypertrophic cardiomyopathy be managed?• What are the indications for surgical versus percutaneous treatment strategies

in hypertrophic cardiomyopathy?

More than 150 mutations in at least 10 different genes have been associated withhypertrophic cardiomyopathy. Most of the mutations involve the proteins that makeup the cardiac sarcomere. These abnormal proteins may lead to secondary myo-cardial hypertrophy through alterations in sarcomeric function, or possibly to directhypertrophy. The mutations are transmitted in an autosomal dominant pattern. Thelarge number of mutations makes genetic screening impractical for general clinicaluse. Screening of family members of known affected persons continues to rely onphysical examination, electrocardiography, and echocardiography. Screening of rela-tives should be done periodically throughout adolescence and adulthood, as somemutations are known to have early and others, late clinical expression (penetrance)in the fifth or sixth decade of life (Maron et al.). Presentation in childhood isuncommon.

The annual incidence of sudden cardiac death in hypertrophic cardiomyopathy,as established in population-based studies, is approximately 1%. Patients who havesurvived cardiac arrest or have documented sustained ventricular tachycardia orventricular fibrillation are at the highest risk and should receive implantable cardio-verter-defibrillators. Other identified risk factors include nonsustained ven-tricular tachycardia on Holter monitoring, abnormal blood pressure response to

77

Ammash NM, Seward JB, Bailey KR,Edwards WD, Tajik AJ. Clinical profile andoutcome of idiopathic restrictive cardiomy-opathy. Circulation. 2000;101:2490-6.PMID: 10831523

K E Y P O I N T S

• The main differential diagnosis ofrestrictive cardiomyopathy is constric-tive pericarditis.

• Restrictive physiology (ischemic orhypertensive heart disease) is seen inmany patients who do not have restric-tive cardiomyopathy.

• The treatment of restrictive cardiomy-opathy is limited. Digoxin and calciumchannel blockers should be avoided in patients with cardiac amyloid.β-Blockers usually have no role.

• The prognosis of cardiac involvement inprimary amyloid may be improved withuse of melphalan and prednisone.

Maron BJ, Moller JH, Seidman CE,Vincent GM, Dietz HC, Moss AJ, et al.Impact of laboratory molecular diagnosis on contemporary diagnostic criteria forgenetically transmitted cardiovascular dis-eases: hypertrophic cardiomyopathy, long-QT syndrome, and marfan syndrome: astatement for healthcare professionals fromthe councils on clinical cardiology, cardiovas-cular disease in the young, and basic science,american heart association. Circulation.1998;98:1460-71. PMID: 9760303

Aortic Aneurysm

78

exercise, syncope in younger patients, family history of sudden cardiac death intwo or more family members, and perhaps the severity of hypertrophy. Thepresence or absence of any single risk factor is not sufficient to justify deviceimplantation, but this should be considered if two or more factors coexist(Elliott et al.)( Figure 17).

The treatment of symptomatic hypertrophic cardiopmyopathy is welldescribed for the 30% of patients with left ventricular outflow tract obstruction.Initial management is with medications that have negative inotropic and nega-tive chronotropic properties: β-blockers, nondihydropyridine calcium channelblockers, or disopyramide. Their use in the asymptomatic patient has not beensystematically studied. Table 27 lists pharmacologic and nonpharmacologicthings to avoid in obstructive hypertrophic cardiomyopathy. The treatment ofnonobstructive hypertrophic cardiomyopathy is difficult and not well studied.

For patients with continued symptoms despite pharmacologic therapy, several invasive strategies are available. Dual-chamber pacing has been used toreduce obstruction, but results were disappointing in randomized trials.Surgical septal myectomy has been established as the definitive therapy. In expe-rienced hands, this operation is safe and effective. A catheter-based alternativeto septal myectomy has recently emerged. Percutaneous septal ablation is per-formed by instilling alcohol into the septal perforator artery that supplies theobstructing myocardium. The resulting focal infarction halts myocardial con-traction in this territory, and over time, leads to scarring and thinning in thisarea. Short- to intermediate-term studies suggest similar symptomatic improve-ment as septal myectomy. The procedural mortality is similar to myectomy, butthere is more need for permanent pacemaker implantation owing to infarct-related complete heart block with the ablation procedure (Nagueh et al.).Long-term safety data are not yet available for this procedure. For patients withdrug-refractory symptoms, septal debulking by either procedure should be con-sidered. Patients with isolated basal septal hypertrophy are the best candidatesfor either procedure. Patients with concomitant valvular pathology (mitral valveflail or prolapse), abnormal papillary muscles, or more diffuse hypertrophy canbe more definitively managed via the surgical approach.

Aortic Disease

The following aortic diseases are discussed in this chapter: aortic aneurysm, aortic dissection, aortic atheroembolic disease, and Marfan syndrome.

Aortic Aneurysm• Who should be screened for abdominal aortic aneurysm?• What are the indications for aneurysm repair?• When should percutaneous repair of an abdominal aneurysm be considered?

Case 10A 76-year-old man with a history of stable coronary artery dis-ease presents for intermittent right upper quadrant pain. Hestopped smoking 5 years earlier when he had an inferiormyocardial infarction. He takes metoprolol, 50 mg twice daily,and acetylsalicylic acid, 325 mg/d. On physical examination,blood pressure is 145/85, pulse rate is 62/min, and tempera-ture is normal. Cardiovascular examination reveals normaljugulovenous pressure, a sustained apical impulse, S4, and nomurmur. Abdominal examination is significant only for mild

Elliott PM, Gimeno Blanes JR, Mahon NG,Poloniecki JD, McKenna WJ. Relationbetween severity of left-ventricular hypertro-phy and prognosis in patients with hyper-trophic cardiomyopathy. Lancet.2001;357:420-4. PMID: 11273061Nagueh SF, Ommen SR, Lakkis NM,Killip D, Zoghbi WA, Schaff HV, et al.Comparison of ethanol septal reduction ther-apy with surgical myectomy for the treat-ment of hypertrophic obstructive cardiomy-opathy. J Am Coll Cardiol. 2001;38:1701-6.PMID: 11704383

K E Y P O I N T S

• Genetic testing for hypertrophic cardio-myopathy is not yet clinically available.

• Other than out-of-hospital cardiac arrestor sustained ventricular arrhythmia, nosingle risk factor for sudden death inhypertrophic cardiopmyopathy is ade-quate to warrant placement of animplantable cardioverter-defibrillator.

• Most symptomatic patients with hyper-trophic cardiomyopathy can be man-aged medically using agents with nega-tive inotropic and chronotropic proper-ties, such as β-blockers.

• Surgical septal myomectomy or percuta-neous septal ablation can be consideredin symptomatic patients who do notrespond to medical therapy.

Aortic Aneurysm

right upper quadrant tenderness. Laboratory values, includingcomplete blood count, alkaline phosphatase, and amylase, arenormal. Abdominal ultrasonography reveals cholelithiasis with-out dilated biliary ducts, and a 4.3-cm suprarenal aneursym is noted.

Aortic aneurysm is defined a dilatation of the aortic that is at least 1.5 timesnormal or larger than 3.0 cm in adults. The abdominal aorta is the most com-mon site. Risk factors for aortic aneurysm include smoking, white race, malesex, age older than 60 years, coronary artery disease, and family history. Mostabdominal aortic aneurysms are asymptomatic. Abdominal or back pain maysignify an expanding aneurysm. Distal embolic disease may result fromatheroma or superimposed mobile thrombus within the aneurysm. Aneurysmslarger than 5.5 cm in diameter and those expanding at a rate greater than 0.5cm in 6 months are at highest risk for rupture.

The need for routine screening, other than directed physical examination,for an asymptomatic abdominal aortic aneurysm remains controversial. Physicalexamination is highly sensitive for an aneurysm larger than 5.0 cm in a patientwith an abdominal girth less than 100 cm (Fink et al.). Ultrasonography is asensitive and specific screening technique, but results are technician dependent

79

F I G U R E 1 7 .Algorithm for risk stratification and preven-tion of sudden death.

ECG = electrocardiography; Echo = echocardiography; ICD = implantable cardioverter defibrillator; VF = ventricularfibrillation; VT = ventricular tachycardia

Reproduced with permission from: McKenna WJ, Behr ER.Hypertrophic Cardiomyopathy: management, risk stratificationand prevention of sudden death. Heart 2002;87:169-76.

Fink HA, Lederle FA, Roth CS, Bowles CA,Nelson DB, Haas MA. The accuracy ofphysical examination to detect abdominalaortic aneurysm. Arch Intern Med.2000;160:833-6. PMID: 10737283

TABLE 27 Things To Avoid InObstructive HypertrophicCardiomyopathy*

Nonpharmacologic

Dehydration

Alcohol

Hot tub or sauna

Anaerobic exercise

Isometric exercise

Competitive athletics

Intra-aortic balloon pump

Pharmacologic

Any pure vasodilators

Nitrates

Dihydropyridine calcium channelblockers

Hydralazine

Angiotensin-converting enzymeinhibitors

Angiotensin receptor blockers

α-Adrenergic antagonists

Minoxidil

Sildenafil

Any positive inotropes

Epinephrine

Norepinephrine

Isoproteronol

Dopamine

Dobutamine

Digoxin

High-dose diuretics

Over-the-counter stimulants, includingcaffeine and tobacco

*These are general guidelines. The risk–benefit ratio needsto consider each patient individually. Research is ongoingregarding several of the above pharmacologic agents, par-ticularly for nonobstructive hypertrophic cardiomyopathy.

HistoryECGEcho

Exercise testHolter

Identify and treatTRIGGERS

Sustained orsymptomatic VT

or VF

?DNA

Diagnosis?

ICD±

amiodarone

NO sustainedVT

or VF

≥ 2Risk

factors

1Risk

factor

Individualizedecision

0Risk

factor

Reassureadults and

reassesschildren

RISK FACTOR STRATIFICATION

K E Y P O I N T S

• Routine screening other than a directedphysical examination for abdominal aortic aneurysm is not indicated.

• Patients with abdominal aorticaneurysm 4.0 to 5.4 cm in size shouldhave surveillance with computedtomography or ultrsonography every 6 months.

• Repair is indicated for abdominal aorticaneurysms 5.5 cm or larger or rapidlyexpanding aneurysms (>0.5 cm in 6months). Repair is indicated for thoracicaortic aneurysms larger than 5.0 cm inthe ascending aorta or larger than 6.0 in the descending aorta and rapidlyexpanding aneurysms (>1.0 cm in 1 year). Symptomatic patients should be referred for repair independent of location.

• Percutaneous endovascular repair canbe performed by experienced operators,with a high procedural success rate andnegligible mortality. Indications forchoosing the percutaneous approachover surgery are not yet established.

Aortic Aneurysm

80

and it may be less sensitive than computed tomography or magnetic resonanceangiography in measuring small changes in aneurysm dimension.

The risk of rupture of an abdominal aortic aneurysm is related to the ini-tial diameter of the aneurysm at the time of diagnosis. According to severalolder studies in the literature, the 5-year risk of rupture is less than 5% foraneurysms smaller than 5.0 cm and approximately 25% for those 5.0 cm orlarger. Very large aneursyms (>6.0 cm) have an even higher rate of rupture.Additional information suggests that larger aneurysms (>5.0 cm) expand morerapidly than smaller ones. The rate of expansion is greater among aneurysmsthat rupture (approximately 0.8 cm/y) than among those that do not rupture(approximately 0.4 cm/y). Therapy with β-blockers may reduce the rate ofexpansion (Godowski et al.).

Two recently published large randomized trials in patients with abdominalaortic aneurysm measuring 4.0 cm to 5.5 cm demonstrate that early interven-tion with surgery is not associated with improved survival compared with sur-veillance and intervention when the diameter reaches 5.5 cm. In the AneurysmDetection and Management study, the operative mortality rate was low (2.1%).The rate of cross-over to surgery was 61% and was highest in patients with thelargest aneurysms at entry (Lederle et al.). In the UK Small Aneurysm Trial,there was a slight but statistically significant improvement in total survival in thesurgically treated group at 8 years that was not attributable to a decreased rateof rupture. Women were at an increased risk for rupture, suggesting that a cut-off of 5.5 cm for surgical referral may be too high in women. The decrease intotal mortality in the early surgery group may be attributed to the higher rateof smoking cessation in this group, leading to reduced cardiovascular mortalityfrom stroke and myocardial infarction (UK Small Aneurysm Trial).

In Case 10, the abdominal pain is unlikely to be related to the aneurysmand is more likely related to cholelithiasis. Surgical intervention would offer noclear advantage, and the patient should be followed every 6 to 12 months withcomputed tomography or ultrasonography. The greater cost of magnetic reso-nance imaging probably does not warrant its use.

Percutaneous endovascular repair is now possible for many infrarenalabdominal aortic aneurysms. Precise criteria for patient selection have not beenestablished. Initial reports of the procedural success rate have ranged from 60%to 99%. Leaks between the graft and the aneurysm (“endoleaks”) are common.Their management is controversial. Some close spontaneously and othersrequire further intervention, but the need for surgical repair is uncommon(Howell et al.). Further ongoing study and comparison of percutaneousendovascular repair to surgery is needed.

Thoracic aortic aneurysms are far less common and, therefore, less wellstudied. The etiologies of thoracic aortic aneurysm have been enumerated(Table 28). Recently, a familial form of thoracic aneurysm has been linked togene 5q13-14 (Guo et al.). No features of Marfan syndrome or other connec-tive tissue disease were present, and there appeared to be an autosomal domi-nant pattern of inheritance. Screening of family members may be warranted.The risk of rupture varies with the size of the aneurysm and approaches 60% inaneurysms larger than 6.0 cm. Moreover, the rate of aneurysm expansion isgreatest in patients with the largest aneurysms. Indications for surgery includesymptoms, a diameter larger than 5.0 cm in the ascending aorta or larger than6.0 in the descending aorta, and rapid expansion (>1.0 cm in 1 year). Anothercomplication of ascending aortic aneurysm that involve the aortic root is aorticinsufficiency. In these patients, serial echocardiography is required not only tofollow aortic root expansion but also to assess severity of aortic insufficiency andleft ventricular size and function. Endovascular repair is now being performedfor descending thoracic aneurysm in some centers.

Gadowski GR, Pilcher DB, Ricci MA.Abdominal aortic aneurysm expansion rate:effect of size and beta-adrenergic blockade.J Vasc Surg. 1994;19:727-31.

PMID: 7909340Lederle FA, Wilson SE, Johnson GR,Reinke DB, Littooy FN, Acher CW, et al.Immediate repair compared with surveillanceof small abdominal aortic aneurysms. N EnglJ Med. 2002;346:1437-44.PMID: 12000813Long-term outcomes of immediate repaircompared with surveillance of small abdomi-nal aortic aneurysms. N Engl J Med.2002;346:1445-52. PMID: 12000814Howell MH, Strickman N, Mortazavi A,Hallman CH, Krajcer Z. Preliminaryresults of endovascular abdominal aorticaneurysm exclusion with the AneuRx stent-graft. J Am Coll Cardiol. 2001;38:1040-6.PMID: 11583879Guo D, Hasham S, Kuang SQ, Vaughan CJ,Boerwinkle E, Chen H, et al. Familialthoracic aortic aneurysms and dissections:genetic heterogeneity with a major locusmapping to 5q13-14. Circulation.2001;103:2461-8. PMID: 11369686

Aortic Dissection

Aortic Dissection• What are the major risk factors for aortic dissection?• How should aortic dissection be managed acutely?• What is the best test for diagnosing aortic dissection?• How should patients with chronic aortic dissection be followed?

Case 11A 58-year-old man presents with a 1-hour history of severechest pain that came on suddenly. No specific maneuverschanged the severity of the pain. He denied a history of anginaor hypertension. He was told in the past that he had a heartmurmur and took antibiotics before dental work. On examina-tion, blood pressure is 128/60 mm Hg and heart rate is95/min, and the patient is afebrile. There is an early systolicclick, a soft S2, a 2/6 systolic ejection murmur, and a 3/6 shortdiastolic murmur beginning after S2. Electrocardiography showsleft ventricular hypertrophy with secondary T-wave changes.Chest radiography shows cardiomegaly and widening of themediastinum. The patient is referred for transesophagealechocardiography.

Aortic dissection is a potentially life-threatening event, especially when itinvolves the ascending aorta. The most common risk factor for dissection ishypertension. In younger patients, risk factors include connective tissue dis-eases, such as Marfan syndrome; bicuspid aortic valve; coarctation of the aorta;trauma; and pregnancy (Table 28). Sudden onset of pain is the presentingsymptom in most patients. A recent large registry showed a low prevalence ofclassic signs, with aortic insufficiency in 32% of patients and pulse deficits in15%. Transesophageal echocardiography and helical computed tomography arethe preferred methods for diagnosis because of their high diagnostic accuracyand the rapidity with which they can be performed. Magnetic resonanceangiography is preferred to follow patients with chronic dissection. Ultimately,the best diagnostic method for a given patient depends on local availability andexpertise. Invasive aortography is indicated only when accurate localization ofthe tear is needed and in the setting of coexisting coronary ischemia.

The patient described in Case 11 is hemodynamically stable and requiresprompt relief of pain. His history and physical examination suggest bicuspidaortic valve, which may be associated with chronic aortic insufficiency.However, the chest pain should raise the clinical suspicion of dissection.

Dissections should be defined anatomically as involving the ascendingaorta (type A) or descending aorta (type B). Other important features includethe severity of aortic root dilation and aortic insufficiency, involvement of coro-nary arteries and great vessels, and rupture.

Acute management typically requires aggressive antihypertensive therapywith agents that reduce shear stress on the aortic wall. The best agents are thosewith β-blocking activity that can be administered rapidly with the goal of reduc-ing the systolic blood pressure to 100 to 120 mm Hg; these agents includemetoprolol, inderal and labetolol. If β-blockers are absolutely contraindicated,diltiazem or verapamil can be substituted. Vasodilators, such as nitroprusside,should not be used without a β-blocker. Hypotension may be due to containedrupture with tamponade, rupture with exsanguination or cardiogenic shock dueto severe aortic insufficiency, or associated myocardial infarction. In all cases,rapid triage to surgery may be life-saving, although the mortality rate is high.

81

TABLE 28 Etiologies and RiskFactors in Thoracic Aortic Aneurysmand Dissection

Aneurysm or dissection:

Atherosclerosis

Hypertension

Marfan syndrome

Bicuspid aortic valve

Coarctation of the aorta

Ehlers–Danlos syndrome

Aneurysm only:

Infectious

Syphilis

Myocotic aneurysm due to endocarditis

HLA-B27–related diseases and otherarthritidies

Ankylosing spondylitis

Reiter’s syndrome

Reactive arthritis

Psoriatic arthritis

Rheumatoid arthritis

Other

Giant-cell arteritis

Takyasus’s disease

Wegener’s granulomatosis

Dissection only:

Pregnancy

Trauma

Aortic Atheroembolic Disease

82

In acute type A dissection, emergency surgery is indicated to avoid tam-ponade and rupture. In a recent international registry of 464 patients, the mor-tality rate was 26% with early surgical treatment and 58% with medical man-agement in patients excluded from surgery because of advanced age or signifi-cant comorbid conditions. According to recently published guidelines from theEuropean Society of Cardiology, surgery is indicated in acute type B dissectiononly for complications, such as recurrent or persistent pain, early expansion,rupture, or peripheral ischemia. Recent registry data showed a mortality rate intype B dissection of 31% with early surgery and 11% with medical therapy(Hagan et al.; Erbel et al.). There are an increasing number of reports of suc-cessful endovascular stenting in acute and chronic aortic dissection.

Long-term therapy in survivors should include continued antihypertensivemanagement and avoidance of strenuous exercise. The 10-year survival rate isapproximately 50%. Indications for late surgery in medically treated survivorswith type A dissection include progressive aortic insufficiency or dilation. Inpatients with type B dissection, repair is indicated if the descending thoracicaortic diameter expands to greater than 6 cm. Magnetic resonance angiographyshould be performed every 6 months for the first year and then, if stable, yearly.

Aortic Atheroembolic Disease• What is the significance of mobile atheroma identified by transesophageal echo-

cardiography in a patient with a recent stroke?• What is the appropriate treatment in this setting?

Case 12A 68-year-old woman is referred for transesophageal echo-cardiography after a transient episode of monocular blindness.Carotid ultrasonography was negative for obstructive disease.Mobile plaques were present in the descending aorta. A patentforamen ovale was not identified.

Aortic atherosclerotic disease with plaques protruding more than 4 mm into thelumen is a well-recognized risk factor for embolic disease, including stroke,peripheral embolization, and renal embolic disease. Ulcerated plaques andmobile debris are associated findings evident in the thoracic aorta on trans-esophageal echocardiography. The presence of a pedunculated mobile plaque isassociated with the highest risk of emboli. In patients with a history of embolicevents, warfarin has been shown to reduce the recurrence rate (Dressler et al.;Salem et al.).

Marfan Syndrome• What is the risk associated with aortic dilation in the patient with Marfan syndrome?• What is the role of prophylactic β-blocker therapy?

Case 13A 28-year-old woman with suspected Marfan syndrome pre-sents for counseling regarding pregnancy. She has a family his-tory of sudden death due to suspected aortic dissection. She istall with long arms. Blood pressure is 110/75 mm Hg andpulse rate is 65/min. The apical impulse is not displaced. A softdiastolic murmur is detected along the right sternal border. Amidsystolic click and a late systolic murmur are audible at theapex. Electrocardiography is normal. Chest radiography showsprominence of the ascending aorta.

Hagan PG, Nienaber CA, IsselbacherEM, Bruckman D, Karavite DJ, RussmanPL, et al. The International Registry ofAcute Aortic Dissection (IRAD): newinsights into an old disease. JAMA.2000;283:897-903. PMID: 10685714Erbel R, Alfonso F, Boileau C, Dirsch O,Eber B, Haverich A, et al. Diagnosis andmanagement of aortic dissection. Eur HeartJ. 2001;22:1642-81. PMID: 11511117

Dressler FA, Craig WR, Castello R,Labovitz AJ. Mobile aortic atheroma andsystemic emboli: efficacy of anticoagulationand influence of plaque morphology onrecurrent stroke. J Am Coll Cardiol.1998;31:134-8. PMID: 9426031Salem DN, Daudelin HD, Levine HJ,Pauker SG, Eckman MH, Riff J.Antithrombotic therapy in valvular heart disease. Chest. 2001;119:207S-219S.PMID: 11157650Loeys B, Nuytinck L, Delvaux I, De Bie S,De Paepe A. Genotype and phenotypeanalysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syn-drome. Arch Intern Med. 2001;161:2447-54. PMID: 11700157

K E Y P O I N T S

• Sudden chest pain is the most commonpresenting symptom in aortic dissection.

• Transesophageal echocardiography andhelical computed tomography are thepreferred methods for diagnosisbecause of their high diagnostic accu-racy and the rapidity with which theycan be performed.

• In general, surgery is indicated acutelyfor type A dissection and medical therapy for type B dissection.

• β-Blockers are the primary treatmentfor hypertension in acute and chronicdissection. Vasodilators should be usedonly with β-blockers.

• In medically treated patients, continuedsurveillance with magnetic resonanceangiography is indicated for aorticdilatation, which may be an indicationfor surgery (type A >5.0 cm or type B>6.0 cm).

K E Y P O I N T S

• Atherosclerotic disease in the thoracicaorta is a risk factor for cerebral, renal,and peripheral embolic events.

• Warfarin reduces the incidence of recur-rent stroke in patients with mobile aor-tic atheroma.

Acyanotic Congenital Heart Disease

Marfan syndrome is a congenital disorder caused by various mutations of thefibrillin-1 gene (FBN-1). These mutations are uncommon in patients who donot fulfill clinical criteria for the disease (Loeys et al.). Marfan syndrome maybe inherited in an autosomal dominant pattern, but new mutations result insporadic occurrence. Clinical criteria for diagnosis have been enumerated(Table 29). Aortic disease is a major source of morbidity and the primarysource of mortality because of the risk of dissection and rupture. Dilation occursin as many as 50% of children and progresses with age. Yearly echocardiographyis indicated to follow the size of the aortic root until it reaches 4.5 cm andshould then be repeated every 6 months. Recent studies suggests that aorticdistensibility is reduced. Therapy with β-blockers, specifically propranolol, hasbeen shown to reduce the rate of aortic dilation and the risk of dissection(Rossi-Foulkes et al.). Elective repair is indicated when the aortic diameterreaches 5.5 cm. Earlier intervention may be indicated in women who desirepregnancy despite the increased risk of pregnancy. Most patients will require acomposite graft that contains a prosthetic valve. Long-term results with thisprocedure are excellent, with 83% survival at 20 years (Gott et al.).

The patient described in Case 13 has mild aortic insufficiency on examina-tion. Echocardiography revealed an aortic root dimension of 5.2 cm. She hadmitral valve prolapse with elongated leaflets and mild mitral insufficiency. She was advised to have elective aortic root replacement before proceeding with pregnancy.

Congenital Heart Disease in the Adult

With the availability of life-saving palliative surgical and nonsurgical interven-tions, the number of adult patients with congenital heart disease has increasedto more than 500,000 in the United States. This section addresses the mostcommon acyanotic and cyanotic lesions.

Genetic counseling should be considered in all patients with congenitalheart disease (Hoess et al.). Patterns of inheritance are rarely clearly defined.The risk of congenital heart disease in the offspring and siblings of patients isincreased. Knowledge of the genetic basis for specific lesions is emerging(Brickner et al.).

Acyanotic Congenital Heart Disease• What are the indications for closure of atrial septal defect in the adult?• When should device closure be considered as an alternative to surgical closure?• What are the indications for closure of a patent foramen ovale?

Atrial Septal DefectAtrial septal defect is the second most common congenital heart lesion encoun-tered in adults (after bicuspid aortic valve). Atrial septal defects are classifiedaccording to location (Figure 18). Ostium secundum defects in the mid por-tion of the septum account for the majority. Ostium primum defects are in thelower portion of the septum and are associated with abnormalities of the atrio-ventricular valves. Sinus venosus defects are usually located near the entrance of the superior vena cava and are associated with partial anomalous pulmonaryvenous drainage. In the absence of pulmonary vascular disease, the shunt direc-tion is left to right, predominantly during diastole, resulting in volume overloadof the right ventricle. With advancing age, diminished left ventricular compli-ance can lead to an increase in the shunt fraction, with consequent right heart

83

Rossi-Foulkes R, Roman MJ, Rosen SE,Kramer-Fox R, Ehlers KH, O’LoughlinJE, et al. Phenotypic features and impact ofβ-blocker or calcium antagonist therapy onaortic lumen size in the Marfan syndrome.Am J Cardiol. 1999;83:1364-8.PMID: 10235096Gott VL, Cameron DE, Alejo DE, GreeneMarfanPS, Shake JG, Caparrelli DJ, DietzHC. Aortic root replacement in 271patients: a 24-year experience. Ann ThoracSurg. 2002;73:438-43. PMID: 11845856

K E Y P O I N T S

• Aortic disease is a major source of mor-bidity and the primary source of mortal-ity in Marfan syndrome.

• A family history of aortic disease is animportant risk factor for dissection.

• Yearly echocardiography is indicated tofollow aortic dimension until it reaches4.5 cm, when it should be repeatedevery 6 months.

• Propranolol has been shown to reducethe rate of dilatation. Calcium channelblockers can be substituted in patientsintolerant of β-blockers.

• Elective aortic repair is indicated whenthe diameter exceeds 5.5 cm, or earlierin women who desire pregnancy.

K E Y P O I N T S

• The indication for closure of atrial septal defects and ventricular septaldefects is a pulmonary-to-systemicshunt ratio of 1.7:1 or greater, with evi-dence of right ventricular or left ventric-ular volume overload, respectively.

• A patent ductus arteriosus associatedwith a murmur should be closed evenwhen the shunt is small to reduce the risk of endoarteritis.

• Percutaneous device closure of atrialseptal defects, patent foramen ovale,and patent ductus arteriosus is nowpossible in most patients.

• The specific indications for closure of apatent foramen ovale after a cerebralembolic event remain uncertain.

Hoess K, Goldmuntz E, Pyeritz RE.Genetic counseling for congenital heart disease: new approaches for a new decade.Curr Cardiol Rep. 2002;4:68-75. PMID:11743925Brickner ME, Hillis LD, Lange RA.Congenital heart disease in adults. First oftwo parts. N Engl J Med. 2000;342:256-63.PMID: 10648769


84

failure. Atrial fibrillation is common in older adults with atrial septal defects.The frequency of atrial fibrillation and the potential for paradoxical embolismlead to a high incidence of embolic stroke.

TABLE 29 Major and Minor Manifestations of Marfan Syndrome

Skeletal findings

Major (4 of 8 required)

Upper to lower segment ratio ≤0.85 (normal, 0.93)

Arm span > height (ratio >1.05)

Arachnodactyly of fingers and toes with positive wrist and thumb signs

Scoliosis >20˚ or kyphosis

Pectus carinatum or pectus excavaatum requiring surgery

Reduced extension of elbows (<170˚)

Medial displacement of medial malleolus, causing pes planus

Protrusio acetabulae

Minor

Dolichostenomelia (limbs disproportionately large for trunk size)

Dolichocephaly

Tall stature (>95th percentile)

Generalized joint hypermobility

Osteopenia or osteoporosis

Cardiovascular findings

Major (1 of 2 required)

Dilatation of the aorta involving sinuses of Valsalva

Dissecting aortic aneurysm

Minor

Mitral valve prolapse

Mitral regurgitation

Left ventricular dilatation

Dilation of the pulmonary artery (<40 years of age)

Calcification of the mitral annulus (<40 years of age)

Dilation or dissection of descending aorta (<50 years of age)

Tricuspid valve prolapse

Ocular findings

Major

Ectopia lentis

Secondary myopia, retinal detachment, glaucoma, and iritis

Minor

Myopia

Flat cornea

Increased axial globe length

Other

Major

Dural ectasia affecting the lumbosacral spinal canal

Minor

Spontaneous pneumothorax

Apical blebs

Cutaneous striae distensae

Recurrent or incisional hernias

Reproduced with permission from: Shapiro, JR, Wright, MJ. The Marfan Syndrome. In UpToDate, Rose BD (Ed), UpToDate, Inc., Wellesley, MA 2003.


Case 14A 42-year-old fireman is referred for routine physical examina-tion. He has no specific medical symptoms. His medical historyis significant only in that he was told he had mitral valve pro-lapse at a sports physical examination in high school when hetried out for the football team. He played during all four yearsof high school and now exercises for 1 hour daily, by running 3 to 4 miles and lifting weights up to 150 lb. He has usedamoxicillin for antibiotic prophylaxis before dental work, onthe basis of his diagnosis of mitral valve prolapse.

On physical examination, the patient is fit and well devel-oped. Blood pressure is 124/70 mm Hg, pulse rate is 70/minand regular. Jugulovenous pressure is estimated at 5 cm. Thelungs are clear, and there are no thoracic abnormalities. Cardiacexamination reveals at prominent right parasternal impulse,nondiplaced apical impulse, normal S1, fixed split S2, 2/6 earlypeaking systolic murmur at the upper left sternal border, andno diastolic murmur.

Case 14 typifies the presentation with a systolic flow murmur at the upper leftsternal border and the pathognomonic fixed split S2. In the majority of cases,electrocardiography shows an incomplete right bundle-branch block and right-axis deviation consistent with the right ventricular overload. Chest radiographyshows right ventricular prominence on the lateral film and pulmonary plethora.The diagnosis is suspected on transthoracic echocardiography in the presence ofright ventricular enlargement and increased pulmonary flow. Color flowDoppler imaging may demonstrate flow across the interatrial septum. However,the left-sided appearance of agitated saline after intravenous injection is moredefinitive. Transesophageal echocardiography provides clear anatomic defini-tion, which is important for sizing the defect and determining suitability forpercutaneous closure.

The indications for closing an atrial septal defect include a systemic-to-pulmonary shunt ratio of 1.7:1 or greater or evidence of right ventricular volumeoverload (Figure 19). In a recent prospective study (Attie et al.), 473 patientswith atrial septal defects, a systemic-to-pulmonary shunt ratio of 1.7:1 orgreater, and a pulmonary artery systolic pressure less than 70 mm Hg were ran-domized to medical or surgical therapy. The primary end point, a compositeindex of major cardiovascular events (cardiac-related death, heart failure, pul-

85

F I G U R E 1 8 .Atrial septal defects (ASD).

IVC = inferior vena cava; FO = fossa ovalis; RV = rightatrium; SVC = superior vena cava; TV = tricuspid valve

Attie F, Rosas M, Granados N, Zabal C,Buendia A, Calderon J. Surgical treatmentfor secundum atrial septal defects in patients>40 years old. A randomized clinical trial. J Am Coll Cardiol. 2001;38:2035-42.PMID: 11738312

IVC

TV

Ostium primum ASD

Ostium secundum ASD

SVC

Sinus venosus ASD

Interatrial septumviewed from rightatrium

FO

RV


86

monary or systemic embolism, recurrent pulmonary infection, sustained ven-tricular tachyarrhythmia, and progression of pulmonary hypertension) was lessfrequent in the surgically treated group (11.1% vs. 20.7%). The improved out-come was mainly due to a reduced incidence of pneumonia and fewer suddendeaths at a mean follow-up of 7.3 years. Risk factors for primary events wereage and mean pulmonary artery pressure of greater than 35 mm Hg.

Percutaneous devices for atrial septal defect closure were recently approvedby the U.S. Food and Drug Administration. Device closure is feasible in mostostium secundum atrial septal defects. In the hands of experienced operators, itcan be performed with low risk. Surgical closure is required for ostium primumand sinus venosus atrial septal defects. No data are available comparing deviceclosure to surgical closure.

Before repair, prophylaxis for endocarditis is not indicated for atrial septaldefects unless there are associated valvular or other congenital abnormalities(Morris et al.). Following atrial septal defect closure, antibiotic prophylaxis forbacterial endocarditis is recommended for the first 6 months until the patch ordevice becomes endothelialized, then indefinitely if there are residual abnormalities.

Patent Foramen OvaleIn the fetus, the foramen ovale permits oxygenated placental blood to reach thesystemic circulation. In approximately 20% of people, this interatrial communi-cation persists. They vary in size and may be associated with redundancy of theinteratrial septum that leads to an interatrial septal aneurysm. They can be diag-nosed on contrast echocardiography by demonstration of right-to-left shuntingduring a maneuver that increases right atrial pressure sufficiently to force theflap valve open, such as cough or release of the Valsalva maneuver. Becauseshunting is rarely present in the basal state, there is usually no right ventricularenlargement. The major clinical significance of a patent foramen ovale is itsassociation with cerebrovascular events due to paradoxical embolization. Arecent study suggested that among patients taking aspirin, recurrent embolicevents are far more common in patients with interatrial septal aneurysm and

Morris CD, Reller MD, Menashe VD.Thirty-year incidence of infective endocarditisafter surgery for congenital heart defect.JAMA. 1998;279:599-603. PMID: 9486754

F I G U R E 1 9 .Indications for closure of an atrial septal defect (ASD).In the presence of a left-to-right shunt, the pul-monary flow (Qp) is equal to the systemic flow(Qs) plus the flow across the defect (Q shunt). Theshunt is considered hemodynamically significantwhen the shunt flow is more than 70% of sys-temic flow. In that case, the ratio of pulmonary to systemic flow (Qp:Qs) would be 1.7:1.

LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle

Pulmonary veins

Vena cavaeRA

RV

Pulmonary artery Aorta

LV

LA

ASD

Qshunt

Qp Qs


patent foramen ovale than in those with patent foramen ovale alone (Mas et al.).The optimal treatment for patients with patent foramen ovale and stroke is asyet undetermined, although device closure is now feasible (Hung et al.). Otherclinical syndromes associated with patent foramen ovale include ortho-deoxia–platypnea (cyanosis in the upright position), severe decompression ill-ness in divers, and hypoxemia associated with right heart failure (for example,after right ventricular infarction). Occasionally, patients with these conditionsrequire surgical or percutaneous closure.

It was suggested that migraine episodes may decrease or resolve after clo-sure of a patent foramen ovale, but this observation requires further studybefore its clinical significance is known (Wilmshurst et al.). Likewise, use ofprophylactic antithrombotic therapy in asymptomatic patients with the inciden-tal finding of patent foramen ovale or an atrial septal defect too small for clo-sure is unresolved (Albers et al.). Low-dose aspirin therapy is consideredoptional, as no prospective data support its use.

Other Acyanotic Congenital Heart LesionsThe most common congenital anomaly is the bicuspid aortic valve. It is morecommon in men and can progress to hemodynamically significant aortic insuf-ficiency or stenosis. This lesion should be suspected in the presence of an earlysystolic ejection click associated with an outflow murmur. Early recognition anddiagnosis by echocardiography are important because of the relatively highassociated risk of endocarditis. Indications for surgical intervention are similarto those for acquired aortic valve disease and are covered in that section. Theaortopathy associated with bicuspid aortic valve poses an added risk of aorticdissection in these patients. Bicuspid aortic valve and coarctation of the aortaare strongly associated, and up to 6% of patients with the former condition alsohave coarctation of the aorta. Screening for coarctation should be performed atthe time of transthoracic echocardiography with a suprasternal notch view.Simultaneous palpation of the brachial and femoral pulses may reveal a pulsedelay in the femoral artery. Familial clustering of bicuspid aortic valve suggeststhat genetic counseling is warranted.

In the acyanotic adult with a ventricular septal defect, the shunt is usuallysmall. Larger ventricular septal defects usually present in childhood, with con-gestive heart failure or pulmonary hypertension. The most common location in adults is the perimembranous region near the tricuspid valve. A loud holo-systolic murmur is typically associated with a small defect and normal pulmonaryvascular resistance. The natural history of unoperated patients with small ven-tricular septal defects and no clear surgical indications during childhood (sys-temic-to-pulmonary shunt ratio <1.5:1, normal pulmonary vascular resistance,and no significant aortic insufficiency) is excellent, with 95% event-free survivalat 8 years reported in a recent series. The incidence of endocarditis was 1.8%,and there were no deaths (Gabriel et al.). Closure of ventricular septal defectsis not indicated for prevention of endocarditis alone. In adulthood, indicationsfor closure include a large shunt fraction with a systemic-to-pulmonary shuntratio of 1.7:1.0 or greater or left ventricular volume overload. Left ventricularvolume overload occurs because the shunt is primarily confined to systole andthe right ventricle never serves as a “reservoir” for the shunted blood. The leftventricular diastolic volume is increased because the stroke volume includesboth forward flow and shunted flow. The physical examination in a patient witha hemodynamically significant ventricular septal defect may reveal a displacedapical impulse, a mitral diastolic rumble, and an S3, even in the absence of heartfailure. There is usually echocardiographic evidence of left ventricular hyper-trophy. The presence of right ventricular hypertrophy suggests pulmonary hyper-tension or associated pulmonary valve stenosis.

87

Mas JL, Arquizan C, Lamy C, Zuber M,Cabanes L, Derumeaux G, Coste J.Recurrent cerebrovascular events associatedwith patent foramen ovale, atrial septalaneurysm, or both. N Engl J Med.2001;345:1740-6. PMID: 11742048Hung J, Landzberg MJ, Jenkins KJ, KingME, Lock JE, Palacios IF, Lang P. Closureof patent foramen ovale for paradoxicalemboli: intermediate-term risk of recurrentneurological events following transcatheterdevice placement. J Am Coll Cardiol.2000;35:1311-6. PMID: 10758974Wilmshurst PT, Nightingale S, Walsh KP,Morrison WL. Effect on migraine of closureof cardiac right-to-left shunts to preventrecurrence of decompression illness or strokeor for haemodynamic reasons. Lancet.2000;356:1648-51. PMID: 11089825Albers GW, Amarenco P, Easton JD,Sacco RL, Teal P. Antithrombotic andthrombolytic therapy for ischemic stroke.Chest. 2001;119:300S-320S.PMID: 11157656

Gabriel HM, Heger M, Innerhofer P,Zehetgruber M, Mundigler G, Wimmer M,et al. Long-term outcome of patients withventricular septal defect considered not torequire surgical closure during childhood. J Am Coll Cardiol. 2002;39:1066-71.PMID: 11897452

Cyanotic Congenital Heart Disease

88

In the acyanotic adult patient with a patent ductus arteriosus, the commu-nication is usually small. The murmur is usually soft and confined to systole, andthe diagnosis is made by echocardiography. Most adults with large patent duc-tus arteriosus have pulmonary vascular disease with Eisenmenger’s physiologyand are not candidates for surgery. In these patients, the physical examinationis dominated by signs of pulmonary hypertension with cyanosis and clubbing inthe toes, but not in the fingers. The murmur across the patent ductus arterio-sus is no longer present. Occasionally, elevated pulmonary pressures are due toincreased pulmonary flow, and the resistance is low enough to permit closure.The extracardiac left-to-right shunt at the level of the great vessels results in avolume overload to the left ventricle. Similar to patients with large ventricularseptal defects, there is evidence of left ventricular hypertrophy on physicalexamination and echocardiography. In these patients, the murmur is usuallyloud and continuous. Percutaneous closure with a coil or device is now possi-ble in many patients. Most experts agree that closure is indicated if the patentductus arteriosus is associated with a murmur to prevent the complication ofendarteritis independent of the magnitude of the shunt. Closure of a silentpatent ductus arteriosus, one that is incidentally found on echocardiography,remains controversial.

Valvular pulmonary stenosis is relatively uncommon in adults. Whensevere, it may present with exercise intolerance. Right-heart failure only occursin the very late stages of the disease. Clinical hallmarks are a systolic ejectionclick and systolic murmur over the second left intercostal space. Echo-cardiography shows right ventricular hypertrophy and right-axis deviation.Indications for treatment include a peak resting gradient greater than 40 mmHg. Intervention should also be considered in patients with exercise-inducedgradients greater than 50 mm Hg and echocardiographic evidence of right ven-tricular hypertrophy, independent of severity of the resting gradient. Echo-cardiography is usually adequate for diagnosis. Percutaneous balloon valvulo-plasty can be performed by experienced operators, with excellent long-termresults in adults (Rao).

Coarctation of the aorta should be excluded in young adults who presentwith hypertension. Physical examination may reveal a radial-to-femoral pulsedelay and lower blood pressure in the legs. Chest radiography may show theclassic “3” sign and rib notching due to dilated intercostal arteries that providecollateral blood flow to the descending aorta. Doppler echocardiography candefine the gradient across the area of coarctation, whereas magnetic resonanceangiography provides excellent anatomic definition that can guide percutaneousor surgical repair. Repair is usually indicated when there is proximal hyper-tension and a gradient exceeding 20 mm Hg. A discrete coarctation is usuallyamenable to percutaneous repair, while longer segments may require surgicalintervention. Small series of properly selected adult patients undergoing percu-taneous repair using angioplasty with an intravascular stent have demonstrateda high rate of success and low complication rate (Hamdan et al.).

Antibiotic prophylaxis is indicated for almost all patients with unoperatedcongenital heart disease. An exception is an isolated atrial septal defect.

Cyanotic Congenital Heart Disease• What are the indications for phlebotomy in patients with cyanotic heart disease?• Which cyanotic patients are at risk for stroke?• Which patients are at highest risk for complications of endocarditis, heart failure,

and arrhythmias after repair of congenital heart disease?• Which patients should be followed in a specialized center for adults with congenital

heart disease?

Rao PS. Long-term follow-up results afterballoon dilatation of pulmonic stenosis, aorticstenosis, and coarctation of the aorta: areview. Prog Cardiovasc Dis. 1999;42:59-74.PMID: 10505493Hamdan MA, Maheshwari S, Fahey JT,Hellenbrand WE. Endovascular stents forcoarctation of the aorta: initial results andintermediate-term follow-up. J Am CollCardiol. 2001;38:1518-23.PMID: 11691533

Cyanotic Congenital Heart Disease

Case 15A 35-year-old woman with Down’s syndrome and a history of heart disease presented with a 2-day history of nausea andvomiting. Her caretaker claims that she was working daily in aworkshop before the recent illness. She has been refusing to eatand has been very lethargic. On examination, blood pressure ofis 95/60 mm Hg, pulse rate is 98/min, and temperature is38 °C (100.4 °F). She is cyanotic and clubbed. The lungs areclear. Cardiac examination reveals an RV left, a loud P2, and nomurmur. The abdomen is soft, and bowel sounds are normal.Laboratory values are as follows: leukocyte count, 14,300/µL;hemoglobin, 22 g/dL; hematocrit, 74%; blood urea nitrogen,32 mg/dL; and serum creatinine, 1.2 mg/dL.

Most patients with unoperated cyanotic heart disease have developedEisenmenger’s syndrome, severe pulmonary vascular disease due to a lesionoriginally associated with a large left-to-right shunt (atrial septal defect, patentductus arteriosus or ventricular septal defect). With the development of pulmonary hypertension, shunt reversal occurs, leading to cyanosis. Secondaryerythrocytosis is compensatory and usually not associated with symptoms. Thehyperviscosity syndrome can develop when the hematocrit is greater than 65 mg/dL; however, phlebotomy is indicated only to treat symptoms.Phlebotomy in an asymptomatic patient can lead to iron depletion and adecompensated state. Iron deficiency, rather than the absolute hemoglobinlevel, in such patients is associated with stroke. When necessary, phlebotomyshould be followed by isovolumic saline repletion to avoid hypovolemia. In thepresence of heart failure, 5% dextrose in water should be used. In Case 15, theelevated hematocrit is due to volume depletion; volume repletion is indicated,not phlebotomy. Pregnancy is strictly contraindicated in patients withEisenmenger’s syndrome. The maternal mortality rate exceeds 50%, with deathusually occurring in the early post-partum period. No evidence indicates thatcesarean section offers an advantage over normal vaginal delivery.

Most other categories of patients with cyanotic congenital heart diseasehave had palliative surgery in childhood. These patients remain at high risk forendocarditis, arrhythmias, sudden death, and heart failure. Pregnancy is usuallywell tolerated in the absence of overt heart failure, uncontrolled arrhythmias,and pulmonary vascular disease, as long as the patient is in functional class I. Allcyanotic patients should be followed in conjunction with a center specializingin adult congenital heart disease (32nd Bethesda Conference).

Tetralogy of Fallot is the most common form of cyanotic congenital heartdisease. Occasionally, a patient with only a palliative aortopulmonary shunt pro-cedure is encountered. Most adults have had a total intracardiac repair, with closure of the ventricular septal defect and relief of the pulmonary stenosis.Pulmonary valve insufficiency leading to right-heart dilation is common. Theappropriate timing for pulmonary valve replacement remains uncertain. Recentstudies suggest that the yearly mortality rate increases after 25 years, predomi-nantly because of sudden death. A QRS duration greater than 180 ms seems tobe the best predictor of sudden death. Because of the apparent interactionbetween progressive right-heart dilation and lengthening of the QRS, there isgeneral agreement that pulmonary valve replacement is indicated when theQRS exceeds 180 ms.

Most adult patients with transposition of the great arteries have had anatrial switch procedure (Mustard or Senning operation). The morphologic rightventricle continues to support the systemic circulation and is subject to failure.Survival is highly dependent on right ventricular function. The sick sinus syn-

89

Summary of recommendations—care of theadult with congenital heart disease. J AmColl Cardiol. 2001;37:1167-9.PMID: 11300417

Clinical Evaluation

90

drome and atrial arrhythmias will frequently require pacemaker insertion,radiofrequency ablation, or use of antiarrhythmic drugs.

Patients with rarer forms of cyanotic heart disease and a pulmonary circu-lation protected from vascular disease may remain surgical candidates as adults.

Peripheral Arterial Disease

Peripheral arterial disease affects approximately 12% of U.S. adults and isequally prevalent in men and women. More than half of patients with periph-eral arterial disease are asymptomatic and do not have symptoms of claudicationon exertion or limb ischemia at rest. Approximately one third of patients haveclaudication (pain in the legs on walking, primarily in the calves, that does notgo away with continued walking and is relieved by rest). Less than 5% to 10%of patients have critical leg ischemia (ischemic pain in the distal foot, ischemiculceration, or gangrene); risk of limb loss in these patients is substantial.

Clinical Evaluation• What are the clinical characteristics of peripheral arterial disease?• What is the natural history of peripheral arterial disease in terms of mortality risk

and symptoms?• On what basis can clinicians recognize and screen for peripheral arterial disease?

Palpation of arterial pulses, including the brachial, femoral, and pedal arteries,should be performed in all patients. Absence of a femoral pulse indicates inflowdisease of the aorta or iliac arteries. Patients with a palpable femoral pulse butno pedal pulse have disease confined to the arteries in the leg. Any patient withreduced or absent pulses in the leg should be suspected of having peripheralarterial disease and should have ankle blood pressure measured. Patients withcritical leg ischemia develop pain in the distal foot at rest that can progress toischemic ulceration and gangrene. The ulcers are painful, do not bleed whenmanipulated, and often have a dark necrotic base. Physical examination revealspallor of the foot on elevation because of inadequate arterial pressure and flow.When the foot is dependent, it becomes red because of chronic dilation of theperipheral vascular bed distal to server and multiple occlusions. The foot maybe edematous from being kept continually dependent in an attempt to relievethe ischemic pain. Recent studies have evaluated the diagnostic accuracy of thehistory (intermittent claudication) and examination (absent pulses) for periph-ereal artery disease as objectively diagnosed by the ankle–brachial index. A his-tory of leg pain on exertion (typical or atypical claudication) significantly under-diagnoses periphereal arterial disease, and a pulse abnormality overestimates disease prevalence.

Natural HistoryIn patients with claudication, symptoms remain relatively stable over 5 years, inthat only 25% will develop worsening claudication and 4% will undergo ampu-tation. Despite this relatively benign natural history, symptomatic patients haveseverely limited walking ability and functional capacity. In contrast, patientswith peripheral arterial disease have a threefold increased risk of all-cause mor-tality and a sixfold increased risk of cardiovascular mortality. The mortality riskis approximately equal between men and women and is increased even inasymptomatic patients. In addition, the severity of peripheral arterial disease inthe legs is closely associated with the risk of myocardial infarction, ischemicstroke, and vascular death. The lower the ankle–brachial index, the greater therisk of cardiovascular events. Patients with critical leg ischemia have an annualmortality rate of 25%.

K E Y P O I N T S

• In patients with cyanotic heart disease,phlebotomy should be used only totreat hyperviscosity symptoms when thehematocrit is greater than 65 mg/dL;iron deficiency should be avoided.

• The risk of endocarditis is substantialexcept in operated patients with pul-monary stenosis, atrial septal defect,ventricular septal defect, and patentductus arteriosus. If residual ventricularseptal defect or patent ductus arterio-sus leaks are present, the risk persistspostoperatively.

• Adult patients with congenital heart disease, except those with operated pulmonary stenosis, atrial septal defect,ventricular septal defect and patentductus arteriosus, should be followed in conjunction with a specialized centerfor adult congenital heart disease.

K E Y P O I N T S

• The prevalence of peripheral arterialdisease defined by the ankle/brachialindex (values <0.90) is 12% amongadults but increases to more than 20%among elderly persons.

• More than half of patients with periph-eral arterial disease do not have classicsymptoms of claudication, approxi-mately 30% to 40% have claudicationduring exertion, and less than 10%experience symptoms of critical legischemia (pain in the distal foot at rest and ischemic ulceration).

• The history and physical examinationcan suggest the presence of peripheralarterial disease, but confirmationrequires measurement of the ankle–brachial index. An index less than 0.90 is considered diagnostic for peripheralarterial disease.

• Patients with peripheral arterial disease,whether symptomatic or not, are at highrisk for myocardial infarction, stroke,and death. This risk is increased sixfoldcompared with persons without periph-eral arterial disease.

• In contrast to the severe natural historyof the systemic disease, symptoms ofclaudication remain stable over 5 years.These patients are at low risk of limb loss.

Clinical Evaluation

Ankle–Brachial IndexPatients who meet the criteria in Figure 20 should be considered at risk forperipheral arterial disease. These patients should have measurement of systolicblood pressure in the arms and ankles by using a simple, continuous-waveDoppler. In each ankle, pressures are obtained in the posterior tibial and dor-salis pedis arteries; those values are divided by the value obtained from the armwith the highest pressure. In healthy persons, the ankle–brachial index is greaterthan 1.00; ratios of 0.90 or less are considered diagnostic of peripheral arterialdisease. When performed in primary care office sites, this simple test detectedsignificant peripheral arterial disease in 29% of patients older than 70 years ofage or those 50 to 69 years of age who had diabetes or smoked. In patients con-sidered for revascularization, further disease localization can be performed non-invasively in a vascular laboratory.

91

F I G U R E 2 0 .Evaluation of patients in whom peripheral arterial disease (PAD) is suspected.Patients should be evaluated for PAD if they if they are at increased risk from age or presence of atherosclerotic risk factors, have leg symptoms on exertion, orhave distal limb ulceration for which history and examination do not provide an obvious explanation.

ABI = ankle–brachial index; PVR = pulse volume recordings

Reprinted with permission from: Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med. 2001;344:1608-21.

Measure ABI

>1.300.91–1.30

• Age 50–69 years and smoking or diabetes• Age ≥70 years• Leg symptoms with exertion• Abnormal leg vascular examination, or ischemia• Coronary, carotid, or renal arterial disease

Vascular laboratory:PVRToe pressureDuplex imaging

Normal results: no PAD

Abnormalresults

Evaluate othercauses of legsymptoms

Normal postexerciseABI: no PAD Decreased

postexercise ABI

Claudication symptomsABI treadmill test

≤0.90


Management of Atherosclerotic Risk Factors

92

Management of Atherosclerotic Risk Factors• What are the risk factors for peripheral arterial disease?• What medications reduce the risk of ischemic events in peripheral arterial disease?• How should symptomatic patients be treated for claudication and critical leg

ischemia?

The major risk factors for peripheral arterial disease include increasing age after40 years, cigarette smoking, and diabetes mellitus. Hyperlipidemia, hyperten-sion and hyperhomocysteinemia are also important risk factors. Given these riskfactors, the systemic nature of atherosclerosis, and the high risk for ischemicevents, patients with peripheral arterial disease should be considered candidatesfor secondary prevention strategies that include aggressive risk factor modifica-tion and use of antiplatelet drugs. Observational studies have suggested thatsmoking cessation will slow the progression to critical leg ischemia and reducethe risk of myocardial infarction and vascular death. Smoking cessation is alsocritical to the success of angioplasty or vascular surgery in terms of maintainingpatency. In patients with diabetes, intensive blood glucose control preventsmicrovascular complications, but the benefits on arterial disease are less certain.Several studies have shown that intensive therapy was associated with a trendtoward fewer cardiovascular events, but the risk of peripheral arterial disease wasnot reduced, because patients with peripheral arterial disease received less inten-sive treatment for lipid disorder and hypertension (Dormandy andRutherford; Hirsch et al.).

Lipid-lowering therapy has been shown to reduce the risk for peripheralarterial disease and symptoms of claudication. The Heart Protection Studydemonstrated that use of a statin in patients with peripheral arterial disease(with or without prior cardiac disease) reduced the risk of subsequent myo-cardial infarction, stroke, and vascular death (MRC/BHF Heart ProtectionStudy). The current recommendation for patients with peripheral arterial disease is to achieve a low-density lipoprotein cholesterol level less than 100mg/dL and a triglyceride level less than 150 mg/dL. A statin should be givenas initial therapy. Niacin is also an important drug because it increases serumhigh-density cholesterol concentrations, decreases serum triglyceride concen-trations, and does not worsen glucose metabolism in these patients.

Hypertension should be treated according to the guidelines of the SixthJoint National Committee, taking into account that patients with peripheralarterial disease are at particularly high risk for cardiovascular events (SixthReport of the Joint National Committee). Data from the Heart OutcomesPrevention Evaluation Study suggest that angiotensin-converting enzymeinhibitors are particularly beneficial in patients with peripheral arterial disease toprevent myocardial infarction, stroke, and death and to decrease blood pressure(Yusuf et al.). β-Adrenergic antagonist drugs were once thought to worsensymptoms of claudication. However, a meta-analysis and a critical review of sev-eral randomized, controlled studies concluded that β-adrenergic antagonists aresafe in patients with peripheral arterial disease. β-Blockers should also be con-sidered in patients undergoing vascular surgery, since these drugs reduce thepreoperative risk of cardiovascular events.

Antiplatelet TherapyIn patients with cardiovascular disease, antiplatelet drugs reduce the risk of sub-sequent nonfatal myocardial infarction, ischemic stroke, and vascular death.These conclusions are based primarily on the meta-analyses conducted by the Antiplatelet Trialists’ Collaboration of antiplatelet drug therapy. Amongpatients with peripheral arterial disease, antiplatelet therapy was associated with

Dormandy JA, Rutherford RB.Management of peripheral arterial disease(PAD). TASC Working Group. TransAtlanticInter-Society Concensus (TASC). J VascSurg. 2000;31:S1-S296. PMID: 10666287Hirsch AT, Criqui MH, Treat-Jacobson D,Regensteiner JG, Creager MA, Olin JW,et al. Peripheral arterial disease detection,awareness, and treatment in primary care.JAMA. 2001;286:1317-24.PMID: 11560536MRC/BHF Heart Protection Study of cho-lesterol lowering with simvastatin in 20,536high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22.PMID: 12114036The sixth report of the Joint NationalCommittee on prevention, detection, evalua-tion, and treatment of high blood pressure.Arch Intern Med. 1997;157:2413-46.PMID: 9385294Yusuf S, Sleight P, Pogue J, Bosch J,Davies R, Dagenais G. Effects of anangiotensin-converting-enzyme inhibitor,ramipril, on cardiovascular events in high-riskpatients. The Heart Outcomes PreventionEvaluation Study Investigators. N Engl JMed. 2000;342:145-53. PMID: 10639539

K E Y P O I N T S

• The risk factors for peripheral arterialdisease are similar to those for coronaryartery disease. All patients requireaggressive risk modification by smokingcessation, decreasing of glucose levels,reduction of low-density lipoproteincholesterol level to less than 100 mg/dL,and control of blood pressure.

• All patients with peripheral arterial dis-ease should receive antiplatelet therapy,including aspirin or clopidogrel.

• Medical therapy for claudication is mosteffectively accomplished with a super-vised exercise program or medications,such as cilostazol.

• Angioplasty is most effective forpatients with disease of the iliac artery.This procedure may be indicated inpatients with severe claudication notresponsive to medical therapy or thosewith critical leg ischemia.

• Peripheral vascular surgery is requiredfor patients with critical leg ischemia.


a statistically significant 23% reduction in the likelihood of cardiovascular events(Collaborative meta-analysis of randomised trials of antiplatelet therapy).In terms of drug selection, aspirin is approved for secondary prevention inpatients with a history of cardiac disease and ischemic stroke. Among patientswith peripheral arterial disease, aspirin was associated with a nonsignificant 18%reduction in the likelihood of events. Although only a trend toward benefit was found, the American College of Chest Physicians recommends aspirin atdosages of 81 to 325 mg/d in patients with peripheral arterial disease.Clopidogrel, a thienopyridine drug, may be superior to aspirin in peripheralarterial disease on the basis of the results of the Clopidogrel Versus Aspirin inPatients at Risk of Ischemic Events (CAPRIE) study. Clopidogrel is the onlyantiplatelet agent that is approved by the U.S. Food and Drug Administrationfor use in patients with peripheral arterial disease who do not also have a his-tory of myocardial infarction or ischemic stroke (CAPRIE SteeringCommittee).

Medical Treatment of ClaudicationPatients with claudication have marked impairment in exercise performance,with peak oxygen consumption that is 50% of the age-predicted value; this find-ing is similar to that in patients with New York Heart Association class III heartfailure. Thus, the goals of therapy for claudication are to relieve exertionalsymptoms, improve walking capacity, and increase quality of life (Figure 21).These goals are similar for patients with critical leg ischemia, with the additionaldesired outcomes of relieving ischemic rest pain, healing ischemic ulceration,and preventing limb loss (Hiatt).

Patients with claudication should first consider a formal exercise trainingprogram. Exercise improves not only treadmill walking distance but also qual-ity of life and community-based functional capacity. Furthermore, an exerciseprogram for claudication results in clinical benefits similar to those of surgicalbypass and possibly greater benefits than angioplasty. The best results require a motivated patient in a supervised setting, typically modeled after cardiac rehabilitation. A reimbursement code is now available for these programs(Stewart et al.).

Drug therapy can also be considered for claudication. Pentoxifylline isapproved by the U.S. Food and Drug Administration, but most patients maynot notice an improvement in walking distance, and the drug has been shownin multiple randomized, controlled studies to be no more effective thanplacebo. Cilostazol is also approved, and several randomized, controlled trialshave documented a benefit in terms of walking distance and quality of life(Dawson et al.). Cilostazol cannot be recommended in patients with claudica-tion who also have heart failure. This black box warning was required by theU.S. Food and Drug Administration because of the known association of thisclass of drugs with excess mortality in patients with heart failure.

Indications and Results of Angioplasty and Vascular SurgeryPatients with critical leg ischemia should be considered for vascular surgery orangioplasty, which is necessary to heal ischemic lesions, relieve ischemic restpain, and prevent amputation. Angioplasty can also be considered to treat clau-dication. Angioplasty guidelines emphasize that more proximal lesions havebetter patency rates and durability than do more distal lesions. Below theinguinal ligament, rates of initial success and long-term patency have been lesswell studied but are not as good as for more proximal lesions. Surgery is prin-cipally used to treat severe critical leg ischemia rather than claudication becauseof the associated morbidity and mortality of surgery, the relatively benign nat-

93

Collaborative meta-analysis of randomisedtrials of antiplatelet therapy for prevention ofdeath, myocardial infarction, and stroke inhigh risk patients. BMJ 2002;324:71-86.PMID:11786451A randomised, blinded, trial of clopidogrelversus aspirin in patients at risk of ischaemicevents (CAPRIE). CAPRIE SteeringCommittee. Lancet. 1996;348:1329-39.PMID: 8918275Hiatt WR. Medical treatment of peripheralarterial disease and claudication. N Engl JMed. 2001;344:1608-21. PMID: 11372014Stewart KJ, Hiatt WR, Regensteiner JG,Hirsch AT. Exercise training for claudica-tion. N Engl J Med. 2002;347:1941-51.PMID: 12477945Dawson DL, Cutler BS, Hiatt WR,Hobson RW 2nd, Martin JD, Bortey EB,et al. A comparison of cilostazol and pentoxif-ylline for treating intermittent claudication.Am J Med. 2000;109:523-30.PMID: 11063952


94

F I G U R E 2 1 .Treatment of peripheral arterial disease.All patients with peripheral arterial disease, regardless of symptom severity, should undergo risk factor modification to achieve the listed treatment goals andreceive antiplatelet therapy with aspirin or clopidogrel. Angiotensin-converting-enzyme (ACE) inhibitors should be considered to help prevent ischemic eventsindependent of blood pressure (BP) lowering. Treadmill testing can be considered to define changes in the absolute claudication distance (ACD) and the initialclaudication distance (ICD) before and after therapy. Questionnaires, including the Medical Outcomes Short Form 36 (SF-36) and the Walking ImpairmentQuestionnaire (WIQ), can provide information on changes in functional status and quality of life with claudication therapy. Patients who do not improve andremain disabled and those have worsening symptoms should have additional localization of the occlusive lesions to plan endovascular or surgical intervention.

HbA1c = hemoglobin A1c; LDL = low-density lipoprotein; MRA = magnetic resonance angiography

Reprinted with permission from: Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med. 2001;344:1608-21.

Continue


Assess cardiovascularrisk factors

Risk factor modification:Smoking cessation LDL cholesterol <100 mg/dLHbA1c <7.0% BP <130/85 mm Hg

ACE inhibition Antiplatelet therapy

Aspirin or clopidogrel Improvedsymptoms

Symptomsdeteriorate

Localize the lesion:Hemodynamic localizationDuplex ultrasonographyMRAConventional angiography

RevascularizationAngioplastyBypass surgery

Claudication therapy:Supervised exerciseCilostazol

Assess claudication severity:Treadmill ACD and ICDSF-36 and WIQ

Critical legischemia

Valve Disease in Pregnancy, Including Anticoagulation

ural history of claudication, and the efficacy of medical (particularly exercise)therapies. In aortoiliac disease, prosthetic materials are usually implanted.Aortoiliac surgery is associated with an average mortality rate of 3% and mor-bidity rate of 8%. In patients with femoropopliteal disease, the best conduit issaphenous vein. Femoropopliteal surgery with vein bypass is associated with amortality rate of 2%, a morbidity rate of 5% to 10%, and a 5-year patency rateof 70% to 80%. The use of prosthetic material (which is required if a vein is notavailable) reduces 5-year patency rates to 50%. Distal femorotibial operationsfor limb salvage have similar morbidity and mortality rate as does femoro-popliteal surgery but slightly lower 5-year patency rates of 50% to 60%.

Pregnancy and Cardiovascular Disease

Approximately 2% of pregnancies occur in women with heart disease. Congenitalheart disease is the predominant form of heart disease among pregnant womenin developed countries, whereas rheumatic heart disease predominates in devel-oping countries. Heart disease does not preclude successful pregnancy, but therisk to mother and fetus is increased and requires special management.

Valve Disease in Pregnancy, Including Anticoagulation• Which valve lesions are poorly tolerated in pregnancy?• What are the risks of and options for anticoagulation for a woman with a mechanical

heart valve who wishes to become pregnant?

During normal pregnancy, physical findings may mimic heart disease. The pul-monic S2 may be prominent, and there often is persistent splitting of the sec-ond heart sound. S3 is audible in more than 80% of normal pregnant women.An early peaking ejection systolic murmur is audible in more than 90% of normal pregnant women and is caused by a pulmonary outflow murmur(Figure 22). Abnormal physical findings include S4, a loud (≥3/6) systolicmurmur, and a diastolic murmur or fixed splitting of S2.

Because of the blood volume expansion and resultant increase in strokevolume and cardiac output during pregnancy, fixed obstructive cardiac lesions,particularly left-sided obstructive lesions (such as mitral and aortic valve steno-sis), generally are poorly tolerated during pregnancy. In contrast, regurgitantvalve lesions are relatively well tolerated because of the decrease in systemic vas-cular resistance. The effect of pregnancy on a patient with valve disease dependson the effect of the specific valve lesion on ventricular function and pulmonaryartery pressures and on the New York Heart Association (NYHA) functionalclass (Hameed et al.).

Percutaneous Valve InterventionInterventional procedures are effective alternatives to surgery in several cardiacdisorders that occur during pregnancy. Preliminary reports are optimistic; how-ever, no large series have reported on the safety of cardiac interventions duringpregnancy.

Percutaneous mitral commissurotomy is the strategy of choice in pregnantwomen with severe mitral stenosis whose symptoms cannot be controlled withmedication. Marked relief of symptoms and excellent maternal and fetal out-comes have been reported (de Souza et al.). This procedure should beattempted only in centers that have extensive experience with percutaneousmitral procedures and also have surgical backup. Special considerations for bal-loon valvuloplasty in the gravid state include radiation exposure and pregnancy

95

Hameed A, Karaalp IS, Tummala PP,Wani OR, Canetti M, Akhter MW, et al.The effect of valvular heart disease on mater-nal and fetal outcome of pregnancy. J AmColl Cardiol. 2001;37:893-9.PMID: 11693767de Souza JA, Martinez EE Jr, AmbroseJA, Alves CM, Born D, Buffolo E,Carvalho AC. Percutaneous balloon mitralvalvuloplasty in comparison with open mitralvalve commissurotomy for mitral stenosisduring pregnancy. J Am Coll Cardiol.2001;37:900-3. PMID: 11693768

K E Y P O I N T S

• Normal physical findings during preg-nancy may be misinterpreted as abnormal.

• Cardiac output increases by 30% to 50%during normal pregnancy and to about80% above baseline during labor anddelivery.

• Use of warfarin during the firsttrimester of pregnancy is associatedwith an increased risk of miscarriageand warfarin embryopathy, but it maybe the preferred method of anticoagula-tion for patients with older mechanicalmitral prostheses, particularly if thewarfarin dose is low.

• Vaginal delivery is the preferred modeof delivery in most women with heartdisease; however, cesarean deliveryshould be performed if labor occurs dur-ing warfarin anticoagulation because ofthe risk of fetal intracranial hemorrhage.

Bhargava B, Agarwal R, Yadav R, BahlVK, Manchanda SC. Percutaneous balloonaortic valvuloplasty during pregnancy: use ofthe Inoue balloon and the physiologic ante-grade approach. Cathet Cardiovasc Diagn.1998;45:422-5. PMID: 9863752Chambers CE, Clark SL. Cardiac surgeryduring pregnancy. Clin Obstet Gynecol.1994;37:316-23. PMID: 8033446


96

outcome. No increase in the incidence of reported congenital malformations orabortions has been reported with fetal radiation exposure of less than 500 cGy,which can be achieved by shielding the gravid uterus and keeping fluoroscopytime to a minimum. Transesophageal echocardiographic guidance has also beenused during the procedure to reduce radiation exposure. Percutaneous balloonaortic valvuloplasty has been reported as a safe and effective palliative procedureduring pregnancy (Bhargava et al.). Pulmonary balloon valvuloplasty is rarelyrequired during pregnancy but has been reported. These procedures should beconsidered alternatives to surgery in patients with severe symptomatic native-valve stenosis identified during pregnancy.

Cardiac Surgery during PregnancyCardiac surgery should be reserved for patients refractory to medical manage-ment in whom further delay would prove detrimental to maternal health.Cardiopulmonary bypass can adversely affect both the mother and fetus(Chambers and Clark). High-flow, high-pressure, normothermic perfusionappears safest from a fetal standpoint. Fetal heart rate monitoring is recom-

F I G U R E 2 2 .Normal hemodynamics of pregnancy.

Aldo = aldosterone; Ang II = angiotensin II; Epo = erythropoietin; hCSm = human chorionic somatomammotropin; PG = prostaglandins; Prl = prolactin

Reproduced with permission from: Teerlink JR, Foster E. Valvular heart disease in pregnancy. A contemporary perspective. Cardiol Clin. 1998;16:573-98.

0 8 16 24 32 40

↑ Estrogens

↑ Renin

↑ Ang II

↑ Aldo

H2O & Na+

Retention

↑ Plasma Volume

Weeks of Pregnancy

↑ SympatheticOutput

Low-resistancePlacental Circulation

Vasodilation

↑ Estrogens, PG,Heat Production

↓ Systemic VascularResistance

↓ Stroke Volume

↑ Vena cavalObstruction

Enlarged Uterus

Heart rate

Stroke Volume

30-50%Increase inCardiacOutput

+

↑ hCSm, Prl, Epo

↑ Erythrocytes

↑ Total BloodVolume

↑ Stroke Volume


mended during cardiopulmonary bypass. When cardiac surgery is necessaryduring pregnancy, the optimal time is between the 24th and 28th week of preg-nancy, and the duration of cardiopulmonary bypass should be kept as short aspossible. A multidisciplinary team approach is required to optimize maternaland fetal outcomes. The data on maternal and fetal outcome for cardiac surgeryrequiring cardiopulmonary bypass are mostly derived from small, single-centerseries. The maternal mortality rate ranges from 1% to 5%, and fetal mortalityrates are 15% to 38%.

Anticoagulation during Pregnancy

Case 16A 25-year-old woman with a St. Jude mitral prosthesis is in herearly first trimester of pregnancy. She is referred for review ofrecommended anticoagulation options.

Hematologic changes that occur during normal pregnancy result in an overallincreased risk of thrombosis or embolism. The safety of anticoagulation duringpregnancy (Chan et al.) raises serious concerns, including the fact that heparinmay not prevent mechanical valve thrombosis and that warfarin can causeembryopathy. In addition, although the data are divergent, accelerated biopros-thesis deterioration has been reported during pregnancy (Salazar et al., 1999).

Prosthetic Heart ValvesThe management of patients with mechanical prosthetic valves or other con-ditions that require anticoagulation during pregnancy poses a therapeuticdilemma because of the competing risks to mother and fetus. Patients shouldundergo prepregnancy counseling to discuss the risks and benefits to motherand fetus. Data are limited on the safety of various anticoagulation regimens,and controversy persists regarding the best treatment option. The best type ofheart valve prosthesis to use in women of childbearing age who require valvereplacement is debated. Some data have suggested that premature valve deteri-oration may occur in bioprosthetic valves during pregnancy, but this has notbeen documented conclusively or demonstrated experimentally (North et al.).One report suggested that reoperation (required for most young patients withbioprosthetic valves) carries a higher risk of morbidity and mortality than doesthe risk of anticoagulation during pregnancy.

Pregnant women with a mechanical heart valve have approximately a 10%risk for development of prosthetic valve thrombosis or another life-threateningcomplication. The best management for a pregnant woman who requires anticoagulation is controversial.

HeparinHeparin does not cross the placenta. The primary concern with heparin use isthe 12% to 24% incidence of thromboembolic complications, including fatalvalve thrombosis, in high-risk pregnant women given subcutaneous unfraction-ated heparin. The efficacy of adjusted-dose subcutaneous heparin has not beenestablished (Salazar et al., 1996; Elkayam). The heparin dose should beadjusted so that the partial thromboplastin time is at least two to three timesthe control value 6 hours after the dose is administered. Recent reports havesuggested that subcutaneous heparin may not provide sufficient anticoagulationfor very high-risk patients (for example, those with caged-ball or tilting-diskmechanical mitral prosthesis) (Figure 23).

97

Chan WS, Anand S, Ginsberg JS.Anticoagulation of pregnant women withmechanical heart valves: a systematic reviewof the literature. Arch Intern Med.2000;160:191-6. PMID: 10647757Salazar E, Espinola N, Roman L,Casanova JM. Effect of pregnancy on theduration of bovine pericardial bioprosthesesAm Heart J. 1999;137(4 Pt 1):714-20.PMID: 10097235North RA, Sadler L, Stewart AW,McCowan LM, Kerr AR, White HD.Long-term survival and valve-related compli-cations in young women with cardiac valvereplacements. Circulation. 1999;99:2669-76.PMID: 10338461Salazar E, Izaguirre R, Verdejo J,Mutchinick O. Failure of adjusted doses ofsubcutaneous heparin to prevent throm-boembolic phenomena in pregnant patientswith mechanical cardiac valve prostheses. J Am Coll Cardiol. 1996;27:1698-703.PMID: 8636556Elkayam UR. Anticoagulation in pregnantwomen with prosthetic heart valves: a doublejeopardy. J Am Coll Cardiol. 1996;27:1704-6.PMID: 8636557


98

Prolonged heparin therapy (intravenous or subcutaneous) can result inthrombocytopenia, osteoporosis, and alopecia. Erratic absorption of subcuta-neously delivered heparin may occur, and frequent monitoring of the partialthromboplastin time to ensure therapeutic anticoagulation is mandatory.

WarfarinBecause warfarin has a low molecular weight, it crosses the placenta and resultsin fetal anticoagulation. The effect of warfarin on the fetus is greater than thaton the mother because of reduced vitamin K–dependent factors in the fetalliver. Fetal anticoagulation increases the risk for spontaneous abortion, prema-turity, fetal deformity, and stillbirth. Retroplacental hemorrhage and fetalintracranial hemorrhage are additional risks to the fetus.

Historic reports describe a 30% risk of embryopathy with administration ofwarfarin during the first trimester. More recent data suggest the incidence ofwarfarin embryopathy to be between 4% and 10%. The maternal dose of war-farin during the first trimester appears to be important. The risk of warfarinembryopathy appears to be very low with a warfarin dose less than 5 mg/d(Vitale et al.). The risk is highest if exposure occurs during the 6th to 12thweek of gestation. Warfarin embryopathy results in bone and cartilaginousabnormalities with chondrodysplasia, nasal hypoplasia optic atrophy, blindness,mental retardation, and seizures. Warfarin does not enter breast milk and, thus,can be administered safely to women who breast-feed their infants.

Anticoagulation Management during PregnancyThe American Heart Association and American College of Cardiology providedrecommendations regarding anticoagulation during pregnancy (Bonow et al.).For patients with high-risk prostheses or prior thromboembolic events, contin-uous intravenous heparin during the first trimester or continuation of warfarinand aspirin are considered the treatment options of choice. Subcutaneous dose-adjusted heparin with a partial thromboplastin time two to three times the con-trol value is considered a less safe regimen. In the United States, owing to therisk of embryopathy, informed consent should be obtained if warfarin is usedduring the first trimester of pregnancy.

Warfarin is the anticoagulation agent of choice for patients during the sec-ond trimester of pregnancy. The warfarin dose should be adjusted to the inter-national normalized ratio.

F I G U R E 2 3 .Anticoagulation options during pregnancy.

PTT = partial thromboplastin time

Vitale N, De Feo M, De Santo LS, PolliceA, Tedesco N, Cotrufo M. Dose-depend-ent fetal complications of warfarin in preg-nant women with mechanical heart valves. J Am Coll Cardiol. 1999;33:1637-41.PMID: 10334435Bonow RO, Carabello B, de Leon AC Jr,Edmunds LH Jr, Fedderly BJ, Freed MD,et al. Guidelines for the management ofpatients with valvular heart disease: executivesummary. A report of the American Collegeof Cardiology/American Heart AssociationTask Force on Practice Guidelines(Committee on Management of Patientswith Valvular Heart Disease). Circulation.1998;98:1949-84. PMID: 9799219

Current Recommendations

First TrimesterEarly warfarin cessation

Subcutaneous heparinPTT >2.5 times control

Second TrimesterWarfarin

Treatment of choiceINR adjusted

Third TrimesterDiscontinue warfarin

36-38 weeksStart IV heparinStop peripartumResume heparin

4 hr after delivery

Continue warfarinHigh-risk patientInformed consentDose <5 mg/day

OR

Cardiomyopathy during Pregnancy, including Peripartum Cardiomyopathy

During the third trimester, warfarin therapy should be continued until 36weeks of pregnancy. In anticipation of delivery, patients should be hospitalizedand treatment with intravenous heparin should be started. The partial thrombo-plastin time should be 2.5 to 3.5 times the control value.

Labor and delivery is a particularly high-risk time for patients who requireanticoagulation during pregnancy. Delivery should be planned, and intravenousheparin treatment should be stopped peripartum and resumed 4 to 6 hoursafter delivery, in the absence of bleeding. Vaginal delivery is the preferred modeof delivery in most women with heart disease; however, cesarean deliveryshould be performed if labor occurs during warfarin anticoagulation because ofthe risk of fetal intracranial hemorrhage (Table 30). Heparin should beresumed 4 to 6 hours after delivery in the absence of bleeding.

Currently, data are insufficient to support use of low-molecular-weightheparin for anticoagulation during pregnancy. No teratogenic effects have beenreported with low-molecular-weight heparins, and they do not cross the pla-centa. The Sixth ACCP Conference on Antithrombotic Therapy supports useof low-molecular-weight heparin (adjusted dose: enoxaparin, 1 mg/kg every 12hours subcutaneously, or dalteparin, 200 IU/kg daily) throughout pregnancyexcept 24 hours before delivery, when the recommendation is to switch tointravenous unfractionated heparin (American College of Chest Physicians).However, a recent advisory from the U.S. Food and Drug Administration haschanged the product labeling to state that enoxaparin is not recommended forprosthetic valves, including during pregnancy.

Low-dose aspirin (81 mg) is safe to use during pregnancy. It is recom-mended for patients with shunts (for example, those with atrial septal defect),cyanosis, or a biologic-valve prosthesis. However, the antiplatelet effect has not beenproven. A low dose of aspirin may also decrease the incidence of preeclampsia.

Dipyridamole should not be used during pregnancy. No data are availableon the effects of ticlopidine or clopidigrel during pregnancy. Information is lim-ited on administration of glycoprotein IIB/IIIA inhibitors during pregnancy.Thrombolytic therapy has been used in pregnancy, and several cases of emer-gency use have been reported. Thrombolytic therapy should be considered inthe critically ill patient with valve thrombosis or acute coronary syndrome whois not a candidate for cardiac surgery or percutaneous intervention.


• Is the risk of pregnancy increased in a patient with a left ventricular ejection fractionless than 40%?

• Are angiotensin-converting enzyme inhibitors safe to use during pregnancy?• Is pregnancy contraindicated in a patient with a history of peripartum cardiomyopathy?

The management of pregnant women with cardiomyopathy in NYHA func-tional class I or II should include limiting strenuous exercise, getting adequatesleep and rest, maintaining a low-salt diet, avoiding anemia (maintaining ahemoglobin level >11 g), and undergoing frequent prenatal examinations (bothobstetric and cardiovascular). A Holter monitor is indicated to screen for malig-nant arrhythmias. In symptomatic women (NYHA functional class >II) andthose with systemic ventricular function less than 40%, pregnancy should beavoided because of the risk of pregnancy-related complications (Siu et al.). Theoption to continue or interrupt the pregnancy should be discussed with thepatient. If the patient opts to continue her pregnancy, bed rest is often required

99

American College of Chest Physicians.Sixth ACCP Consensus Conference onAntithrombotic Therapy. Available at:http://www.chestnet.org/guidelines/antithrombotic/.Siu SC, Sermer M, Colman JM, AlvarezAN, Mercier LA, Morton BC, et al.Prospective multicenter study of pregnancyoutcomes in women with heart disease.Circulation. 2001;104:515-21.PMID: 11479246

TABLE 30 Indications for CesareanSection in Women withCardiovascular Disease

Obstetric reasons

Anticoagulation with warfarin

Fixed obstructive cardiac lesion*

Pulmonary hypertension*

Unstable aortic lesion*

*These items are controversial.


100

during part of the pregnancy, and close cardiac and obstetric monitoring aremandatory. Treatment of congestive heart failure is more difficult in pregnantthan in nonpregnant women. Conservative measures are very important; how-ever, pharmacologic therapy may be required.

Pharmacologic Therapy for Congestive Heart Failure during PregnancyDiuretics can be used to treat congestive heart failure that is not controlled bysodium restriction and other conservative measures. No single diuretic is clearlycontraindicated. Experience is greatest with the thiazide diuretics and furo-semide. Diuretics impair uterine blood flow and placental perfusion.Continuation of diuretic therapy initiated before conception does not seemunfavorable. However, routine initiation of diuretic medications during preg-nancy is not recommended. Use of diuretics should be limited to the treatmentof symptomatic congestive heart failure with clear evidence of elevated centralvenous pressure.

Use of angiotensin-converting enzyme inhibitor therapy is contraindicatedduring pregnancy. Maternal–fetal transfer of captopril has been documented,and, in animals, exposure to angiotensin-converting enzyme inhibitors duringpregnancy produced prolonged fetal hypotension and death. In addition, use ofangiotensin-converting enzyme inhibitors during pregnancy increases the riskfor early delivery, low birth weight, oligohydramnios, or neonatal anuria andrenal failure (or some combination of these). Angiotensin II blocking agentsshould also be avoided during pregnancy, as similar problems with these agentshave been reported. Digoxin can be administered safely during pregnancy.

β-Blockers, particularly metoprolol, atenolol, and labetolol, have beensafely used during pregnancy. Fetal monitoring is recommended because of therisk of intrauterine growth retardation and fetal bradycardia. Hydralazine andnitrate therapy in combination can also be used to treat congestive heart failureduring pregnancy.

Peripartum Cardiomyopathy

Case 17A 29-year-old woman with a history of peripartum cardio-myopathy and mild persistent left ventricular dysfunction isreferred for pregnancy counseling. She has one healthy childand is interested in having another pregnancy.

Peripartum cardiomyopathy is defined as congestive heart failure that occurslate in pregnancy or during the early postpartum period (the last trimester orup to 6 months postpartum) in the absence of congenital, coronary, or valvularheart disease or another recognized cause of heart failure. Most commonly, it isdiagnosed during the first month postpartum. The incidence ranges from1:1,300 to 1:15,000 pregnancies in the United States and is higher in certainparts of Africa. Peripartum cardiomyopathy occurs more frequently in twinpregnancies, multiparous women, women older than 30 years of age, and blackwomen. The cause is unknown and the prognosis varies; improvement in leftventricular function within 6 months after delivery is expected in 50% of women(Pearson et al.). Management is supportive and includes standard treatmentfor congestive heart failure. Recurrence with subsequent pregnancies is com-mon, and the risk of recurrence is greater in women with persistent left ven-tricular dysfunction (Elkayam et al.). Thus, women who have a history of aserious episode of peripartum cardiomyopathy and those with persistent leftventricular dysfunction should be counseled to avoid pregnancy.

K E Y P O I N T S

• Fifty percent of women with peripartumcardiomyopathy have improvement inleft ventricular function within 6 monthsafter delivery.

• Because recurrence of peripartum cardiomyopathy is common, repeatedpregnancy is contraindicated.

• Administration of angiotensin-convert-ing enzyme inhibitors and angiotensin IIinhibitors is contraindicated duringpregnancy. Digoxin and hydralazine areconsidered safe during pregnancy andbreast feeding.

• Pregnancy should be avoided if the leftventricular ejection fraction is less than40% or the NYHA functional class ishigher than II.

Pearson GD, Veille JC, Rahimtoola S,Hsia J, Oakley CM, Hosenpud JD, et al.Peripartum cardiomyopathy: National Heart,Lung, and Blood Institute and Office ofRare Diseases (National Institutes of Health)workshop recommendations and review.JAMA. 2000;283:1183-8. PMID: 10703781Elkayam U, Tummala PP, Rao K, AkhterMW, Karaalp IS, Wani OR, et al. Maternaland fetal outcomes of subsequent pregnan-cies in women with peripartum cardiomy-opathy. N Engl J Med. 2001;344:1567-71.PMID: 11372007

Congenital Heart Disease in Pregnancy

Congenital Heart Disease in Pregnancy• Is the risk of congenital heart disease higher in the offspring of a mother with

congenital heart disease than in the general population?• Is prophylaxis against endocarditis required during an uncomplicated delivery

in a patient with repaired congenital heart disease?

Case 18A 25-year-old woman presents at 18 weeks of gestation.Physical examination and echocardiography confirm a 1.5-cmsecundum atrial septal defect with a normal right ventricularpressure.

Elective closure of an atrial septal defect with an important left-to-right shuntbefore pregnancy is usually recommended. Closure during pregnancy is notrecommended in the absence of symptoms. Meticulous management aroundthe time of delivery is recommended to avoid paradoxical embolism (Zuber et al.).

Currently, an increasing number of women with congenital heart diseaseare reaching childbearing age and are considering pregnancy (Colman et al.).This is primarily because congenital heart disease is being diagnosed and man-aged earlier. Patients should be counseled about pregnancy and the increasedrisk of congenital heart disease in the fetus (Romano-Zelekha et al.). The inci-dence of congenital heart disease in the general population is about 1%. Theoffspring of women with congenital heart disease have a 5% to 6% incidence ofcongenital heart disease. Usually, the lesion in the offspring is not the same kindas in the mother, except for syndromes in which the incidence of recurrencewith each pregnancy may be up to 50% (for example, Marfan syndrome orhypertrophic cardiomyopathy). Occasionally, familial left-sided obstructive lesionsand atrial septal defects may occur.

Patients with Marfan syndrome, bicuspid aortic valve, coarctation of theaorta, and other aortopathies are predisposed to aortic dissection and aneurysmformation, particularly during pregnancy. Prepregnancy aortic assessment isimperative in these patients. Once pregnancy occurs, β-blockers may decreasethe rate of dilation of the aortic root; this therapy should be considered in allpregnant patients with aortopathy. Regular aortic follow-up is recommendedduring pregnancy in patients with Marfan syndrome or other aortopathies.

Fetal echocardiography is used routinely in women with congenital heartdisease to detect congenital heart disease in the fetus. Endocarditis prophylaxisis generally recommended around the time of delivery in high-risk patients.

Cyanosis inhibits fetal growth and development. Pregnancy is generallycontraindicated in women with severe cyanosis. Surgical repair of the underlyingcardiac anomaly should be considered before pregnancy, if possible (for exam-ple, Ebstein’s anomaly with right-to-left shunt related to an atrial septal defect).

In patients with repaired complex congenital heart disease, uncertaintyremains about the ability to conceive, the effects of pregnancy on maternalheart disease, and the effects of heart disease on the fetus.

Primary and Secondary Pulmonary Hypertension• Is severe pulmonary hypertension always a contraindication to pregnancy?• Above what pulmonary artery pressure is it unsafe to proceed with pregnancy?

Case 19A 31-year-old woman presents with dyspnea during early preg-nancy. She has severe primary pulmonary hypertension. You areasked to review the management options.

101

Zuber M, Gautschi N, Oechslin E,Widmer V, Kiowski W, Jenni R. Outcomeof pregnancy in women with congenitalshunt lesions. Heart. 1999;81:271-5.PMID: 10026351Colman JM, Sermer M, Seaward PG, SiuSC. Congenital heart disease in pregnancy.Cardiol Rev. 2000;8:166-73.PMID: 11174890Romano-Zelekha O, Hirsh R, Blieden L,Green M, Shohat T. The risk for congenitalheart defects in offspring of individuals withcongenital heart defects. Clin Genet.2001;59:325-9. PMID: 11359463

K E Y P O I N T S

• Congenital heart disease is the mostcommon form of structural heart dis-ease that affects women of childbearingage in the United States.

• Pregnant cyanotic women have a highrisk of fetal loss. Cyanosis is a recog-nized handicap to fetal growth, result-ing in low-birth-weight infants.

• The incidence of congenital heart dis-ease in the offspring of women withcongenital heart disease is about 5%.

Primary and Secondary Pulmonary Hypertension

102

Severe pulmonary hypertension in pregnancy (pulmonary artery pressure >70%systemic), whether primary or secondary, carries a 30% to 50% risk of maternaldeath. If pulmonary hypertension is identified, the patient should be counseledagainst pregnancy. If pregnancy occurs in a patient with established severe pul-monary hypertension, she should be counseled against continuing the preg-nancy. If the pregnancy is continued, meticulous medical monitoring is recom-mended (Avila et al.).

Pregnancy should be avoided in certain cardiac conditions, and if preg-nancy occurs, termination should be considered (Table 31). Additional contra-indications to pregnancy are also outlined in this table.

Exercise Guidelines

In 1992, the American Heart Association declared that physical inactivity is anindependent risk factor for coronary artery disease (Fletcher et al., 1992).Consequently, promotion of physical activity has become an integral part of thenational public health agenda in the United States, as seen in the publication ofthe Report of the U.S. Surgeon General on Physical Activity and Health (U.S.Department of Health and Human Services).

Physical activity is defined as any bodily movement produced by skeletalmuscles that results in energy expenditure. Exercise is a subset of physical activ-ity that is planned, structured, repetitive, and purposeful in the sense thatimprovement or maintenance of physical fitness is the objective. Physical fitnessincludes cardiorespiratory fitness, muscle strength, body composition, and flex-ibility, comprising a set of attributes that people have or achieve that relates tothe ability to perform physical activity. When defining the amount of physicalactivity or exercise, an important interrelationship exists between the total doseof activity and the intensity at which the activity is performed. Dose refers tothe total amount of energy expended in physical activity, whereas intensityreflects the rate of energy expenditure during such activity (Pate et al.). Lowlevels of physical fitness are associated with an increased risk of all-cause and cardiovascular disease mortality, with age-adjusted relative risks of approximately4.0 for unfit groups compared with their most fit counterparts (Myers et al.).Most studies with multiple increments of physical activity demonstrate a gradi-ent of decreasing risk of disease or mortality with increasing levels of physicalactivity, wherein the risk of cardiovascular disease increases as physical activitydecreases. However, the exact upper and lower dose limits and the intensity ofactivity required to confer a benefit have not been fully elucidated. Exercisetraining among persons with known coronary artery disease has been shown toyield various important benefits, including reduced mortality, reduced levels ofmyocardial ischemia at a given level of effort, and improved myocardial perfusion.

K E Y P O I N T S

• Severe pulmonary hypertension is anabsolute contraindication to pregnancy.

Avila WS, Grinberg M, Snitcowsky R,Faccioli R, Da Luz PL, Bellotti G, PileggiF. Maternal and fetal outcome in pregnantwomen with Eisenmenger’s syndrome. EurHeart J. 1995;16:460-4. PMID: 7671889

Fletcher GF, Blair SN, Blumenthal J,Caspersen C, Chaitman B, Epstein S, et al.Statement on exercise. Benefits and recom-mendations for physical activity programs forall Americans. A statement for health profes-sionals by the Committee on Exercise andCardiac Rehabilitation of the Council onClinical Cardiology, American Heart association. Circulation. 1992;86:340-4.PMID: 1617788U.S. Department of Health and HumanServices: Physical activity and health: a reportof the Surgeon General. Atlanta, GA: U.S.Department of Health and Human Services,Centers for Disease Control and Prevention,National Center for Chronic DiseasePrevention and Health Promotion, 1996.Pate RR, Pratt M, Blair SN, Haskell WL,Macera CA, Bouchard C, et al. Physicalactivity and public health. A recommenda-tion from the Centers for Disease Controland Prevention and the American College ofSports Medicine. JAMA. 1995;273:402-7.PMID: 7823386Myers J, Prakash M, Froelicher V, Do D,Partington S, Atwood JE. Exercise capacityand mortality among men referred for exercisetesting. N Engl J Med. 2002;346:793-801.PMID: 11893790

TABLE 31 Cardiac Contraindications to Pregnancy

Severe pulmonary hypertension (pulmonary artery pressure >70% systemic)

Eisenmenger’s syndrome

Cardiomyopathy with New York Heart Association class II or higher congestive heartfailure or left ventricular ejection fraction <40%

Severe obstructive cardiac lesions

Marfan syndrome with aortic root diameter ≥40 mm

Severe cyanosis

Previous peripartum cardiomyopathy with persistent left ventricular dysfunction or aserious episode of heart failure during a previous pregnancy

Exercise Training Responses

It is now clear that exercise modulates many biologic domains to confercardioprotection. Although exercise appears to modify and improve cardio-vascular risk factors (hypertension, lipid profile, insulin resistance, and obesity), thebeneficial effect of physical activity cannot be accounted for solely by means ofrisk factor reduction, since the association with reduced mortality is independ-ent of other coronary risk factors. Emerging data demonstrate that exerciseappears to positively affect several integral components of cardiovascular physi-ology, including endothelial function, thrombosis and hemostasis, and auto-nomic function.

Exercise Training Responses• What are the physiologic effects of exercise training?• How much exercise is needed for consistent benefit?

Exercise training affects such factors as maximal oxygen uptake, central hemo-dynamic function, autonomic nervous system function, peripheral vascular andmuscular function, as well as submaximal exercise capacity. Collectively, theseadaptations result in an exercise training effect, which allows a person to exer-cise to higher peak work rates with lower heart rates at each submaximal levelof exercise. The increase in maximal oxygen uptake (VO2max ) as a result oftraining in healthy persons is due to a higher maximum cardiac output and togreater extraction of oxygen from the systemic circulation, reflecting both cen-tral and peripheral adjustments. Submaximal heart rate is reduced after training,but cardiac output remains unchanged because stroke volume is increased.Greater oxidative potential in the skeletal muscles after training also contributesto more endurance.

Quality and Quantity of Exercise Needed for a Beneficial EffectPhysical activity may be measured in terms of metabolic equivalents (METs), aunit used to estimate the metabolic cost, or oxygen required to perform a givenactivity. One MET equals the resting metabolic rate of approximately 3.5 mLO2/kg/min. Cardiorespiratory fitness is best assessed by measurements of peakVO2. This can be accurately determined by measuring the composition ofexpired air and respiratory volume during maximal exercise, or it can be esti-mated from the peak exercise workload, or MET level, during maximal exercisewithout measuring expired gases. Any activity performed for training should beassessed in terms of intensity, frequency, duration, mode, and progression. Doserefers to the total amount of energy expended in physical activities that requirerepetitive muscular movement (usually expressed in kilojoules or kilocalories).Intensity can be defined in absolute or relative terms. Absolute intensity reflectsthe rate of energy expenditure during exercise and is usually expressed in METs,kJ/min–1, or kcal/min–1. Relative intensity refers to the relative percentage ofmaximal aerobic power that is maintained during exercise, and is expressed as apercentage of maximal heart rate or a percentage of VO2max. For example, briskwalking at 4.8 km/h–1, or 3 mi/h–1, has an absolute intensity of approximately4 METs. In relative terms, this intensity is considered light for a 20-year-oldhealthy person but difficult for an 80-year-old. Activities that are 40% to 60% ofVO2max are generally categorized as moderate. This concept is well illustratedand further defined in Table 32 (American College of Sports Medicine). Theintensity of activity needed to improve physical conditioning varies among indi-viduals and may be as low as 40% of VO2max for 20 minutes three times weekly.However, the relationship of exercise intensity to duration suggests that low-intensity exercise requires more time to increase functional capacity than doeshigher-intensity exercise. From a health and conditioning standpoint, the major

103

K E Y P O I N T S

• Emerging data demonstrate that exer-cise appears to positively affect severalintegral components of cardiovascularphysiology.

• Exercise training affects such factors asmaximal oxygen uptake, central hemo-dynamic function, autonomic nervoussystem function, peripheral vascular and muscular function, as well as submaximal exercise capacity.

• Any activity performed for trainingshould prescribed in terms of intensity,frequency, duration, mode, and progression.

• The intensity of activity needed toimprove physical conditioning variesamong individuals and may be as low as40% of VO2max for 20 minutes threetimes weekly. Significant health benefitscan be obtained by including a moderate-intensity activity for 30 minutes on most or all days of the week, aiming for a minimum total energy expenditureof 700 to 1000 kcal/wk.

American College of Sports MedicinePosition Stand. The recommended quantityand quality of exercise for developing andmaintaining cardiorespiratory and muscularfitness, and flexibility in healthy adults.MedSci Sports Exerc. 1998;30:975-91.PMID: 9624661

How to Develop the Exercise Prescription

104

advantage of low- to moderate-intensity exercise is the decreased likelihood ofcardiovascular and musculoskeletal complications, whereas vigorous exercisehas the advantage of accomplishing the goal in less time. A threshold of inten-sity is probably required to achieve benefit, although the exact value is notknown and may vary from one person to another. Although a threshold cannotbe defined from available information, much of the exercise described in pub-lished reports and associated with good health is moderate in intensity, such asbrisk walking. Significant health benefits can be obtained by including a mod-erate-intensity activity for 30 minutes on most or all days of the week, aimingfor a minimum total energy expenditure of 700 to 1000 kcal/wk.

How to Develop the Exercise Prescription• What factors should be considered when prescribing exercise to an individual

patient?• What exercise options are available?• What are the particular considerations in patients with cardiovascular disease?

Detailed recommendations on the preexercise medical evaluation and exercisetraining prescription are provided in the American Heart Association ExerciseStandards for Testing and Training (Fletcher et al., 2001). These recommen-dations are summarized in the following sections.

Exercise has both risks and benefits, and the challenge to the physician andother health care professionals is to provide guidelines that minimize risks andmaximize benefits. Although many factors affect risk of exercise, three of themost important are age, presence of heart disease, and intensity of exercise.Screening procedures can be used that identify a person who is at risk for anexercise-related cardiac event, and although these procedures are not perfect,they can be helpful in reducing such events. It is generally believed that the ben-

K E Y P O I N T S

• Although many factors affect risk ofexercise, three of the most importantare age, presence of heart disease, andintensity of exercise.

• Screening procedures can be used thatidentify a person who is at risk for anexercise-related cardiac event, andalthough these procedures are not per-fect, they can be helpful in reducingsuch events.

Fletcher GF, Balady GJ, Amsterdam EA,Chaitman B, Eckel R, Fleg J, et al.Exercise standards for testing and training: astatement for healthcare professionals fromthe American Heart Association. Circulation.2001;104:1694-740. PMID: 1158115226th Bethesda Conference: recommenda-tions for determining eligibility for competi-tion in athletes with cardiovascular abnor-malities. January 6-7, 1994.J Am CollCardiol. 1994;24:845-99. PMID: 7798484

TABLE 32 Classification of Physical Activity Intensity

Intensity Endurance-Type Activity Strength-Type Exercise: Relative

Intensity, as MaximumVoluntary

Contraction (%)*

Relative Intensity Absolute Intensity in Healthy Adults (METs)†

Middle-VO2max or Maximum Young Aged Old Very Old Heart Rate Heart RPE (20–39 (40–64 (65–79 (≥80 RPE Reserve (%) Rate (%)‡ Score Years) Years) Years) Years) Score

Very light <20 <35 <10 <2.4 <2.0 <1.6 ≤1.0 <10 <30

Light 20–39 35–54 10–11 2.4–4.7 2.0–3.9 1.6–3.1 1.1–1.9 10–11 30–49

Moderate 40–59 55–69 12–13 4.8–7.1 4.0–5.9 3.2–4.7 2.0–2.9 12–13 50–69

Hard 60–84 70–89 14–16 7.2–10.1 6.0–8.4 4.8–6.7 3.0–4.25 14–16 70–84

Very hard ≥85 ≥90 17–19 ≥10.2 ≥8.5 ≥6.8 ≥4.25 17–19 ≥85

Maximum 100 100 20 12.0 10.0 8.0 5.0 20 100

MET = metabolic equivalent; RPE = Borg rating of relative perceived exertion (scale of 6 to 20)

*Based on 8 to 12 repetitions for persons younger than 50 to 60 years of age and 10 to 15 repetitions for persons 50 to 60 years of age or older.

†Absolute intensity (metabolic equivalents [METs]) values are approximate mean values for men. Mean values for women are approximately 1 to 2 METs lower than those for men.

‡Maximum values are mean values achieved during maximum exercise by healthy adults.

Adapted from American College of Sports Medicine Position Stand. The recommended quantity and quality of exercise for developing and maintaining cardiorespiratory and muscular fitness,and flexibility in healthy adults. Med Sci Sports Exerc. 1998;30:975-91.


efits of exercise exceed the risks, and people should be encouraged to exerciseprudently.

The following preexercise screening procedures and activity classificationsare presented as a means of beginning exercise with the lowest possible risk.They do not consider comorbid conditions (for example, morbid obesity, severepulmonary disease, or debilitating neurologic or orthopedic conditions) thatmay necessitate closer supervision during training sessions. As a person gainsexperience, the decision may be made to place that person in another category.

Preexercise ScreeningBefore a person starts an exercise program, the following recommendationsshould be applied.

1. A recent medical history and physical examination should be performed.a. If the history or physical examination indicates significant cardiovascular

disease, risk stratification and exercise prescription should be provided accord-ing to the guidelines that follow in the next section. Examples of cardiovascu-lar disease include previous myocardial infarction, coronary artery bypass surgery, angina pectoris, valvular heart disease, heart failure, and congenitalheart disease.

b. If the person knows of no cardiovascular disease but has symptoms orsigns that suggest the presence of significant disease or major coronary risk fac-tors, an exercise test is needed before beginning an exercise program to evalu-ate for the presence of a high-risk condition. Further evaluation should followaccordingly. If an exercise test cannot be performed, activity should be limited.

2. Age should be considered.a. Among men younger than 45 years of age and women younger than

55 years of age without known or suspected cardiovascular disease, no furthercardiovascular workup is needed, provided that the person is healthy accordingto the criteria outlined above.

b. Among men 45 years of age or older and women 55 years of age orolder, particularly those with diabetes or two other risk factors for cardiovascu-lar disease: (1) An exercise test should be recommended if vigorous exercise isplanned. If the test is normal, no further restrictions are needed. (Because ofchanges in blood glucose that may occur after exercise, diabetic persons requirespecial consideration and counseling.) If the test is abnormal, further work-upshould follow accordingly and, for the purposes of exercise, the person shouldbe treated as if he or she has coronary artery disease. (2) If the person choosesnot to undergo an exercise test, he or she should follow the activity guidelinesoutlined for class B in Table 33 (26th Bethesda Conference).

Classification for Exercise RiskAfter the medical evaluation is complete, persons can be classified by risk on thebasis of their characteristics. This classification (Table 33) is used to determinethe need for subsequent supervision and the level of monitoring required.When resistance training is prescribed in clinical populations, the hemodynamicresponse (heart rate and blood pressure product) is often less that that attainedduring endurance exercise. Thus, the risk classification provided should be con-sidered for endurance training as well as resistance training. Aortic diseases (forexample, aortic aneurysm) are not specifically addressed in the risk classificationschema. Therefore, individual judgment on the part of the clinician shouldguide the prescription or prohibition of endurance or resistance training in such patients.

105

K E Y P O I N T S ( C O N T ' D )

• Before a person starts an exercise pro-gram, a recent medical history andphysical examination should be per-formed; if significant cardiovascular disease, is suspected, risk stratificationand exercise prescription should be provided.

• If the person knows of no cardiovascu-lar disease but has symptoms or signsthat suggest the presence of significantdisease or major coronary risk factors,an exercise test is needed before begin-ning an exercise program to evaluatefor the presence of a high-risk condition.

• Among men younger than 45 years ofage and women younger than 55 yearsof age without known or suspected car-diovascular disease, no further cardio-vascular workup is needed, providedthat the person is healthy.

• Among men 45 years of age or olderand women 55 years of age or older,particularly those with diabetes or twoother risk factors for cardiovascular dis-ease, an exercise test should be recom-mended if vigorous exercise is planned;if the test is normal, no further restric-tions are needed, and if it is abnormal,further work-up should follow and, forthe purposes of exercise, the personshould be treated as if he or she hascoronary artery disease.

• Exercise training should consist of peri-ods of warm-up and cool-down,endurance exercise (e.g., walking or run-ning), flexibility exercise, and resistancetraining (weight-lifting).

• Endurance exercise should be shouldperformed at least three times weeklyfor a minimum of 30 minutes per ses-sion at a minimum intensity of 40% to60% VO2max, and up to 85% VO2max forthose who have appropriately pro-gressed to this level.

• Persons initiating a resistance trainingprogram should be carefully screenedfor cardiovascular limitations and pre-existing orthopedic problems.

• For persons with cardiovascular disease,exercise testing allows establishment ofappropriate specific safety precautions,target exercise training heart rate, andinitial levels of exercise training workrates; it should be performed on all car-diac patients entering an exercise train-ing program and should be repeatedannually or at any time the patient’scondition warrants.


106

Exercise Training TechniquesExercise training should consist of periods of warm-up and cool-down,endurance exercise, flexibility exercise, and resistance training (Table 34)(Shephard and Balady). Such activities aim to reduce the risk of injury orother events associated with sudden onset of activity, increase functional capac-ity and muscular strength, improve the ability to sustain activities of daily living,and promote personal independence and positive self-image.

Warm-up and cool-downExercising at a low intensity for 5 to 10 minutes before (warm-up) and after(cool-down) the training session is recommended to help stretch and warm upmuscles and ligaments in preparation for the activity session. The cool-downperiod also prevents hypotension, which may occur with sudden cessation of exercise.

Shephard RJ, Balady GJ. Exercise as cardiovascular therapy. Circulation.1999;99:963-72. PMID: 10027821

TABLE 33 American Heart Association Risk Classification for Exercise Training

Class A: Apparently healthy persons

A1: Children, adolescents, men <45 years, and women <55 years who have no symptoms or known presence of heart disease or majorcoronary risk factors.

A2: Men ≥45 years, and women ≥55 years who have no symptoms or known presence of heart disease and with <2 majorcardiovascular risk factors.

A3: Men ≥45 years, and women ≥55 years who have no symptoms or known presence of heart disease and with ≥2 majorcardiovascular risk factors.

Activity guidelines: No restrictions other than basic guidelines

Supervision required: None*

ECG and blood pressure monitoring: Not required

Class B: Presence of known, stable cardiovascular disease with low risk for complications with vigorous exercise, butslightly greater risk than that in apparently healthy personsThis classification includes persons with any of the following diagnoses:

Coronary artery disease (angina. myocardial infarction, coronary revascularization, abnormal exercise test, and abnormal coronaryangiograms) whose condition is stable and who have the clinical characteristics outlined below

Valvular heart disease, excluding severe valvular stenosis or regurgitation with the clinical characteristics as outlined below

Congenital heart disease: risk stratification for patients with congenital heart disease should be guided by the 26th BethesdaConference recommendations

Cardiomyopathy: ejection fraction ≤30%; includes stable patients with heart failure with clinical characteristics as outlined below; not hypertrophic cardiomyopathy or recent myocarditis

Exercise test abnormalities that do not meet any of the high risk criteria outlined in class C

Clinical characteristics (must include all of the following):New York Heart Association class 1 or 2

Exercise capacity ≥6 METs

No evidence of congestive heart failure.

No evidence of myocardial ischemia or angina at rest nor on the exercise test at or below 6 METs

Appropriate increase in systolic blood pressure during exercise

Absence of sustained or nonsustained ventricular tachycardia at rest or with exercise

Ability to satisfactorily self-monitor intensity of activity

Activity guidelines: Activity should be individualized, with exercise prescription provided by qualified person and approved byprimary health care provider

Supervision required: Medical supervision during initial prescription session is beneficial. Supervision by appropriate trainednonmedical personnel for other exercise sessions until the patient understands how to monitor his or her activity

Medical personnel should be trained and certified in Advanced Cardiac Life Support; nonmedical personnel should be trained andcertified in Basic Life Support (which includes cardiopulmonary resuscitation)

ECG and blood pressure monitoring: Useful during the early prescription phase of training, usually 6 to 12 sessions

(Continued on next page)


Endurance exerciseActivities that cause the greatest increase VO2max are dynamic in nature andinvolve high-repetition and high-frequency movements using large musclegroups: for example, walking or running. Exercise should be should performedat least three times weekly for a minimum of 30 minutes per session at a mini-mum intensity of 40% to 60% VO2max, and up to 85% VO2max for those who haveappropriately progressed to this level. More simply, a heart rate method to pre-scribe intensity can be used, in which the training heart rate range is 50% to 75%(and up to 90%) of maximum predicted heart rate. The maximum predictedheart rate can be calculated by using the equation (220 – age). Another useful

107

TABLE 33 (cont ’d ) American Heart Association Risk Classification for Exercise Training

Class C: Those at moderate to high risk for cardiac complications during exercise or unable to self-regulate activity or tounderstand recommended activity level†

This classification includes persons with any of the following diagnoses:

Coronary artery disease with the clinical characteristics outlined below

Valvular heart disease, excluding severe valvular stenosis or regurgitation with the clinical characteristics as outlined below.

Congenital heart disease: risk stratification for patients with congenital heart disease should be guided by the 26th BethesdaConference recommendations

Cardiomyopathy: ejection fraction <30%; includes stable patients with heart failure with clinical characteristics as outlined below; nothypertrophic cardiomyopathy or recent myocarditis

Complex ventricular arrhythmias not well controlled.

Clinical characteristics (any of the following):HA class 3 or 4

Exercise test results.

Exercise capacity <6 METs

Angina or ischemic ST depression at a workload <6 METs

Decrease in systolic blood pressure below resting levels during exercise

Nonsustained ventricular tachycardia with exercise

Previous episode of primary cardiac arrest: i.e., cardiac arrest that did not occur in the presence of an acute myocardial infarction orduring a cardiac procedure

A medical problem that the physician believes may be life-threatening.

Activity guidelines: Activity should be individualized with exercise prescription provided by qualified persons and approved byprimary health care provider

Supervision: Medical supervision during all exercise sessions until safety is established.

ECG and blood pressure monitoring: Continuous during exercise sessions until safety is established, usually 12 sessions or more.

Class D: Unstable disease with activity restriction; exercise for conditioning purposes is not recommendedThis classification includes persons with any of the following:

Unstable ischemia

Severe and symptomatic valvular stenosis or regurgitation

Congenital heart disease: criteria for risk that would prohibit exercise conditioning in patients with congenital heart disease shouldbe guided by the 26th Bethesda Conference recommendations

Heart failure that is not compensated

Uncontrolled arrhythmias

Other medical conditions that could be aggravated by exercise

Activity guidelines: No activity is recommended for conditioning purposes. Attention should be directed to treating the patient andrestoring him or her to class C or better. Daily activities must be prescribed on the basis of individual assessment by the patient’spersonal physician

ECG = electrocardiogram; METs = metabolic equivalents

*It is suggested that persons classified as class A2 and particularly class A3 undergo a medical examination and possibly a medically supervised exercise test before engaging in vigorous exer-cise.

†Class C patients who have successfully completed a series of supervised exercise sessions may be reclassified to class B provided that the safety of exercise at the prescribed intensity is satis-factorily established by appropriate medical personnel and that the patient has demonstrated the ability to self-monitor.

Information from: Fletcher GF, Balady GJ, Amsterdam EA, Chaitman B, Eckel R, Fleg J, et al. Exercise standards for testing and training: a statement for healthcare professionals from theAmerican Heart Association. Circulation. 2001;104:1694-740.


108

approach to activity prescription is to identify the desirable rating of perceivedexertion and instruct participants to adhere to that intensity. A suggested ratingof perceived exertion for most healthy persons is 12 to 16 (“somewhat hard tohard”) on a Borg scale of 6 to 20, an approach that is both effective and accept-able (Table 35). The prescription of exercise intensity differs for patients withcardiovascular disease (see below). Calculation of maximum predicted heartrate by using the equation (220 – age) is not valid for persons taking cardio-active medications that slow the heart rate.

Resistance trainingResistance exercise training, which involves activities that use low- or moderate-frequency movements against high resistance, has been accepted as a primarycomponent of a comprehensive exercise program for both apparently healthypersons and patients with cardiovascular disease (Pollock et al.). Although theeffect of resistance exercise has less influence on risk factor modification thandoes traditional endurance exercise, the increases in strength and potential forincreased muscle mass may improve a person’s ability to become more physi-cally active and increase the basal metabolic rate. Persons initiating a resistancetraining program should be carefully screened for cardiovascular limitations andpreexisting orthopedic problems. Programs including a single set (8 to 12 rep-etitions) of 8 to 10 different exercises that train the major muscle groups, per-formed 2 or 3 days per week, will elicit favorable adaptation and improvement.Although greater frequencies of training and more sets may be used, the addi-tional gains among those in adult fitness programs are usually small. Trainingthe front and back of major muscle groups (for example, chest and back, bicepsand triceps) is recommended. For detailed recommendations on resistancetraining, see the American Heart Association Advisory “Resistance Exercise inIndividuals with and without Cardiovascular Disease.”

Pollock ML, Franklin BA, Balady GJ,Chaitman BL, Fleg JL, Fletcher B, et al.AHA Science Advisory. Resistance exercise inindividuals with and without cardiovasculardisease: benefits, rationale, safety, and pre-scription: An advisory from the Committeeon Exercise, Rehabilitation, and Prevention,Council on Clinical Cardiology, AmericanHeart Association; Position paper endorsedby the American College of Sports Medicine.Circulation. 2000;101:828-33.PMID: 10683360

TABLE 34 Exercise Prescription for Endurance and Resistance Training

Characteristic Endurance Exercise Resistance Training

Frequency 3–5 d• wk–1 2–3 d• wk–1

Intensity 50%–70% maximum heart rate,* or 1–3 sets of 8–15 RM for each muscle group40%–60% maximum VO2 or heart rate reserve†

Duration 20–60 min –

Example‡

Lower extremity Walking Leg extensions, curls, press

Jogging/running Adductor/abductor

Stairclimber

Upper extremity Arm ergometry Biceps curl

Triceps extension

Bench or overhead press

Lateral pull-down or raises

Bench-over or seated row

Combined Rowing –

Cross-country ski machine

Combined arm/leg cycle

Swimming

Aerobics

RM = maximum number of times a load can be lifted before fatigue; VO2 = measured oxygen uptake

*Maximum heart rate = 220 − age, or peak heart rate on exercise test

†Heart rate reserve = (peak heart rate − resting heart rate ) × % (+ resting heart rate)

‡Types of exercise listed are not all-inclusive.

Adapted from: Shephard RJ, Balady GJ. Exercise as cardiovascular therapy. Circulation. 1999;99:963-72.