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WHITE PAPER gRECSj
Practice Guidelines for the Diagnosis and Management ofSystolic Heart Failure in Low- and Middle-IncomeCountriesRagavendra R. Baliga*, G. William Decy, Jagat Narulaz
Columbus, OH, USA; Boston, MA, USA; and New York, NY, USA

TABLE OF CONTENTSClinical assessment.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

GLOBJune

Symptoms of HF and relevant facets in history ... 141Physical examination .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144

Diagnostic tests .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
Laboratory ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150BNP and amino-terminal proBNP ... . . . . . . . . . . . . . . . . 150ECG ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150Chest x-ray .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152Echocardiography and Doppler .. . . . . . . . . . . . . . . . . . . . . 152Stress testing .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153Six-minute walk test, cardiopulmonary stress test/regular stress test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
Right heart catheterization .. . . . . . . . . . . . . . . . . . . . . . . . . . . 155Left heart catheterization and coronaryangiography ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156

Endomyocardial biopsy .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156Cardiac magnetic resonance imaging .. . . . . . . . . . . . . . 156

Management of HF .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157

From the *Division ofCardiovascular Medicine,

Wexner Medical Center,The Ohio State University,Columbus, OH, USA;yCardiology Division,Massachusetts GeneralHospital Heart Center, Har-

vard Medical School,Boston, MA, USA; and thezCardiovascular ImagingProgram, Zena and MichaelA. Wiener CardiovascularInstitute, Icahn School ofMedicine at Mount Sinai,

New York, NY, USA. Corre-spondence: R. Baliga([email protected]).

GLOBAL HEART© 2013 Published byElsevier Ltd. on behalf of

Goals of therapy ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157Lifestyle changes .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157Pharmacological therapy of HF ... . . . . . . . . . . . . . . . . . . . 157

ACE inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157ARB ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158Beta-blockers . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159ACE inhibitors or beta-blockers first .. . . . . . . . . . . 159Aldosterone antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . 159Diuretic therapy ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161Digoxin .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164Hydralazine and isosorbide dinitratecombination.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

Anticoagulant/antiplatelet therapy .. . . . . . . . . . . . . . 164Prophylactic implantable cardioverter-defibrillatorplacement .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

Cardiac resynchronization .. . . . . . . . . . . . . . . . . . . . . . . . . . . 165Surgical approaches .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

Coronary artery bypass graft . . . . . . . . . . . . . . . . . . . . . 165LV remodeling surgery or mitral valve repair .. 165LVAD .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165Cardiac transplantation .. . . . . . . . . . . . . . . . . . . . . . . . . . . 165

World Heart Federation(Geneva).

Comorbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

All rights reserved.VOL. 8, NO. 2, 2013

ISSN 2211-8160/$36.00.http://dx.doi.org/10.1016/

HF and kidney disease .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165HF and angina.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166Sleep disordered breathing .. . . . . . . . . . . . . . . . . . . . . . . . . . 166HF in the elderly .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166

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Conclusions .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166References .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166

Heart failure (HF) occurs when the cardiac output isnot adequate to meet the metabolic demands of the tissuesor is able to do so only at an elevated ventricular fillingpressure.

j.gheart.2013.05.002

CLINICAL ASSESSMENT

Symptoms of HF and relevant facets in historyCompiling the history of a patient with heart failure shouldfocus on establishing the diagnosis; determining theetiology; evaluating functional status including shortness ofbreath, dizziness, history of hospitalizations, and fluidstatus; determining precipitating factors; and assessingcomorbidities including thyroid function, sleep apnea,arthritis, and reviewing all medications.

History taking can often separate heart failure intoischemic cardiomyopathy and nonischemic cardiomyop-athy, and the latter includes that due to hypertension,rheumatic heart disease, peripartum cardiomyopathy,human immunodeficiency virus (HIV) cardiomyopathy,alcoholic cardiomyopathy, and rarely chemotherapy-induced cardiomyopathy. The natural history of cardio-myopathy depends on the etiology (Figure 1) [1], withperipartum cardiomyopathy having the best prognosis andHIV cardiomyopathy having the worst prognosis.

Symptoms of heart failure such as edema, weight gain,and shortness of breath generally precede heart failurehospitalizations (Figure 2) [2]. Shortness of breath andorthopnea suggest left-sided heart failure. The presence ofparoxysmal nocturnal dyspnea is due to alveolar edema andtypically occurs 1 to 3 h after the patient retires to bed andresolves 10 to 30 min after the patient arises. In the EPICA(Epidemiologia da Insuficiência Cardiaca e Aprendizagem[Epidemiology of Heart Failure and Learning]) registry, thepresence of paroxysmal nocturnal dyspnea, orthopnea, andshortness of breath suggested a high specificity (w99%) forheart failure [3]. Orthopnea has a sensitivity of 90% andspecificity of 95% for elevated left ventricular (LV) fillingpressure. In the ADHERE (Acute Decompensated HeartFailure National Registry) and OPTIMIZE-HF (OrganizedProgram to Initiate Lifesaving Treatment in HospitalizedPatients with Heart Failure) registries, approximately 90% ofpatients reported shortness of breath and about one-third ofthe patients had shortness of breath [4,5]. The severity of

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http://dx.doi.org/10.1016/j.gheart.2013.05.002

http://dx.doi.org/10.1016/j.gheart.2013.05.002

Proportion of Patients Surviving

Tim

e

0

5

10

15

Cardiomyopathy due to HIV infection

Cardiomyopathy due to infiltrative myocardial disease

Cardiomyopathy due to doxorubicin therapy

Cardiomyopathy due to ischemic heart disease

Idiopathic cardiomyopathy

Peripartum cardiomyopathy

0.00 0.25 0.50 0.75 1.00

FIGURE 1. Adjusted Kaplan-Meier estimates of survivalaccording to the underlying cause of cardiomyopathy.HIV, human immunodeficiency virus. Adapted, withpermission, from Felker GM et al. [1]. Redrawn figure byAnthony Baker.

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shortness of breath is used to determine the functional class.The New York Heart Association (NYHA) functional classsheds light not only on the prognosis, but it also determinestherapy for systolic heart failure [6]. In the SOLVD (Studies ofLeft Ventricular Dysfunction) database, 2-year mortality onoptimal angiotensin-converting enzyme (ACE) inhibitor therapyin systolic heart failure patients with NYHA functional class IVwas 40% to 50%, class III heart failure 30% to 40%, class IIheart failure 20%, and NYHA class I was 10% (Table 1).Cheyne-Stokes respiration, or periodic breathing, is commonin advanced HF, is usually associated with low-output states,andmay be perceived by the patient (and the patient’s family)as either severe shortness of breath or transient cessation ofbreathing (often mistaken for sleep apnea). Shortness ofbreath can also be used to monitor response to therapy usingthe self-reported 7-point Likert dyspnea scale [7] (Table 2). A

recent study using invasive hemodynamic measurementsfound that the short-term improvement of shortness ofbreath during therapy with vasodilators and diureticsdepends on 2 hemodynamic variables: pulmonary capillarywedge pressure and mean pulmonary artery pressure(PAP). The improvement in shortness of breath correlatedwith both the absolute level and the magnitude of reductionof these 2 variables [8]. And the likelihood of achievingimprovement in shortness of breath is particularly highwhen both pulmonary capillary wedge pressure and meanPAP were effectively reduced. However, there is no corre-lation between shortness of breath and improvements inother hemodynamic variables such as cardiac index andsystemic vascular resistance. When patients are able toperform moderate levels of activity, shortness of breath isa relatively sensitive symptom of HF. However, it may notbe prominent in patients who are inactive, and the diag-nosis of HF is often delayed or overlooked. Also, shortnessof breath may become less prominent with the onset ofright ventricular (RV) failure and tricuspid regurgitation,which may lead to lower pulmonary venous pressures. Itmust be remembered that shortness of breath is alsoa common symptom of patients with pulmonary disease,obesity, or anemia and of sedentary individuals.

Chest pain is an important symptom that needs to beevaluated in all HF patients. The RESOLVD (RandomizedEvaluation of Strategies for Left Ventricular Dysfunction)investigators [9] found that myocardial ischemia was thecause for hospitalization in 12% of the patients withsystolic dysfunction, and in another study, the chest painin HF patients was the presenting symptom for acutecoronary syndrome in nearly one-third of the patients [10].The presence of chest pain suggests demand ischemia, orin those without coronary artery disease, it suggestsmyocarditis, pulmonary embolism, pulmonary hyperten-sion, or significant limitations in pericardial blood flow.

Fatigue in HF suggests low-flow state, but it may alsobe due to the presence of associated sleep apnea ordepression. Patients with HF can be screened for depres-sion with 2 questions: 1) Over the past 2 weeks, have youfelt down, depressed, or hopeless? and 2) Over the past 2weeks, have you felt little interest or pleasure in doingthings [11,12]? According to the U.S. Preventive ServicesTask Force Recommendation Statement, these 2 simplequestions are more sensitive and specific than lengthystatements or questionnaires [12]. The presence ofdepression is associated with increased likelihood ofrecurrent hospitalizations or mortality due to HF [13]. Thepresence of fatigue should also prompt evaluation for sleepapnea. Patients with HF may manifest either obstructivesleep apnea or central sleep apnea. The former is acomorbidity usually seen in overweight or obese patients,whereas central sleep apnea is a clinical manifestation ofHF. Identification of central sleep apnea is importantbecause treatment may benefit patients [14,15].

Lightheadedness or dizziness suggests that pulsepressure and/or systolic blood pressure (BP) is low or that

GLOBAL HEART, VOL. 8, NO. 2, 2013June 2013: 141-170

FIGURE 2. Number of days from onset of worsening of selected symptoms of heart failure to admission to hospital:cumulative percentage of patients. Adapted, with permission, from Schiff et al. [2].

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the patient has orthostatic dizziness or severe valvularaortic stenosis. Abdominal distension and fluid retentionsuggests associated right-sided heart failure.

Dietary indiscretion including fluid intake and sodiumintake needs to be assessed. Fluid intake exceeding 3 to 4 la day can contribute significantly to fluid retention. Threesimple questions [16] regarding sodium intake include thefollowing: 1) Is salt added at the table after the food isserved? 2) Does the patient eat processed foods particularlypickles, canned foods, potato chips, TV dinners? 3) Howoften does the patient eat out for meals including cafeteriasat work, or restaurants [16]?

TABLE 1. NYHA class and 2-year mortality

NYHA

Class Physical Activity

2-Year

Mortality (%)

on ACE-I

I Asymptomatic (no limitation of

physical activity; there is no

shortness of breath, fatigue,

or palpitations with ordinary

physical activity)

10

II Slight limitation (shortness of

breath, fatigue, or palpitations

with ordinary physical activity)

20

III Marked limitation (shortness of


with activities of daily living)

30e40

IV Symptoms at rest (shortness of


at rest)

40e50

ACE-I, angiotensin-converting enzyme inhibitors; NYHA, New York

Heart Association.


History taking should include assessment of frailty,particularly physical exhaustion and weight loss [17]. Onequestion to determine physical exhaustion is: Over the past2 weeks have you been bothered by feeling tired or havinglittle energy? Patients who answered “more than half thedays” or “nearly every day” should be considered asexperiencing physical exhaustion [17]. Unintentionalweight loss can be assessed by the following question: Inthe past year, have you lost any weight unintentionally(without trying)? A response of “10 pounds or more”should be considered as unintentional weight loss. If thisassessment suggests that patient may be frail, then theyshould be formally tested for weak grip strength, slowness,and low physical activity. Patients should be considered asfrail if they met 3 or more of the following criteria: weakgrip strength; physical exhaustion; slowness; low physicalactivity; and unintentional weight loss. Intermediate frailtywas defined as meeting 1 or 2 criteria [17].

Drugs such as nonsteroidal anti-inflammatory drugsand rosiglitazone are associated with sodium retention andmay precipitate acute HF. Calcium channel blockers suchas diltiazem and verapamil are negative inotropes that arebest avoided in chronic HF patients.

History regarding substance abuse including tobaccoand alcohol [18] should be obtained. Observational studies

TABLE 2. 7-Point Likert dyspnea scale

Markedly better

Moderately better

Minimally better

No change

Markedly worse

Moderately worse

Minimally worse

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FIGURE 3. Physical exam in heart failure. CHF, chronicheart failure. Adapted, with permission, from Runge MSet al. [21].

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suggest that tobacco cessation is associated with decreasedmortality and morbidity [19,20]. Alcohol is responsible for21% to 36% of all cases of nonischemic dilated cardio-myopathy. Patients who consume >90 g of alcohol a day(w7 to 8 standard drinks per day) for >5 years are at riskfor the development of asymptomatic LV dysfunction.Those who continue to drink may become symptomaticand develop signs and symptoms of overt HF. Withoutcomplete abstinence, the 4-year mortality for alcoholiccardiomyopathy approaches 50%. Therefore, accurate anddetailed assessment of alcohol use in chronic heart failure(CHF) is essential.

Physical examinationPhysical examination includes assessment of outerappearance, height, weight, body mass index (BMI), waisthip ratio, vital signs (including pulse, BP, respiration andtemperature), neck veins including hepatojugular venousreflux, chest and lungs, precordial and cardiovascularexamination, abdomen, and the extremities [21] (Figure 3).The physical exam also involves supplemental maneuversincluding Valsalva maneuver.

The outer appearance gives signs of distress, depres-sion, hygiene, cachexia, and obesity that are importantprognostic markers and are usually determined by a quicklook at the patient. Measurements of height, weight, waistcircumference, and hip circumference are useful to deter-mine BMI and waist hip ratio. Generally, the waistcircumference should be less than one-half the patient’sheight. Obesity is more frequently associated with diastolicHF, diabetes mellitus, and ischemic heart disease. TheFramingham Heart Study findings indicate that obesity andbeing overweight are strong predictors of subsequentclinical HF. The study reported that for every 1 kg/m2

increase in BMI, the risk of HF during a 14-year follow-upincreased by 5% in men and 7% in women, with gradedincreases in the risk of HF noted across all BMI categories[22]. However, the relationship between HF and obesity iscomplex; in several studies, obesity appears to be associ-ated with a better overall clinical prognosis—the so-calledobesity paradox [23]. Conversely, the presence of cachexiaindicates that the HF is more advanced and is associatedwith worse prognosis [24].

Examination of the pulse for rate and rhythm isimportant in the evaluation of a HF patient. An elevatedheart rate of >110 beats/min for prolonged periods shouldsuggest a tachycardia-induced cardiomyopathy. In theADHERE registry [25], about 30% of the patients had atrialfibrillation and was present on the electrocardiogram (ECG)in 20% of the patients in the OPTIMIZE-HF trial [26]. Thepresence of pulsus alternans (Figure 4) suggests that the ejectionfraction (EF) is low and the LV volumes are large [27].

The systolic blood pressure (SBP) can be helpful indetermining the cardiac reserve. For example, in 2 patientswith similar EF, if one’s SBP is 140 mm Hg and the other’sis low, then the former has a much better cardiac reserve.The LVEF is, therefore, best interpreted in the context of

SBP. When patients with severely depressed LV systolicdysfunction have SBP <80 mm Hg, the prognosis is worseeven when they are asymptomatic. In the Framinghamstudy, all 3 BP parameters were related to the risk for HF,but the relation was strongest for systolic and pulse pres-sure [28]. A 1-SD (20 mm Hg) increment in systolicpressure conferred a 56% increased risk for HF (hazardratio [HR]: 1.56, 95% confidence interval [CI]: 1.37 to1.77); similarly, a 1-SD (16 mm Hg) increment in pulsepressure conferred a 55% increased risk for CHF (HR:1.55, 95% CI: 1.37 to 1.75). Pulse pressure is an importantpredictor of risk of HF in the elderly because arterialstiffness increases with age. For every 10 mm Hg elevationin pulse pressure, there is a 14% increase in risk of CHF(95% CI: 1.05 to 1.24; p ¼ 0.003) [29]. Those in thehighest tertile of pulse pressure (>67 mm Hg) have a 55%increased risk of CHF (p ¼ 0.02) compared with those inthe lowest tertile (<54 mm Hg). Pulse pressure is more


A

B

C

FIGURE 6. Abnormal jugular venous waveforms [34]. (A)

FIGURE 4. Pulsus alternans in a patient with severe leftventricular systolic dysfunction. The systolic pressurevaries from beat to beat independently of the respiratorycycle. The rhythm is sinus throughout. Adapted, withpermission, from Braunwald E and Bonow RO [34].

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predictive than SBP alone and was independent of diastolicblood pressure (DBP) in the elderly population. A lowpulse pressure is also a risk predictor in both ischemic andnonischemic heart failure [30,31]. In nonischemic HF, lowpulse pressure is an independent predictor of overallmortality (HR: 0.84 per 10 mm Hg; p ¼ 0.036), whereasmean arterial pressure is not. In addition, higher NYHAclass and lower pulse pressure (HR: 0.87 per 10 mm Hg;p ¼ 0.002) were the only independent predictors for firstHF hospitalization in both ischemic and nonischemicpatients [31]. Proportional pulse pressure [(SBP e DBP)/SBP] correlates better with cardiac index (r ¼ 0.82);a proportional pulse pressure—(SBP e DBP)/SBP of <25%—suggests cardiac index <2.2 l/min/m2 with 91% sensitivity and83% specificity [32]. The presence of hypertension hasa sensitivity of 60% to 81% and a specificity of 59% to 70%for detecting diastolic dysfunction [33].

Jugular venous distension (Figures 5 and 6), reflectingthe hemodynamic changes in the right atrium, is an impor-tant marker of both right and left HF [34e36]. Studies havesuggested that estimations of right atrial (RA) pressure bythe bedside do not necessarily correlate with invasive

Large A waves associated with reduced right ventricularcompliance or elevated right ventricular end-diastolicpressure. The phonocardiographic tracing (bottom ofimage) shows timing of the corresponding right-sided S4.(B) Normal jugular venous waveform (bottom), mildTR (middle), and severe TR (top), with correspondingphonocardiogram. With severe TR, there is “ventricula-rization” of the jugular venous waveform, with a prom-inent V-wave and rapid Y descent. The X descent isabsent. (C) Jugular venous waveform in constrictivepericarditis with a prominent Y descent. Note the timingof the pericardial knock (K) relative to S2. The abrupt risein pressure after the nadir of the Y descent is caused bythe rapid rise in venous pressure with ventricular filling.ECG, electrocardiograph; JVP, jugular venous pulse; TR,tricuspid regurgitation. Adapted, with permission, fromAbrams [36].

FIGURE 5. Thenormal jugular venouswaveform recordedat cardiac catheterization. Note the inspiratory fall inpressure and the dominant X/X0 descent. Adapted, withpermission, from Braunwald E and Bonow RO [34].

GLOBAL HEART, VOL. 8, NO. 2, 2013 145June 2013: 141-170

TABLE 3. Tips to assist the clinician in the assessment of the jugular venous pressure

1. Begin with the patient sitting upright at 90�. If no pulsation is visible, lower the patient gradually toward the supine position

until a pulsation is seen. If no pulsation is seen whether the patient is upright, supine, or at a reclining angle between upright

and supine, it will not be possible to estimate the jugular venous pressure.

2. Examine both sides of the neck.

3. Assess both the internal and external jugular veins. If only the external jugular vein is visible, confirm that there are

respirophasic changes in the venous pulsation before using it to estimate right atrial pressure.

4. Compress inferior to an identified pulsation to distinguish the noncompressible arterial pulsation from the compressible

venous pulsation.

Reproduced, with permission, from Vader et al. [52].

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measurements of RA pressure [37]. However, an elevatedjugular venous pulse (JVP) has been shown to be a reflectionof left-sided filling pressures [38] and prognosis [39]. Thepresence of jugular venous distension, at rest or inducible, hasa sensitivity (81%), specificity (80%), and predictive accuracy(81%) for elevation of the pulmonary capillary wedge pressure(�18 mmHg) [38]. In the SOLVD study, an elevated JVP wasassociated with an increased risk of hospitalization for HF(relative risk [RR]: 1.32, 95% CI: 1.08 to 1.62; p < 0.01),death or hospitalization for HF (RR: 1.30; 95% CI: 1.11 to1.53; p < 0.005), and death from pump failure (RR: 1.37,95% CI: 1.07 to 1.75; p < 0.05) [39] but not from cardiacarrhythmia. When the jugular vein is not readily visible(Tables 3 and 4), the hepato-jugular reflex maneuver shouldbe performed to determine whether, indeed, it is elevated ordistended. The hepato-jugular reflux is elicited by gentlecontinuous pressure on the abdomen for about 10 s, and anincrease in JVP by this maneuver reliably predicts a pulmonarycapillary wedge pressure of greater than 15 mm [40] in theabsence of isolated RV dysfunction. Examination of jugularvenous, therefore, can guide therapy of LV filling pressuresin approximately 80% of chronic HF patients withoutobvious noncardiac disease and is an important prognosticmarker of mortality and rehospitalizations.

Palpation is useful to determine LV hypertrophy and RVenlargement. A sustained apical impulse greater than 3 cm indiameter suggests LV hypertrophy, and an impulse displacedlateral to left mid-clavicular line suggests LV enlargement.Experienced clinicians are able to estimate the EF by gauging thestrength of the apical impulse [41]; for example, normal or mildlyhypokinetic, moderately, or markedly hypokinetic corresponds to

TABLE 4. Distinguishing jugular venous pulse from carotid pulse

Feature Internal Jugular V

Appearance of pulse Undulating 2 troughs and 2 peak

cycle (biphasic)

Response to inspiration Height of column falls and trough

prominent

Palpability Generally not palpable (except in

Effect of pressure Can be obliterated with gentle p

vein/clavicle

Reproduced, with permission, from Abrams J [34].

EF >50%, 30% to 50%, and <30%, respectively [41,42](Figure 7). An abnormal apical impulse has a sensitivity of31% to36%and a specificity of 89% to95% for detecting a LVEF less than 40% [33]. A left-sided parasternal heave suggestsRV enlargement.

Auscultation in HF should focus on presence orabsence of third heart sound, loud second heart sound, andfor signs of valvular heart disease. The third heart sound isa low-frequency sound that is heard in diastole about 120to 180 ms after the second heart sound [43]. It is bestheard with the bell of the stethoscope at the point ofmaximal impulse and with the patient in the lateraldecubitus position. Interobserver variability in detectingthe third heard sound is significant [44], because it can bedifficult to hear. A third heart sound in HF is due todecreased ventricular compliance, increased filling pressures(Figure 8), or increased early diastolic filling rates [45e49].Very occasionally, the third heart sound may be “palpable”(Figure 7). In the SOLVD database, the presence of a thirdheart sound was associated with higher risk of all-causemortality (RR: 1.35, 95% CI: 1.17 to 1.55; p < 0.001),hospitalization for HF (RR: 1.70, 95% CI: 1.46 to 1.97; p <0.001), the composite endpoint of death or hospitalizationfor HF (RR: 1.42, 95% CI: 1.26 to 1.60; p < 0.001), anddeath from pump failure (RR: 1.77, 95% CI: 1.46 to 2.15;p < 0.001) but not death from arrhythmia (RR: 1.22, 95%CI: 0.90 to 1.65; p ¼ 0.20). The presence of third heart soundis associated with poor outcomes including progression of HF.Cardiac examination should, therefore, require careful auscul-tation to determine whether third heart sound is audible [50](Figure 9).

ein Carotid Artery

s for every cardiac Single brisk upstroke (monophasic)

s become more No respiratory change to contour

severe TR) Palpable

ressure at base of Cannot be obliterated


FIGURE 7. Apical impulse and palpable third heartsound. RFW, rapid filling wave. Adapted, with permission,from Leier CV and Chatterjee K [41] and Leier CV andChatterjee K [42].

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Pulmonary artery systolic (PAS) pressures tend to trackelevated left-sided filling pressures in the absence of mitralvalve disease or lung disease. In patients with suitable chestanatomy for auscultation, pulmonary artery systolic pres-sure can be estimated by the bedside by the distance of bothcomponents of second heart sound from the left second

mm Hg

Left Ventricular End-Diastolic Pressure

S3

and/or S4

S3

and S4

S3

alone

S4

alone

NoS

3 or S

4

5 010 15 20 25 30 35

A

P = 0.003

P = 0.04

P = 0.002

P < 0.001

FIGURE 8. Median LVEDP (A) and LVEF (B) for patients bafourth heart sound [34]. Median, interquartile ranges, errorare compared with first column. LVEDP, left ventricular end-Adapted, with permission, from Marcus GM et al. [45]. Redr


intercostal space (Figure 10). For detection of pulmonarycapillary wedge pressure (PCWP) �22 mm Hg, positivepredictive value was 95% for PAS �60 mm Hg [35].Pulmonary artery systolic pressure correlated very closely withPCWP (r ¼ 0.79) and could be estimated as 2 � PCWP [35].

The presence of crackles at the lung bases is a sign ofelevated left-sided filling pressures [51] (Table 5). Chestexamination is best performed after the patient has coughedso that crackles due to stasis are cleared. In chronic HF,crackles are often absent even in patients known to have PCWP>20 mm Hg (normal is <12 mm Hg). In the ADHERE andOPTIMIZE-HF registries, crackles was present in only abouttwo-thirds of the patients [4]. LV failure, therefore, cannotbe excluded by the absence of crackles. The sensitivity ofcrackles for elevated LV filling pressures (PCWP >18 mmHg) is 15% to 65%, specificity about 90%, positivepredictive value of 100%, and negative predictive value of35% [38]. Pleural effusion in HF is usually right-sided,reflecting the greater pleural surface area of the right lungand careful percussion of the chest and auscultation is animportant part of the clinical examination.

Examination of the abdomen and extremities for hepa-tomegaly, ascites, and bilateral pitting leg edema should bedone to determine the presence of right-sided HF. Thepresence of ascites is uncommon in HF unless there is asso-ciated tricuspid regurgitation. An acute congested liver maypresent with right upper quadrant pain. The presence ofa pulsatile liver indicates the presence of significant tricuspidregurgitation. Peripheral edema is a sign that tends to alert thephysician of the presence ofHF andwas present in about two-thirds of the patients with decompensatedHF in theADHEREand OPTIMIZE-HF registries [4,52]. However, bilateral legedema is seen in a variety of other conditions includingcirrhosis of the liver and nephrotic syndrome. The accuracy of

Percentage

Left Ventricular Ejection Fraction

S3

and/or S4

S3

and S4

S3

alone

S4

alone

NoS

3 or S

4

0706050403020 01 80 90

B

P = 0.003

P = 0.04

P = 0.002

P < 0.001

sed on phonocardiographic presence of a third and/orbars, and outlier values (circles) are shown. The p valuesdiastolic pressure; LVEF, left ventricular ejection fraction.awn figure by Anthony Baker.

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FIGURE 9. Kaplan-Meier plots demonstrating the prog-nostic value of an elevated jugular venous pressure [34]and S3 in asymptomatic (A, B) heart failure patients withsystolic dysfunction. Adapted, with permission, fromDrazner et al. [50]. Redrawn figure by Anthony Baker.

FIGURE 10. Estimating the pulmonary artery systolicpressure by the location of the pulmonic component ofthe second heart sound [41,42]. Adapted, with permis-sion, from Leier CV and Chatterjee K [42].

TABLE 5. Accuracy of clinical examination for elevated LV filling

pressure [51]

Finding Sensitivity, % Specificity, %

Rales 15e65 90

Edema 25e67 95

Orthopnea 90 95

Elevated JVP 80 90

LV, left ventricular; JVP, jugular venous pulse.Reproduced, with permission, from King M et al. [51].

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edema for elevated LV filling pressure has a sensitivity of 25%to 67% and specificity of 95%. The presence of an elevatedjugular venous pressure increases the specificity [32] of peripheraledema as a sign in decompensated HF. Examination of theperipheries should also focus on signs of poor perfusionincluding cool lower extremities (Figures 11 and 12), which isseen in low outpatient failures such as cardiogenic shock,although the latter is uncommon [4].

The Valsalva maneuver is sometimes done to differ-entiate whether the shortness of breath is due to lungdisease or due to CHF [53,54]. Patients are instructed toperform a Valsalva breath at the end of normal respiratorycycle and then hold it for 10 s followed by normalbreathing. In normal individuals or patients with mildlyabnormal LV function, the Valsalva maneuver results ina brief rise in BP with the onset of strain and then fallsbelow baseline until the strain is released. On releasing thestrain, there is an overshoot response in BP, which thenreturns to baseline. Therefore, in such individuals, the firstKorotkoff sound is heard for 1 to 3 s in early Valsalva(phase 1), completely fades away during the last 6 to 7 s ofValsalva breath (phase 2), and then returns much louder(phase 4) just after the release (phase 3) of the held breathand then followed by normal breathing [41,55](Figure 13). In patients with mild HF, the overshoot isabsent and, therefore, the Korotkoff sound is softer or maynot be heard in the initial 1 to 3 s of Valsalva, then it also


FIGURE 11. Clinical classification of the mode of heart failure (Forrester classification). H-I to H-IV refer to hemo-dynamic severity, with reference figures for CI and pulmonary capillary pressures shown on the vertical and horizontalaxes, respectively. C-I to C-IV refer to clinical severity. CI, cardiac index. Adapted, with permission, from Forrester JS,Diamond GA, Swan HJ. Correlative classification of clinical and hemodynamic function after acute myocardial infarction.Am J Cardiol 1977;39:137-45.

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fades away during the last 6 to 7 s of Valsalva and does notreturn or does so weakly on release of the held breath. Inpatients with severe HF, on release of strain, it returns tobaseline, resulting in the “square-wave” response; theKorotkoff sound is soft and does not fade away during

FIGURE 12. Two minute hemodynamic assessment. Adapted


Valsalva, but will do so during the post-Valsalva period.Apart from difficulty in eliciting this sign, it may not beuseful in patients on beta-blocker therapy.

The accuracy of clinical findings in the diagnosis of HFis shown in Table 6.

, with permission, from Braunwald E and Bonow RO [34].

149

Arte

rial B

P (m

m H

g)

Phase 1Phase 2Phase 3Phase 4Korotkoff sounds heard

StopStart Valsalva

Sinusoidalresponse

Square-waveresponse

Absentovershoot

FIGURE 13. BP tracing with Valsalva maneuver [34] ina normal, healthy person (top line). Briefly audiblesounds during initial strain phase in a patient who hassevere heart failure with a “square-wave” response (middleline). A square-wave response is indicative of pulmonarycapillary wedge pressure >25 mm Hg. Normal sinusoidalresponsewithKorotkoff sounds intermittentduring strain andrelease in (top line) a patient who has mild heart failure with“absent overshoot” (bottom line). That is, it is intermediatebetween normal and the square wave and is reflective ofmodestly elevated filling pressures. Persistence of Korotkoffsounds throughout strain phase. BP, bloodpressure. Adapted,with permission, from Shamsham F and Mitchell J [55].Redrawn figure by Anthony Baker.

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DIAGNOSTIC TESTS

LaboratoryThe initial workup includes hematological studies (completeblood count, hemoglobin, hematocrit, white blood cellcount, platelets, and serum ferritin), chemistries (blood ureanitrogen, serum creatinine and estimated glomerular filtra-tion rate [GFR], serum sodium, and potassium), thyroid-stimulating hormone, B-type natriuretic peptide (BNP),HIV, and factors for connective tissue disorders. A very lowhematocrit may be seen with hyperdynamic HF. Anemia ismore common in the presence of comorbid conditions suchas diabetes mellitus, advanced age, and renal disease. Therelative risk of death increases by a factor of 1.6 in anemicpatients with HF who also have chronic kidney disease.Fasting glucose is worth measuring not only because HF isassociated with diabetes, but also because it is a prognosticmarker of 30-day mortality in acute HF independent ofdiabetes [56]. The presence of hyponatremia portends a

poor prognosis. The presence of hypokalemia may suggestthat secondary hyperaldosteronism and these patients aremost likely to benefit from therapy with mineralocorticoidreceptor antagonists. Elevated serum ferritin suggests ironoverload, and in such instances, hemochromatosis must besuspected. Serum liver function tests at baseline are useful ifamiodarone or warfarin therapy is contemplated.

BNP and amino-terminal proBNPBNP and amino-terminal (NT) proBNP are relativelysensitive and specific markers for clinically confirmed heartfailure [57]. However, levels of both BNP and NT-pro-BNPincrease with age in the absence of clinical HF, particularlyin women, probably reflecting increased ventricular stiffnessassociated with aging and hypertension. Elevated natriureticpeptide levels portend a worse prognosis. Serial measure-ments may be of value in guiding treatment. BNP levels mayalso be increased in a variety of conditions including chronicobstructive pulmonary disease (COPD) in patients in whomelevations may reflect diastolic dysfunction or RV dysfunc-tion, but that nevertheless may lead to a false-positive clinicaldiagnosis of HF. The half-life of BNP is 22 min andNT-proBNP is 60 to 120 min. The cut point for diagnosingHF in acute dyspnea is 100 pg/ml (clinical range 0 to 5,000pg/ml), whereas for NT-proBNP the cutoff to rule out HF is300 pg/ml (clinical range 0 to 35,000), whereas to rule inHF, it is 900 pg/ml (Table 7). NT-proBNP is cleared by thekidney, and, therefore, the levels strongly correlate withGFR, whereas BNP is cleaved by neutral endopeptidasesand, therefore, has only a moderate correlation with GFR(Table 7). Because there is significant variation in BNP levelsbetween individuals, studies have suggested that a 50% to70% increase in levels from “dry” BNP (i.e., BNP levels whenthe patient is euvolemic) is suggestive of acute exacerbationof HF in chronic HF.

ECGECG is useful to determine rate (to confirm the severity oftachycardia) and rhythm (atrial fibrillation). LV hypertrophyon ECG suggests that HF is associated with diastolicdysfunction. The presence of Q waves indicates loss of viablemyocardium. The presence of left bundle branch block(LBBB) with QRS duration >140 ms suggests mechanicaldyssynchrony and identifies a patient who may be a candi-date for cardiac resynchronization therapy (CRT) if optimalmedical management fails to improve symptoms. Thepresence of low-voltage complexes should prompt investi-gation for infiltrative disease, particularly cardiac amyloid.For the diagnosis of HF, an abnormal electrocardiogram hasa sensitivity of 81% and negative predictive value of 75%[58]. The presence of anterior Q waves has a sensitivity of32% to 44% and specificity of 89%, whereas LBBB hasa sensitivity of 18% and specificity of 95% for detecting an EF<40% [33]. When the ECG is completely normal in a patientpresenting acutely with shortness of breath, HF is unlikely(likelihood<2%), whereas in patients presenting nonacutely,


TABLE 6. Accuracy of initial findings in diagnosis of HF

Ruling in HF Ruling out HF

Finding Has Conclusive

Effect

Positive

Likelihood

Ratio >10 Specificity

Finding Has Conclusive

Effect

Negative

Likelihood

Ratio <0.1 Sensitivity

Displaced cardiac apex* 16 0.95 Framingham criteria for

systolic HF

0.04 0.97

Third heart sound 11 0.99

Chest radiography

Interstitial edema 12 0.97

Venous congestion 12 0.96

Finding Has Moderate

Effect

Positive

Likelihood

Ratio of 5 to 10 Specificity

Finding Has Moderate

Effect

Negative

Likelihood

Ratio of 0.1 to 0.2 Sensitivity

History of HF 5.8 0.90 Framingham criteria

Hepatojugular reflex 6.4 0.96 For HF 0.1 0.92

Jugular venous distention 5.1 0.92 For diastolic HF 0.13 0.89

Reduced BNP level 0.1 0.94

Reduced NT-proBNP 0.14 0.92

Finding Has Small Effect

Positive

Likelihood

Ratio of 2 to 5 Specificity

Finding Has Small

Effect

Negative

Likelihood

Ratio of 0.2 to 0.5 Sensitivity

Framingham criteria Dyspnea on exertion 0.48 0.84

For systolic HF 4.57 0.79 Chest radiography

For HF 4.35 0.79 Cardiomegaly 0.33 0.97

For diastolic HF 4.21 0.79 Venous congestion 0.48 0.96

Initial clinical judgment 4.4 0.86 ECG: normal* 0.27 0.84

History of myocardial

infarction

3.1 0.87

RALES (crackles) 2.8 0.78

Murmur 2.6 0.90

Paroxysmal nocturnal

dyspnea

2.6 0.84

Peripheral edema 2.3 0.78

Orthopnea 2.2 0.77

Elevated BNP level 2.92 0.66

Elevated NT-proBNP 2.67 0.65

Chest radiography

Cardiomegaly 3.3 0.78

Pleural effusion 3.2 0.92

ECG

Atrial fibrillation 3.8 0.93

New T-wave change 3.0 0.92

Any abnormality 2.2 0.78

Note: Items are listed by the following groups: clinical criteria; history; physical examination; laboratory tests; chest radiography; and ECG.

BNP, B-type natriuretic peptide; ECG, electrocardiogram; HF, heart failure; NT-proBNP, amino (N)-terminal proeB-type natriuretic peptide; RALES,Randomized Aldactone Evaluation Study.

*Findings from research evaluating only systolic HF.

Reproduced, with permission, from King M et al. [51].

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TABLE 7. Comparison of BNP and NT-pro-BNP

BNP NT-proBNP

Half-life, min 22 60e120

Clearance

Primary mechanism Neutral endopeptidase Renal

Hemodialysis No No

Cut point for diagnosing HF in acute dyspnea 100 pg/ml 300 pg/ml to rule out, 900 pg/ml to

rule in, or age-adjusted cut points

Recommended fluctuation for diagnosing

acute or chronic HF

50% to 70% increase from

baseline

25% increase from baseline

Correlation with GFR Moderate Strong

Clinical range, pg/ml 0e5,000 0e35,000

GFR, glomerular filtration rate; BNP, B-type natriuretic peptide; HF, heart failure; NT-proBNP, amino (N)-terminal proeB-type natriuretic peptide.Reproduced, with permission, from Daniels LB, Maisel AS. Natriuretic peptides. J Am Coll Cardiol 2007;50:2357-68.

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the negative predictive value is lower (likelihood <10% to14%) [59e62]. One study suggested that changes in QRSduration are as useful as BNP is in monitoring HF [63].Therefore, ECG is useful in assessing heart rate, rhythm, andconduction abnormalities; detection of LV hypertrophy, low-voltage complexes, and chamber enlargement; detection ofmyocardial ischemia or infarction; determination of electricaldyssynchrony; and assessment of QT interval corrected forheart rate.

Chest x-rayEvidence of pulmonary venous hypertension (upper loberedistribution, enlarged pulmonary veins), interstitial edema(haziness of the central vascular shadows or increased centralinterstitial lung markings), or pulmonary edema (perihilar orpatchy peripheral infiltrates) is seen more commonly in acuteHF patients and only in a minority of chronic HF patients. Theabsence of these findings in chronic HF reflects the increasedcapacity of the lymphatics to remove interstitial and alveolarfluid and possibly the subjectivity of interpretation. Thisabsenceoffindings on chest x-ray is consistentwith the absenceof crackles in most patients with chronic HF despite markedlyelevated pulmonary venous pressures. Pleural effusions aremore common and larger on the right side than on the left side.Cardiomegaly as evidenced by a cardiothoracic ratio >0.60

TABLE 8. Accuracy of chest x-ray findings for detection of elevated L

Vascular Redistri

Detection of elevated LV filling pressures

Sensitivity 10%e58% [33]; 65

Specificity 79%e100% [33]; 8

Positive predictive value 89% [38]

Negative predictive value 48% [38]

Detection of LVEF <30%

Sensitivity

Specificity

EF, ejection fraction; LV, left ventricular.

suggests HF or valvular heart disease. However, in about one-half of patients with HF, the cardiothoracic ratio is<0.50. Forthe diagnosis of HF, an abnormal chest x-ray had an estimatedsensitivity of 57% and a negative predictive value of 83% [58].Vascular redistribution, cardiomegaly, and interstitial edemacan be useful to detect elevated filling pressures and to detectreduced LVEF [33,38] (Table 8). Chest x-ray, both poster-oanterior and lateral views, is, therefore, helpful to determinecardiac size, evidence of pulmonary edema, and determinationof location of cardiac devices such as a pacemaker. Presence ofhilar adenopathy should raise the suspicion of cardiac sarcoid.Itmust be noted that significant LV systolic dysfunctionmaybepresent in the absence of cardiomegaly on chest x-ray. Overall,chest x-ray is of limited utility in the diagnostic workup ofpatients suspected to have HF.

Echocardiography and DopplerEchocardiography with Doppler examination has replacedthe chest x-ray in the evaluation of HF, and it can provideuseful hemodynamic measurements (Table 9) withoutcardiac catheterization [64,65]. The assessment is directedto determine cardiac anatomy (LV size, RV size, LV wallthickness), cardiac function (LVEF), severity of valvulardisease, presence of pulmonary hypertension, RV function,estimation of RA pressure (Table 9) and Doppler indices ofdiastolic dysfunction, and the presence of pericardial

V filling pressures or reduced EF

bution

Cardiomegaly or Vascular

Redistribution Interstitial Edema

% [38] 27% [38]

0% [38] 87% [38]

83% [38]

33% [38]

4%e33% [34]

87%e100% [34]


TABLE 9. Hemodynamic parameters and their echocardiographic correlates

Hemodynamic Parameter Echocardiographic Correlate Comment

RAP IVC diameter and respirophasic

variation

Not valid in positive pressure ventilation except

to exclude high RAP

Pulmonary artery systolic

pressure

4(VTR)2 þ RAP See Table 11 for RAP estimation

Pulmonary artery diastolic

pressure

4(VPR)2 þ RAP See Table 11 for RAP estimation

PCWP E/Em E/Em >12 (TDE of septal mitral annulus) predicts

PCWP >15 mm Hg in patients who have

reduced EF

Left atrial pressure SBP e 4(VMR)2 Exclude patients with acute MR, prosthetic mitral

valve, and LVOT obstruction or peripheral arterial

disease of the arm

Cardiac output HR �VTI � area Accurate measure of LVOT diameter is critical

dP/dt 32/Dt Dt measured from continuous wave Doppler of

MR jet

Pulmonary vascular resistance 10(VTR/RVOT VTI) þ 0.16

dP/dT, first derivative of left ventricular pressure; EF, ejection fraction; HR, heart rate; IVC, inferior vena cava; LVOT, left ventricular outflow tract;MR, mitral regurgitation; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; RVOT, right ventricular outflow tract; SBP, systolicblood pressure; TDE, tissue Doppler echocardiography; VMR, peak velocity of mitral regurgitant jet; VPR, peak velocity of pulmonary regurgitant jet;

VTI, velocity time integral; VTR, peak velocity of tricuspid regurgitant jet.Reproduced, with permission, from Abraham J and Abraham TP [64].

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effusion. To detect asymptomatic LV dysfunction, echo-cardiography should be considered to assess cardiacstructure and function in patients with coronary arterydisease, particularly after myocardial infarction or revas-cularization, valvular heart disease, first-degree relatives offamilial cardiomyopathy, cardiomegaly, atrial fibrillation orflutter, ECG evidence of LV hypertrophy, LBBB, pathologicQ waves, or complex ventricular arrhythmias. Parametersrelated to systolic function include LVEF (reduced when<50%), LV fractional shortening (reduced when <25%),LV regional function (dyskinesia, hypokinesia, or akinesia),increased LV end-diastolic size (diameter �60 mm,>32 mm/m2, volume >97 ml/m2), and increased LV end-systolic size (diameter >45 mm, >25 mm/m2, volume>43 ml/m2), and reduced LV outflow tract velocity timeintegral (<15 cm). A lower LVEF is associated witha poorer prognosis (Figure 14). Parameters related to dia-stolic function (Table 10) include abnormalities of mitralinflow pattern and tissue velocities or e0 (an E:e0 ratio >15suggests increased elevated left atrial pressure and can behelpful in determining whether the shortness of breath isdue to left-sided HF) (Table 10), increased left atrialvolume index (a volume >34 ml/m2), and increased LVmass index (>95 g/m2 in women or >115 g/m2 in men).Other parameters include RV function (reduced whenTAPSE [Tricuspid Annular Plane Systolic Excursion]<16 mm), tricuspid regurgitation peak velocity (increasedwhen>3.4m/s), systolic PAP (increased when>50mmHg),or dilated inferior vena cava (assessment of inferior vena cavadiameter not only allows estimation of RA pressure, but it isalso helpful in predicting the prognosis; in patients with


chronic HF with or without a reduced LVEF, an increase inthe inferior vena cava’s diameter identifies patients with anadverse outcome [66]) (Table 11). Often, echocardiographycan be used in conjunction with serum BNP to make thediagnosis in difficult cases [67,68] (Figure 15).

Although transesophageal echocardiography is notroutinely useful in assessment of HF, it may be useful whencardiac magnetic resonance imaging (CMR) cannot bedone, as in ventilated patients, or in the absence of goodwindows for transthoracic echocardiography, and whenCMR is not available, as in obese or COPD patients. It is alsouseful in those with complex valvular heart disease or thosewith underlying congenital heart disease.

Stress testingFor ischemia in patients with significant LV dysfunctionand large hypocontractile LV, stress testing is better donewith stress radionuclide angiography than stress echocar-diography. As radionuclide angiography is based on countstatistics, it is a better method to assess LV function in largehypocontractile ventricle, where both end-diastolic andend-systolic counts tend to be large when CMR is notavailable. This allows high-quality assessment of LV func-tion in regular sinus rhythm. Whereas in patients withborderline decreases in LV function, stress echocardiog-raphy is a better tool because it allows excellent discrimi-nation of excellent LV function in hyperdynamic ventricles,with markedly exaggerated motion. The low count densityin end systole with radionuclide angiography results inoverestimation of LV function. Use of radionuclide

153

Ejec

tion

fract

ion

(%)

Number of deaths Number in group

Adjusted hazard ratiocompared to EF ≥ 60%

<20

20-29

30-39

40-49

50-59

>60

1563

2527

2433

1131

794

1237

4035

8567

9749

5854

3868

4798

Death From Any Cause

Ejec

tion

fract

ion

(%)

Number of deaths Number in group

Adjusted hazard ratiocompared to EF ≥ 60%

<20

20-29

30-39

40-49

50-59

>60

175

212

366

956

1232

454

2934

3031

4825

7825

6965

8837

Cardiovascular Death

FIGURE 14. Adjusted hazard ratios (HR) comparing death from any cause and cardiovascular death by groups of leftventricular ejection fraction (with LVEF ‡60% as the reference group). The HR for death in patients with an EF 50%-59% and in those with an EF 40%-49% was not increased compared with patients with an EF of �60%; however, the HRfor death increased steadily with an EF of <40%. (Adapted, with permission, from Meta-analysis Global Group in ChronicHeart Failure (MAGGIC). The survival of patients with heart failure with preserved or reduced left ventricular ejectionfraction: an individual patient data meta-analysis. Eur Heart J 2012;33:1750-7.) Redrawn figure by Anthony Baker.

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angiography for serial assessment requires careful consid-eration of exposure to excessive radiation.

Six-minute walk test, cardiopulmonary stress test/regular stress testRecent data suggests that the 6-minute walk (6MW)test provides prognostic information comparable to

cardiopulmonary exercise testing in ambulatory patientswith systolic HF [69]. 6MW test can be easily performed inthese patients even when they have advanced symptoms ofHF and are physically deconditioned, frail, or elderly.6MW test can be used for serial determinations of func-tional class and exercise capacity to determine diseaseseverity and to monitor response to therapy and progres-sion of HF. The cardiopulmonary stress is useful for


TABLE 10. Grading of diastolic dysfunction

Pathophysiology Normal

Grade I

Y Relaxation

Grade II

Y Relaxation

[ LVEDP

Grade III (Reversible)

Y Relaxation

Y Compliance

[ LVEDP

Grade III (Irreversible)

Y Relaxation

YY Compliance

[[ LVEDP

E/A 0.75e1.5 <0.75 0.75e1.5 >1.5 >1.5

DT, ms 150e200 >200 >200 150e200 <150

IRT, ms 50e100 >100 50e100 Y Y

PVs/PVd >1 PVs > PVd PVs > PVd PVs < PVd PVs < PVdPVa, m/s <0.35 <0.35 �0.35 �0.35 �0.35

adureAdur <20 <20 �20 �20 �20

E/Em <10 <10 �10 �10 �10

DT, deceleration time; dur, duration; IRT, inter-response time; LVEDP, left ventricular end-diastolic pressure; PVa, pulmonary venous atrial; PVd,pulmonary venous diastolic; PVs, pulmonary venous systolic.Reproduced, with permission, from Abraham J and Abraham TP [64].

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identifying candidacy for heart transplantation, determiningfunctional status and disability, and formulating an exerciseregimen, but it is more demanding and more expensive than6MW. When cardiopulmonary stress testing is not available,data from regular Bruce treadmill test are the best optionto determine functional status [70] (Tables 12 and 13).Generally, patients with NYHA class I functional statusshould be able to complete stage 2 on the Bruce protocol,which corresponds to 7.5 metabolic equivalents (METs) ora peak oxygen consumption (VO2) of 26.3 cc/min/kg.NYHA class II functional status patients should be able toattain stages 1 to 2 on the Bruce protocol, which corre-sponds to 6 METs or a peak VO2 of 21.0 cc/min/kg.NYHA class III functional status patients should be able tocomplete stage 1 on the Bruce protocol, which corre-sponds to 4.5 METs or a peak VO2 of 15.8 cc/min/kg.NYHA class IV functional status patients will not be ableto complete stage 1 on the Bruce protocol, which corre-sponds to 3.0 METs or a peak VO2 of 10.5 cc/min/kg.(1 MET ¼ 3.5 cc O2/min/kg.) It has been argued thatneither the 6MW test nor the cardiopulmonary stress testadds incremental prognostic value to clinical variablessuch as NYHA class, the LVEF and biomarker BNP [71].The cardiopulmonary stress test is useful in detecting candi-dacy for heart transplantation or mechanical circulatorysupport, determining prescription for cardiac rehabilitation,

TABLE 11. Estimation of RAP

IVC Diameter, cm

Respiratory

Variation

Estimated RAP,

mm Hg

Small, <1.5 Collapse 0e5

Normal, 1.5e2.5 Decrease by >50% 5e10

Normal Decrease by <50% 10e15

Dilated, >2.5 Decrease by <50% 15e20

Dilated No change >20

RAP, right atrial pressure.

Reproduced, with permission, from Abraham J and Abraham TP [64].


or determining functional capacity for employment capabil-ities.There is poor correlation, however, between exercise capacityand resting hemodynamic parameters including EF.

Right heart catheterizationIndications for right heart catheterization include patientswith uncertain hemodynamics, suspected low cardiacoutput, optimization of outpatient medications, evaluationof potential cardiac transplant candidate, presence ofassociated significant renal dysfunction, or low or unstableBP (Table 14). Right heart catheterization provides infor-mation regarding RA pressure, PAP, PCWP, and cardiacoutput (Table 13). From these parameters, cardiac index,pulmonary vascular resistance, systemic vascular resis-tance, and transpulmonary gradient can be calculated.A transpulmonary gradient >15 mm Hg is associated withpoor prognosis. PCWP approximates left atrial pressure,which in turn approximates LV end-diastolic pressure(EDP) in the absence of significant mitral valve pathology.An important technical consideration in the measurementof PCWP is when is the PCWP measured in the respiratorycycle? In the intensive care units, PCWP is measured atend-expiration, whereas in the cardiac catheterization lab,it is recorded throughout the respiratory cycle. It must alsobe remembered that thermodilution cardiac output maynot be accurate in low cardiac output states, intracardiacshunting, severe tricuspid regurgitation, or in the presenceof cardiac arrhythmias. The Fick method of calculatingcardiac output is the most accurate method if the heart rateor rhythm is irregular, for example, atrial fibrillation.Complications of right heart catheterization include tran-sient arrhythmias, particularly when passing the catheterthrough the RV outflow tract, induction of right bundlebranch block or complete heart block in those with pre-existing LBBB, bleeding at site of insertion, arterial punc-ture during insertion, nerve injury, pneumothorax, airembolism, pulmonary infarction, formation of thrombi inthe veins, or intracardiac and endocarditis.

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FIGURE 15. Combining BNP and echocardiography for diagnosis [67]. Algorithm for integrated use of B-type natriureticpeptide levels and echocardiography for diagnosis of acute heart failure. Use of age-stratified values for amino-terminal pro-B-type natriuretic peptide (NT-proBNP) providesmore accurate test performance:<50 years, use NT-proBNP>450 pg/ml; 50 to75 years, use NT-proBNP>900 pg/ml;>75 years, use NT-proBNP>1,800 pg/ml. Adapted, with permission, from TroughtonRW and Richards AM [68].

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Left heart catheterization and coronaryangiographyCoronary angiography should be considered when anischemic etiology is suspected, including in patients withnew onset heart failure or any unexplained decrease in LVsystolic function, when the risk factor profile suggests anischemic etiology or a history of cardiac arrest. It should alsobe considered in acute cardiogenic shock, acute pulmonaryedema, or when surgical therapy is being considered forvalvular disease. LV hemodynamics (e.g., LVEDP) should beobtained during left heart catheterization. Right and leftcatheterization is helpful to diagnose restrictive cardiomy-opathy. Criteria for restrictive cardiomyopathy includegreater than 5-mm difference between LVEDP and RV dia-stolic pressure, pulmonary artery systolic pressure>55 mmHg, RVEDP less than one-third the RV systolic pressure, LVrapid filling wave <7 mm Hg, and normal >3 mm Hgrespiratory variation in mean RA pressure.

TABLE 13. Functional classification of patients with CHF

VO2max,

Anaerobic

Threshold,

Maximal

Cardiac

Index,

Endomyocardial biopsyEndomyocardial biopsy is occasionally useful whenrestrictive or infiltrative cardiomyopathy (e.g., amyloid) ormyocarditis is suspected and may help establish the

TABLE 12. Using Bruce Treadmill Test to estimate peak VO2

NYHA Class METs VO2 Bruce

I 7.5 26.3 z2

II 6.0 21.0 1e2

III 4.5 15.8 z1

IV 3.0 10.5 <1

METs, metabolic equivalents; NYHA, New York Heart Association;

VO2, oxygen consumption. Permission from James Fang, MD.

diagnosis. The utility of this test has been described indetail in other guidelines [72].

Cardiac magnetic resonance imagingCMR is useful for serial assessment of ventricularmorphology and function [73,74], evaluation of ischemicheart disease [75], determination of myocardial viability andrevascularization [76], identifying the etiology of HF [77],evaluation of hypertrophic and infiltrative cardiomyopathies[78], assessment of pericardial disease and intracardiacthrombus [79], valvular and hemodynamic assessment [80],and risk stratification [81]. CMR is the gold standard for theassessment of cardiac morphology as CMR images canaccurately and reproducibly assess LV andRV chamber sizes,wall thickness, mass, and wall motion [82]. CMR’s abilityto determine the composition of abnormal tissue allowsthe detection of infiltrative cardiomyopathies (such asamyloidosis) or constrictive pericarditis. It is useful in

Class Severity ml/kg/min ml/kg/min l/min/m2

A None to mild >20 >14 >8

B Mild to

moderate

16e20 11e14 6e8

C Moderate to

severe

10e15 8e11 4e6

D Severe 6e9 5e8 2e4

E Very severe <6 3e4 <2

VO2max, maximum oxygen consumption.

Reproduced, with permission, from Weber KT and Janicki JS [70].


TABLE 14. Normal values for heart pressures

Chamber Average

Right atrium 5 � 2

Right ventricle 25 � 5/5 � 2

Pulmonary artery 25 � 5/10 � 2

Left atrium 10 � 2

Left ventricle 120 � 20/15 � 5

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differentiating patients who have significant pericardialconstriction and might benefit after pericardiectomy fromthose with primary restrictive physiology. CMR is theimaging of choice in those with complex congenital heartdisease. CMR is also useful for LV and RV functionalassessment because faster image acquisition allows bettercine assessment and better spatial resolution (makingplanimetry of interface between the LV cavity and themyocardium accurate). The myocardial tagging technique isuseful in determining regional function, assessing rotation,contraction, and strain in the subendocardial, midwall, andsubepicardial layers of the LV wall. CMR can also determinemyocardial perfusion, including contractile reserve andperfusion reserve. Adenosine stress perfusion imaging allowsearly detection of subendocardial perfusion defects that arenot detected by conventionalmethods, whereas dobutaminestress cine CMR is used to detect ischemia-induced wallmotion abnormalities. The high-spatial resolution providedby delayed-enhancement CMR, along with its ability todetect nonviable myocardium, makes it useful for differen-tiating ischemic fromnonischemicmyocardial disorders anddetecting myocardial scarring. The epicardium typically isinvolved in ischemic heart disease because coronaryartery disease progresses as a wave front from the epi-cardium to the endocardium. Isolated midwall or epicardialhyperenhancement strongly suggests a nonischemicetiology. The ability to detect scarring by delayed-enhancement technique makes it useful in the early nonin-vasive detection of sudden death in patients with dilated,hypertrophic, and restrictive cardiomyopathies. Also, withthe development of CMR-compatible pacemakers and defi-brillators, CMR could likely be used increasingly in HFpatients. Limitations of CMR include lack of ready avail-ability and that they cannot be used in a variety of clinical

A B

FIGURE 16. Mode of death in heart failure. (A) NYHA class II;failure; NYHA, New York Heart Association. Adapted, with pe


conditions, including patients with claustrophobia, poorkidney function (GFR <30 ml/min/m2) due to risk ofprogressive systemic fibrosis when linear gadoliniumchelates are used, and those withmetallic objects in the bodyincluding shrapnel and pacemakers/defibrillators.

MANAGEMENT OF HF

Goals of therapyThe goals of therapy in HF are to reduce symptoms, delaythe progression of HF, and prolong survival. Achievementof these goals depends on a combination of lifestylechanges and medical and surgical therapy.

Lifestyle changesThe most important lifestyle changes include dietary sodiumrestriction, limitation of water intake in decompensated HF,weight loss in obese individuals, exercise, and smokingcessation. Patients should be encouraged to restrict theirdaily dietary sodium intake to less than 2,000 mg a day andrestrict daily fluid intake to 2 l (64 oz.). A daily morningweight is recommended; any increments of weight >2 lbs.from dry weight may require incremental diuretic therapy.

Pharmacological therapy of HF

ACE inhibitors ACE inhibitors should be considered inNYHA class I to IV patients with LV systolic dysfunction.In asymptomatic LV dysfunction, ACE inhibitors preventrecurrent rehospitalizations as demonstrated by theSOLVD prevention arm [83]. The CONSENSUS (TheEffects of Enalapril on Mortality in Severe CongestiveHeart Failure) and SOLVD trials were among the firststudies that demonstrated that ACE inhibitors improvesurvival in patients with symptomatic LV systolicdysfunction. The number needed to treat (NNT) ¼ 27(i.e., 27 patients needed to be treated to save 1 life). ACEinhibitors, therefore, should be considered in all NYHAfunctional classes of systolic HF. Angiotensin receptorblockers (ARB) are a reasonable alternative to suppressthe renin-angiotensin system as evidenced by the findingsof the CHARM (Candesartan in Heart Failure) trial inthose intolerant to ACE inhibitors or as first-line therapy.

C

(B) NYHA class III; (C) NYHA class IV. CHF, congestive heartrmission, from [90].

157

40 8 12 16Mortality, %

Placebo

6.25 mgbid

12.5 mgbid

25 mgbid

Car

vedi

lol

Mortality dose response P < 0.001* P < 0.05 vs placebo† P = 0.07 vs placebo

*

*

†

FIGURE 17. Dose-dependent carvedilol effects onmortality. bid, twice a day. Adapted, with permission,from Colucci WS [92]. Redrawn figure by Anthony Baker.

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Adverse effects with ACE inhibitors can be classifiedinto 2 groups: 1) those related to suppression of angio-tensin: hypotension and worsening renal function; and 2)those related to kinin production: cough and angioedema.A dry, hacking cough will require discontinuation therapyin 5% to 10% of the patients. It is important to determinethat the cough is not due to increased LVEDP due tocongestion of HF before discontinuing therapy. ARBshould be started in those who cannot tolerate ACEinhibitors due to cough. Azotemia, when due to mild ormoderate HF, usually improves with initiation of ACE-inhibitor therapy. Worsening kidney function, defined asan increase in creatinine of >0.3 mg/dl within the first2 weeks, is not uncommon (12.0%). Worsening renalfailure with initiation of ACE inhibitor therapy suggestssignificant and usually bilateral renal artery stenosis andmay require discontinuation. When blood urea nitrogenexceeds 50 mg/dl or serum creatinine is >2 mg/dl,adjustment of ACE-inhibitor therapy is best done incollaboration with a nephrologist and cardiologist.

The use of ACE inhibitors during the first [84], second,and third trimesters of pregnancy is contraindicated becauseof their association with an increased risk of fetal malfor-mations. Pregnancy is an absolute contraindication to initiationor continuation of ACE-inhibitor therapy. ACE inhibitors have

TABLE 15. Impact of beta blockers on mortality and hospitalizations

Study Drug Heart Failure

US Carvedilol Carvedilol Mild-mod

CIBIS-II Bisoprolol Moderate

MERIT-HF Metoprolol CR/XL Mild-mod

BEST Bucindolol Moderate

COPERNICUS Carvedilol Severe

SENIORS Nebivolol Mild-mod

BEST, Beta-Blocker Evaluation of Survival Trial; CIBIS-II, The Cardiac InsufficieSevere Chronic Heart Failure; MERIT-HF, Metoprolol CR/XL Randomized Int

Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors With

a small molecular size and therefore readily transfer intobreast milk. Captopril, enalapril, and quinapril are the onlyACE inhibitors that have been designated safe in breast-feeding mothers. Generally, ACE inhibitors are best avoi-ded in the first few weeks after delivery to avoid neonatalhypotension. The other ACE inhibitors and ARB currentlyremain contraindicated while breast-feeding because of lackof data. Captopril, however, is not routinely used because itcontains a sulfhydryl group that is associated with rash,neutropenia, and nephrotic syndrome. All these side effectsare dose-dependent and neutropenia tends to occur in thosewith underlying collagen vascular disease.

Diuretic dosage may sometimes decrease with initia-tion of ACE-inhibitor therapy. It is best to avoid increasingdoses of both diuretics and ACE inhibitors simultaneouslyto avoid the risk of hypotension or pre-renal azotemia.ACE-inhibitor doses are best increased when the patient is“wet” (as opposed to beta-blockers where it is better toincrease the dose or initiate therapy when the patient isrelatively “dry”); increasing ACE-inhibitor dose when thepatient is dry often results in azotemia.

ARB ARB are useful in patients who cannot tolerate ACEinhibitors due to cough because the former do not producedough as a side effect. The CHARM Alternative study foundthat ARB therapy resulted in a RR reduction of 23% of theprimary composite outcome of cardiovascular death orhospitalization in the HF patients on candesartan (absoluterisk reduction of 7 fewer patients experiencing this outcomeper 100 treated) [85]. In the Val-HeFT (Valsartan HeartFailure Trial) and CHARM Added [86] trials, addition ofARB to ACE-inhibitor therapy was found to be beneficial.In the Val-HeFT study, when valsartan was added totherapy (93% were already on ACE inhibitors and 35%on beta-blockers), there was significant reduction ofcombined endpoint of HF hospitalization and mortalityalthough it had no effect on mortality [87]. In the CHARMAdded trial, there was a 15% RR reduction with NNT ¼27 for cardiovascular death or hospitalization for HF inpatients on candesartan in addition to ACE-inhibitortherapy. ARB are therefore useful in patients who areintolerant to ACE inhibitors or in patients with HF whoare still symptomatic despite treatment with optimal

Severity Mortality, % Hospitalization, %

erate Y65 Y27

-severe Y34 Y20

erate Y34 Y18

-severe Y10 (p ¼ 0.13) Y8 (p ¼ 0.08)

Y35 Y20

erate Y12 (p ¼ 0.21) Y10

ncy Bisoprolol Study II; COPERNICUS, Effect of Carvedilol on Survival inervention Trial in Congestive Heart Failure; SENIORS, Study of Effects of

Heart Failure.


+20 +4 +6 +8Change in LVEF, %

+10

Placebo

6.25 mgbid

12.5 mgbid

25 mgbid

Car

vedi

lol

EF dose response P < 0.001* P < 0.05 vs placebo

*

*

*

FIGURE 18. Dose-dependent carvedilol effects on ejec-tion fraction [92]. Abbreviations as in Figures 8 and 17.Adapted, with permission, from Colucci WS [92]. Redrawnfigure by Anthony Baker.

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therapy with beta-blockers and aldosterone antagonist.Using maximum dose ACE inhibitors with ARB increasesrisk of renal dysfunction including the need for renalreplacement therapy. Also, the safety of using combinationtherapy of ACE inhibitors, ARB, and aldosteroneantagonists is uncertain and is best avoided.

Beta-blockers Beta-blockers [88] are useful becauseincreased adrenergic activity occurs even in asymptomaticLV dysfunction and the MERIT-HF (Metoprolol CR/XLRandomized Intervention Trial in Congestive HeartFailure) found that sudden death due to cardiacarrhythmias is more likely in less symptomatic patientswith systolic dysfunction (Figure 16). Although all beta-blockers are not similar, the CIBIS-II (The CardiacInsufficiency Bisoprolol Study II) [89], MERIT-HF [90],and COPERNICUS (Effect of Carvedilol on Survival inSevere Chronic Heart Failure) [91] trials are randomizedcontrolled trials that have shown approximately one-thirdreduction in mortality in patients with systolic HF withbisoprolol, extended release metoprolol, and carvedilol,respectively [92] (Figure 17, Table 15). Beta-blockers also

TABLE 16. Number needed to treat for mortality

Guideline Recommended

Therapy

Relative Risk

Reduction

in Mortality

Number Ne

Treat for M

ACEI/ARB 17% 22 over 42

Beta-blocker 34% 28 over 12

Aldosterone antagonist 30% 9 over 24 m

Hydralazine/nitrate 43% 25 over 10

CRT 36% 12 over 24

ICD 23% 14 over 60

Reproduced, with permission, from Fonarow GC, et al. Am Heart J 2011;1


result in reverse remodeling and improve LV function(Figure 18). The SENIORS (Study of Effects of NebivololIntervention on Outcomes and Rehospitalisation inSeniors With Heart Failure) trial has shown thatnebivolol therapy was associated with significantreduction in composite outcome of mortality orcardiovascular hospitalizations in elderly patients withHF [93]. Beta-blockers, therefore, are recommended forall hemodynamically stable patients with HF due tosystolic dysfunction, unless contraindicated by a historyof asthma, heart block, or symptomatic hypotension.NNT with beta-blocker (vs. no beta-blocker) ranges from15 to 43 when normalized for 1 year [94] (Table 16). Itis not required to be on maximum dose ACE-inhibitortherapy to initiate beta-blockers, as most patientsenrolled in clinical trials were not on high-dose ACEI.Dosing should “start low and go slow” with dosingincrements. It is desirable to achieve target doses iftolerated by the patient. Side effects of beta-blockersinclude bradycardia, hypotension, impotence, fluidretention, and fatigue. Relative contraindications to beta-blockers include decompensated HF (it is best to startbeta-blockers when the patient is dry), bronchial asthma,bradycardia, beta-agonists therapy (such as dobutamine),and hypotension.

ACE inhibitors or beta-blockers first It has beenargued that beta-blockers as monotherapy may be adequatefor management of systolic HF. Others have argued thatbeta-blockers needed to be started first [95,96]. With thecurrent data it is recommended that all patients be onACE-inhibitor therapy and beta-blockers [97]. It is unlikelytrials will be conducted in HF without ACE-inhibitortherapy because of ethical issues to give a final answer onthis ongoing controversy. It has been suggested thatinitiation of therapy with carvedilol before an ACE-inhibitortherapy results in higher tolerable doses of carvedilol andbetter improvements in LV function [98].

Aldosterone antagonists The RALES (RandomizedAldactone Evaluation Study) showed that the addition ofspironolactone (an aldosterone receptor antagonist) to anACE

eded to

ortality

Number Needed to

Treat for Mortality

(Standardized to

36 Months)

Relative Risk

Reduction in HF

Hospitalizations

months 26 31%

months 9 41%

onths 6 35%

months 7 33%

months 8 52%

months 23 NA

61:1024-30.

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TABLE 17. Guidelines for minimizing the risk of hyperkalemia in patients treated with aldosterone antagonists

1. Impaired renal function is a risk factor for hyperkalemia during treatment with aldosterone antagonists. The risk of hyper-

kalemia increases progressively when serum creatinine exceeds 1.6 mg/dl.* In elderly patients or others with low muscle mass

in whom serum creatinine does not accurately reflect glomerular filtration rate, determination that glomerular filtration rate or

creatinine clearance exceeds 30 ml/min is recommended.

2. Aldosterone antagonists should not be administered to patients with baseline serum potassium in excess of 5.0 mEq/l.

3. An initial dose of spironolactone 12.5 mg or eplerenone 25 mg is recommended, after which the dose may be increased to

spironolactone 25 mg or eplerenone 50 mg if appropriate.

4. The risk of hyperkalemia is increased with concomitant use of higher doses of ACE inhibitors (captopril �75 mg daily; enalapril

or lisinopril �10 mg daily).

5. Nonsteriodal anti-inflammatory drugs and cyclo-osygenase-2 inhibitors should be avoided.

6. Potassium supplements should be discontinued or reduced.

7. Close monitoring of serum potassium is required; potassium levels and renal function should be checked in 3 days and at

1 week after initiation of therapy and at least monthly for the first 3 months.

8. Diarrhea or other causes of dehydration should be addressed emergently.

ACE, angiotensin-converting enzyme.

*Although the entry criteria for the trials of aldosterone antagonists included creatinine >2.5 mg/dl, the majority of patients had creatinine much

lower. In 1 trial [98], 95% of patients had creatinine �1.7 mg/dl.Reproduced, with permission, from Pitt B et al. [100].

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inhibitor reduced all-cause mortality by 30% (NNT¼ 9) andcardiacmortality by 31% in systolicHF [99].When comparedwith the placebo group, the spironolactone group wasassociated with a 35% lower frequency of hospitalization forworsening HF. Spironolactone therapy may result ingynecomastia, hyperkalemia, and azotemia. Aldosteronereceptor blockers should be considered in all patients with NYHAclass II to IV HF due to LV systolic dysfunction and creatinine�2.5 mg/dl.

The EPHESUS (Eplerenone Post-AMI Heart FailureEfficacy and Survival Study) showed that eplerenone

FIGURE 19. Cumulative benefits of medical therapy on morPotential impact of optimal implementation of evidence-b2011;161:1024-30.

(also an aldosterone receptor antagonist) improvedsurvival in systolic HF following myocardial infarction[100]. In the EPHESUS study, there was a 13% reduc-tion in mortality from cardiovascular causes or hospi-talization for cardiovascular events in patients oneplerenone therapy (NNT ¼ 30). There was also a 21%relative reduction in the rate of sudden death (NNT ¼83). Eplerenone, therefore, is recommended as additionaltherapy in LV systolic dysfunction and HF to be started 3 to14 days following myocardial infarction unless complicatedby azotemia or hyperkalemia.

tality. Adapted, with permission, from Fonarow GC, et al.ased heart failure therapies on mortality. Am Heart J


TABLE 18. Cumulative benefits of heart failure therapies

Relative Risk 2-Year Mortality

None — 35%

ACE inhibitor Y 23% 27%

Aldosterone ant Y 30% 19%

Beta-blocker Y 35% 12%

CRT � ICD Y 36% 8%

Cumulative risk reduction if all 4 therapies are used: 77%. Absoluterisk reduction: 27%, NNT ¼ 4.Reproduced, with permission, from Fonarow GC. Rev CardiovascMed 2000;1:25-33.

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The EMPHASIS-HF (Eplerenone in Mild PatientsHospitalization and Survival Study in Heart Failure)studied the effect of eplerenone in mild HF; NYHA func-tional class II systolic HF patients with an EF of 30% or less(or if >30% to 35%, a QRS duration of >130 ms) [101]. Itfound that eplerenone reduces the rate of mortality fromcardiovascular causes or hospitalization for HF byapproximately 37%, as compared with placebo, in patientswith functional class II systolic HF (NNT ¼ 19 patients).The NNT to prevent 1 death is 51 patients. Eplerenonewhen compared with spironolactone is less likely to resultin sexual side effects such as gynecomastia, breast pain, ormenstrual irregularities. Eplerenone, therefore, should be

FIGURE 20. Appropriate shocks outnumber control arrhytversus Implantable Cardioverter Defibrillator Trial; AVID, AnNITE, Defibrillators in Non-Ischemic Cardiomyopathy TreatMyocardial Infarction Trial. (Adapted, with permission, fromcauses of implantable cardioverter-defibrillator therapies: is d61, and Tung R, Zimetbaum P, Josephson ME. A critical appraisprevention of sudden cardiac death. J Am Coll Cardiol 2008;


considered in all patients with mild systolic HF if there isno azotemia or hyperkalemia. Usage of spironolactone oreplerenone should be avoided in those patients with serumcreatinine >2.5 mg/dl, estimated creatinine clearance<50ml/min, or serumpotassium>5mgEq/l [102] (Table 17).Initiation of spironolactone or eplerenone should includemonitoring serum potassium and renal function at onset,a week after initiating therapy, and monthly thereafter.Consider dose reduction when serum potassium levelsare >5.5 mEq/l or worsening renal function. The bene-fits of combined neurohormonal blockade are shown inFigure 19 and Table 18.

Diuretic therapy Diuretic therapy is useful for reducingshortness of breath and controlling edema. One meta-analysis reported a 75% reduction in mortality (NNT ¼12) and a 63% improvement in exercise capacity [103].Although the studies included in this analysis were smalland of variable quality, there was enough consistency tosuggest that diuretic therapy will benefit patients withevidence for volume overload. In most cases, a loopdiuretic is the agent of choice. Thiazides may sufficewhen the edema is mild and renal function is preserved.Sequential nephron blockade with loop diuretics andthiazides may be effective in refractory edema. Thisgenerally consists of adding 2.5 mg/day metolazone(maximum dose 10 mg) when edema is resistant to daily

hmic mortality in 6 of 7 trials. AMIOVIRT, Amiodaronetiarrhythmics versus Implantable Defibrillators trial; DEFI-ment Evaluation trial; DINAMIT, Defibrillators in AcuteGermano JJ, Reynolds M, Essebag V, et al. Frequency andevice therapy proarrhythmic? Am J Cardiol 2006;97:1255-al of implantable cardioverter-defibrillator therapy for the52:1111-21.)

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FIGURE 21. Subtypes of cardiorenal syndrome. AKI, acute kidney injury; CHF, congestive heart failure; CKD, chronickidney disease; HF, heart failure. Adapted, with permission, from Ronco et al. [132].

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FIGURE 22. Cardiorenal syndromes: classifications, definitions, and work group statements. *As advised by theEuropean Society of Cardiology guidelines 2008. ACC, American College of Cardiology; ACS, acute coronary syndrome;ADHF, acute decompensated heart failure; ADQI, Acute Dialysis Quality Initiative; AHA, American Heart Association;AHF, acute heart failure; AKI, acute kidney injury; AKIN, Acute Kidney Injury Network; CHF, chronic heart failure; CKD,chronic kidney disease; KDOQI, Kidney Disease Outcome Quality Initiative; KIM-1, kidney injury molecule-1; MPO,myeloper oxidase; NAG, N-acetyl-b-(D)glucosaminidase; NGAL, neutrophil gelatinase-associated lipocalin; NKF, NationalKidney Foundation; RIFLE, risk, injury, failure, loss of kidney function, and end-stage kidney disease; WRF, worseningrenal function. Adapted, with permission, from Ronco et al. [132].

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dose of 200 mg of furosemide. These patients tend to havesevere HF with impaired renal function. Other alternativesare 25 to 100 mg of hydrochlorothiazide or 10 mg ofbendrofluazide. The DOSE (Diuretic OptimizationStrategies Evaluation in Acute Heart Failure) trialsuggested that intravenous loop diuretics are moreeffective in relieving shortness of breath when high dosesare administered more quickly. Also, high doses of loopdiuretics when compared with low doses were notassociated with substantially worse azotemia. It alsoshowed a lack of greater benefit with continuous infusionwhen compared with boluses, making the latter thepreferred regimen. Diuretic therapy may be associatedwith dehydration, azotemia, and hypokalemia.Hypokalemia may be offset by ACE inhibitors, ARB, oraldosterone antagonists. Serum potassium should bemonitored and therapy should be adjusted to maintaina serum potassium concentration in the range of 4 to 5mEq/l. Loop diuretics may precipitate gout, which istreated with colchicine and in refractory cases witha short course of prednisone.

Digoxin One systematic review suggested that digoxintherapy is associated with a 23% reduction in hospitali-zation (NNT ¼ 18) and 64% improvement in symptoms(NNT ¼ 9) [104]. But the DIG (Digoxin InvestigationGroup) trial, which was conducted before beta-blockerand aldosterone antagonists were routinely used in themanagement of systolic HF, dominated all the trialsreviewed in this paper. No improvement in survival withdigoxin therapy has been reported in HF.

Digoxin may be useful in HF to control ventricular ratein patients with atrial fibrillation or atrial flutter whenpatients cannot tolerate beta-blockers, or it can be usefulwhen used in addition to beta-blockers. Digoxin alone doesnot control exercise-induced increases in heart rate andhence is best used as additional therapy to beta-blockade.When excessive bradycardia occurs, digoxin should bediscontinued. Digoxin is also useful in patients with asso-ciated RV dysfunction.

Hydralazine and isosorbide dinitrate combinationCombination of hydralazine and isosorbide dinitrate wasshown to reduce mortality before ACE inhibitors wereused. However, on head-to-head comparison, this combi-nation is less effective than ACE inhibitors are (28%mortality reduction in favor of enalapril) [105]. In AfricanAmerican patients with NYHA class III to IV systolic HF,this combination has been shown to reduce symptoms andthe risk of mortality and hospitalizations for HF whenadded to standard therapy including ACE inhibitors orARB, beta-blockers, spironolactone, digoxin, and diuretics[106]. This combination is useful when ACE inhibitors orARB are contraindicated due to intolerance including renaldysfunction or hyperkalemia. Hydralazine has rarely beenreported to cause a lupus-like syndrome.

Anticoagulant/antiplatelet therapy There have beensome studies suggesting that aspirin may interfere with theefficacy of ACE inhibitors and even increase risk ofhospitalization. However, 1 systematic review [107] foundthat aspirin and ACE inhibitor combination reducescardiovascular events. The WATCH (Warfarin andAntiplatelet Therapy in Chronic Heart Failure Trial)study found no clear winner when comparing warfarin,clopidogrel, and aspirin [108]. In fact, it found thataspirin use was associated with more HF hospitalizations.There is no evidence to support the use or withdrawal ofaspirin in chronic HF. There is no data to support theroutine use of warfarin in HF unless there are otherindications such as atrial fibrillation or valvular disease.In the WARCEF (Warfarin Versus Aspirin in ReducedCardiac Ejection Fraction) study [109] patients with LVsystolic dysfunction and sinus rhythm, there was nosignificant overall difference in the primary outcomebetween treatment with warfarin and therapy withaspirin. A reduced risk of ischemic stroke with warfarinwas offset by an increased risk of major hemorrhage. Thechoice between warfarin and aspirin, therefore, should beindividualized to the patient’s need.

Prophylactic implantable cardioverter-defibrillatorplacementImplantable cardioverter-defibrillators (ICD) are importantin the management of systolic HF [110]; unlike antiar-rhythmic drugs, they are highly effective in reducing risk ofsudden cardiac death (SCD) in both ischemic and non-ischemic cardiomyopathy (Figure 19). In clinical trialsassessing ICD for primary prevention of SCD, LVEF rangedfrom �40% in the MUSTT (Multicenter UnsustainedVentricular Tachycardia Trial) to �30% in the MADIT II(Multicenter Automatic Defibrillator Implantation Trial II).The MADIT I (Multicenter Automatic DefibrillatorImplantation Trial I) and the SCD-HeFT (Sudden CardiacDeath in Heart Failure Trial) used LVEF of �35% as entrycriteria. Therefore, these are used as criteria to implant ICDto prevent SCD. There is about a 2-fold increase in risk ofSCD in patients with coronary artery disease with non-sustained ventricular tachycardia, and reduced (�40%)ventricular function [111,112]. Data from the MUSTT[113] and MADIT [114] studies, which were done prior towidespread utilization of beta-blockers, suggested 4patients would require an ICD to save 1 life over a shortperiod of follow-up. More recent studies includingMADIT-II and ScD-HeFT [115,116] reported that thereduction in absolute mortality was more modest (5% to7%), suggesting that 11 to 17 patients required ICDimplantation to save 1 life over a follow-up period of 1 to 2years. However, implantation of ICD is associated witha 12% complication risk. Another study suggests that ICDimplantation is futile in an identifiable subgroup of patientsin SCD-HeFT because their HF is simply too advanced[117], which is not surprising given that SCD is more likely


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to occur in NHYA class II patients than in those with moreadvanced HF (Figure 16). One review [118] argued that: 1)There has been an overestimation of the clinical benefit ofICD in clinical trials through stacking the deck by usingantiarrhythmic drugs as a control arm and inequitableutilization of beta-blockers. 2) Underestimation of theadverse effects of ICD on morbidity, quality of life, and thepotential for proarrhythmia because of the appropriate ICDshocks do not equal necessary life-saving shocks (Figure20) and pacemaker and lead malfunction. 3) There is anunderstatement of unfavorable cost-effectiveness of ICDtherapy because it did not account for hospitalizations,recurrent shocks, and lead replacement [119]. The esti-mated cost per life-year saved by ICD was relatively highduring the 3.5-year follow-up in the MADIT-II study[119]; the average survival gain for the defibrillator armwas 0.167 years (2 months), the additional costs were$39,200, and the incremental cost-effectiveness ratio was$235,000 per year-of-life saved. Therefore, implantation ofICD requires discussion of cost-effectiveness considerationswith the patient.
Cardiac resynchronizationCardiac resynchronization has been shown to reducemortality in patients with LVEF <35% and QRS duration>120 ms particularly in patients with sinus rhythm. HFhospitalizations are reduced by 32% (RR: 0.68, 95% CI:0.41 to 1.12), with benefits most marked in patients withNYHA class III or IV symptoms at baseline (RR: 0.65, 95%CI: 0.48 to 0.88); NNT ¼ 12). All-cause mortality isreduced by 21% (RR: 0.79, 95% CI: 0.66 to 0.96; NNT ¼24), driven largely by reductions in death from progressiveHF (RR: 0.60, 95% CI: 0.36 to 1.01) [120]. Current class Iindication for CRT is NYHA class IIeIV systolic HF withLBBB and QRS duration �150 ms [121]. Class II recom-mendation for patients with LBBB but QRS duration only120 to 149 ms and NYHA class II to ambulatory class IVsymptoms and those with non-LBBB pattern and QRSduration �150 ms and class IIIeIV, receive a class IIarecommendation. In those with non-LBBB pattern and QRSduration �150 ms and NYHA class II symptoms, CRT is“not recommended” (with a class III recommendation).

Surgical approaches

Coronary artery bypass graft The STICH (SurgicalTreatment for Ischemic Heart Failure) trial evaluated the roleof coronary artery bypass graft (CABG) in the treatment ofpatients with coronary artery disease and HF (LVEF �35%)and found no significant difference between medical treat-ment alone and medical treatment plus CABGwith respect tothe primary endpoint of death from any cause [122]. Patientswho underwent CABG, as compared with those assigned tomedical therapy alone, had lower rates of mortality fromcardiovascular causes and of mortality from any cause orhospitalization for cardiovascular causes. CABG, therefore,is not superior to optimal medical therapy for ischemic LV


dysfunction. Patients with left main disease or severe anginawere not included this trial, and therefore, in the absence ofthese conditions, medical treatment is the therapy of firstchoice. Whereas, in patients with persistent or progressivesymptoms, revascularization should be considered.

LV remodeling surgery or mitral valve repair Thereare no randomized controlled trials comparing the role ofLV remodeling surgery or mitral valve repair with optimaltherapy in patients with HF. The STICH trial investigatorsfound that adding surgical ventricular reconstruction toCABG, as compared to CABG alone, reduced the LVvolume. However, this reduction in LV volume was notassociated with a greater improvement in symptoms orexercise tolerance or with a reduction in the rate of deathor hospitalization for cardiac causes [123]. Observationaldata suggest that, compared with CABG alone or medicaltreatment alone, adding mitral valve repair to CABG inpatients with ischemic LV dysfunction and moderate tosevere mitral regurgitation may improve survival [124].Prospective randomized studies are needed to confirmthese findings.

LVAD LVAD, compared with medical therapy, are asso-ciated with a 48% reduction in the risk of mortality fromany cause. LVAD are associated with a 2-year survival of23% as compared to 8% with medical therapy [125,126].The main complications of LVAD are infection andthromboembolism. As a result of these complications,LVAD are not yet standard therapy for systolic HF. Theindication for LVAD is a moving target and the cost-benefit was discussed in detail in recent documents[126e128].

Cardiac transplantation Registry data has shown thatorthotopic heart transplantation is associated with a 1-yearsurvival of 80% and a 10-year survival of 50% [129].Patients who are refractory to medical therapy should bereferred to heart transplantation center when available.Indications for cardiac transplantation include NYHAclass IV HF with peak myocardial VO2 <12 ml/mg/kg, inthe absence of renal, hepatic, central nervous system, orvascular disease and is discussed in detail elsewhere [130].

COMORBIDITIES

HF and kidney diseaseRenal impairment is common in HF and the etiology ofrenal impairment is multifactorial. Common causesinclude dehydration usually with diuretic therapy, ACEor ARB, and/or use of aldosterone receptor antagonist.Usually this occurs with underlying renal disease. Fivesubtypes of cardiorenal syndromes [131] were describedin a consensus conference, each with distinct patho-physiologies (Figure 21) [132] prevention, and manage-ment strategies (Figure 22):

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� Type 1, or acute cardiorenal syndrome, is acute worseningof heart function leading to kidney injury or dysfunction.About 27% to 40% of the patients with acute decom-pensated HF seem to develop acute kidney injury. Thistype is associated with the poorest prognosis.

� Type 2, or chronic cardiorenal syndrome, includes patientswith chronic abnormalities in heart function leading tokidney injury or dysfunction. This type has been in 63% ofpatients hospitalized with CHF. Serum creatinine, in suchpatients, may not entirely reflect underlying renal function.

� Type 3, or acute renocardiac syndrome, is acute wors-ening of kidney function, leading to heart injury ordysfunction. Factors in addition to volume overload(e.g., acute kidney injury, glomerulonephritis, and renalischemia) affect cardiac function.

� Type 4, or chronic renocardiac syndrome, is a situation inwhich chronic kidney disease leads to heart injury, disease,or dysfunction (e.g., chronic glomerulonephritis).

� Type 5, or secondary cardiorenal syndrome, encom-passes those systemic conditions resulting in injury ordysfunction of heart and kidney (e.g., diabetes mellitus,sepsis, systemic lupus erythematosus, or amyloidosis).

Azotemia in patients withHF caused by dehydrationmayrequire temporary cessation or dose reduction of diuretictherapy. When renal dysfunction is associated with use ofACE inhibitors, ARB, or spironolactone, it may requirereduction or cessation of treatment. Accompanying renovas-cular disease may benefit from renal angioplasty to allowpatients to better tolerate ACE inhibitor or ARB. The presenceof renal disease often requires evaluation such as 24-h urinaryprotein, kidney ultrasound, and Doppler evaluation of renalarteries. The DOSE (Diuretic Optimization Strategies Evalu-ation) trial [133] compared continuous intravenous infusionof the furosemide with administration of intravenous bolusesevery 12 h and a low-dose regimen (in which a dose equal tothe patient’s previous oral dose was used) with a high-doseregimen (in which a dose 2.5� the previous oral dose wasused). The median duration of hospital stay did not differamong the diuretic regimen groups. There was no significantdifference in the mean change in serum creatinine level or inpatients’ global assessment of symptoms between the groupreceiving continuous infusion and the group receivingboluses. The patients in the high-dose group had greater reliefof dyspnea and greater net fluid loss, but they were slightlymore likely to have a transient worsening of kidney function.In the CARRESS-HF (Cardiorenal Rescue Study in AcuteDecompensated Heart Failure), ultrafiltration, as comparedwith pharmacologic treatment, didnot result in greaterweightloss or improved renal function and was associated witha similar rate of mortality or rehospitalization for acutedecompensatedHF.More studies are needed to determine therole of ultrafiltration in cardiorenal syndrome.

HF and anginaIn patients with HF and angina, beta-blockers are thetreatment of choice. Nitrates can also be used. Amlodipine

is the only calcium channel blocker that can be used forangina safely in HF [134]. Other calcium channel blockersare known to worsen symptoms of HF. Angina in patientswith systolic HF is an indication for coronary angiographybecause revascularization may improve symptoms and LVdysfunction.

Sleep disordered breathingBoth central sleep apnea and obstructive sleep apnea areseen in HF patients. Central sleep apnea occurs in about25% to 40% of the patients and is considered to occuras a consequence of HF. The CANPAP (ContinuousPositive Airway Pressure for Heart Failure Patients WithCentral Sleep Apnea) study showed no survival benefitswith continuous positive airway pressure in central sleepapnea despite improved physiological predictors such asLVEF, decreased circulating adrenalin, and increasednocturnal oxygen saturation [135]. In obstructive sleepapnea, continuous positive airway pressure has beenshown to improve LVEF [136] and quality of life insmall studies.

HF in the elderlyThe elderly benefit from HF therapy like the generalpopulation does. However, they are more likely to be frailand have comorbidities such as cognitive dysfunction,depression, falls, renal impairment, postural hypotension,urinary incontinence, and COPD. It is important that theyare considered for vaccinations because a large cohortdemonstrated a 37% reduction in hospital admissions forHF among those immunized against influenza [137]. HFpatients require annual vaccinations for influenza. Caseseries have reported that 23% of decompensated HF isassociated with infection (one-third of which werepulmonary) [138], and another case series reported that12% of hospitalizations due to decompensated HF areassociated with pulmonary infection [139]. Therefore, it isrecommended that all HF patients be immunized withpneumococcal vaccine at least once.

CONCLUSIONSThis white paper serves as a starting point for managementof HF in developing nations where allocation of scarceresources requires thoughtful consideration. It is a work inprogress and will require continuous updating.

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Randomized Amlodipine Survival Evaluation Study Group Effect ofamlodipine on morbidity and mortality in severe chronic heartfailure. N Engl J Med 1996;335:1107–14.

We have started to publish a series of white papers with the prim

global audience in the low and middle income countries. This art

Guidelines (like those from the AHA, ACC, and ESC) have been writt

delivery systems, adequate infrastructure, and monetary sufficien

these resources, and many of those recommendations may seem

taken it upon itself to digest these outlines and present them in a

paper is an authoritative report or guide helping readers to unde

while being an expert consensus statement, it is not an unalterable

may modify its recommendations based on the needs of their ind

consensus statement to provoke a thoughtful debate, just as all g

REFERENCES1. White paper. Available at: http://en.wikipedia.org/wiki/White_

2. Doerr, Audrey D. The role of white papers. In: Doern GB, A

MacMillan; 1971:179e203.

3. Pemberton JE. Government green papers. Library World 1969;

135. Bradley TD, Logan AG, Kimoff RJ, et al., for the CANPAP InvestigatorsContinuous positive airway pressure for central sleep apnea andheart failure. N Engl J Med 2005;353:2025–33.

136. Kaneko Y, Floras JS, Usui K, et al. Cardiovascular effects of contin-uous positive airway pressure in patients with heart failure and

obstructive sleep apnea. N Engl J Med 2003;348:1233–41.137. Nichol KL, Margolis KL,Wuorenma J,Von Sternberg T.The efficacy and

cost effectiveness of vaccination against influenza among elderlypersons living in the community. N Engl J Med 1994;331:778–84.

138. Opasich C, Febo O, Riccardi PG, et al. Concomitant factors ofdecompensation in chronic heart failure. Am J Cardiol 1996;78:354–7.

139. Ghali JK, Kadakia S, Cooper R, Ferlinz J. Precipitating factors leadingto decompensation of heart failure: traits among urban blacks. ArchIntern Med 1988;148:2013–6.

ary intent of translating currently available evidence to fit our

icle is the first of the series of many to follow. Major Society

en with a focus on developed nations with superior health care

cy. Our journal, Global Heart, targets audiences with few of

impractical in their health care environment. Our journal has

form more palatable to users in developing countries. A white

rstand an issue, solve a problem, or make a decision [1], and,

policy statement [1,2]. The expert end users and their societies

ividual health care environment. We intend this expert

ood white papers should [3].

paper. Accessed May 24, 2013.

ucoin P. The Structures of Policy-making in Canada. Toronto:

71:49.






























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