Dr. Nabil Alama (MD. FRCPC)Head of Cardiology Unit

King Abudlaziz University Hospital

CVD is the number one cause 1 death for women

Each year 500,000 women have MI and more than 250,000 die of CAD

Combined with stroke, hypertension and other vascular disease, more than 500,000 women die normally of CAD

Although virtually all women can readily quote lifetime incidence of breast cancer (1in 9), few realise that 50% (1 in 2) all women will die of CVD.

Whereas the death rate from CVD in men has declined steadily during last 20 years. The rate has remained relatively the same for woman.

Despite the magnitude of the problem in women, much lessInformation about optimal primary & secondary. Presentationstrategies, diagnostic modalities and responses to medical & surgical Treatment is available for women than for men.

This lack of data reflects several factors, exclusion of womenFrom many older clinical trials

•Lower prevelance of symptomatic CAD in women than in man until age 70.

• Hormonal effects of gender differences in presenting symptoms

* Relaive effects of various risk factors

Gender difference versus gender bias

clear gender difference has been identified in epidiomology of presentation of disease,Risk factor prevalence, phyioslogy & response to diagnostic test & interventions.

Although there are several factors that solely or predominatelyEffect women, including menopause status, hormone replacementtherapy.

Oral controceptives & pregnancy related heart diease

During last decade, several studies have noted importantGender differences as in clinical outcomes and the use of Diagnostic and therapeutic drugs and informations, especiallyIn evaluation and Rx of Treatment woman with CP and MI

The concern has been raised that women are evaluated lessIntensively, under referred and not treated as aggressivelyas man for comparative presentation and disease

Ischemic Heart Disease

Framingham group reported that more women than man(56% vs. 46%) have angine as their presenting symptomOf cardiac disease. But more men who have angina go on tohave MI 25% vs 14%).

This led to erroneous conclusion that angina is benign condionIn women.

This misconception was clarified with publications (CASS)Which showed that even in women with classical angina symptoms.Rate of normal coronary arteries on angiography is approximately50% compared with less than 20% in men.

In Framingham study angina has defined clinically withoutAngiography, (women are more likely to have non Ischaemiccause of chest pain that has benign prognosis.

Reexamining date, showed prognosis for older women withProbably true ischemic was activity worse than for man in Framingham study.

Presenting Symptoms

On average, women with CAD present with symptoms cardiacEvents or sudden death 10 years later than man. It is largelyProtective effects & endogenous oestrogen in premenopaul in men.

Most men & women present with typical symptoms CAD howeverDisproportinately more women present atypically with dyspnea,Fatigue and referred pain.

Because of late presentation, women are less likely to be eligibleFor emergency PTCA – Thrombolysis for acute MI & often haveAdvanced anatomical disease on coronary angiography

Stress Test

Standard stress ECG testing is less activate in women than in man.

Numrous studies high false positive rate in women compared toMen (Lower prevalence (CAD) until 70 years.

Lower specificity is related to gender specific autonomic and sexHormone effects for ECG.

In older women, failure to achieve an adequate stress level due to Deconditioning or orthopaedic limitation may adversely affectSensitivity of exercise test.

Normal finding of stress ECG at adequate work load in womenAre a good indication that flow limiting CAD is unlikley.

•Because of these limitation imaging stress have gained popolarity for women.•Gender specific antifacts and physiological responses have been described in both nuclear and stress echo standard diagnostic criteria used for interpreting exercise radionuclide angriographic Finding have not proved accurate in women. Abnormal result isDefined as a lack of increase in ejection fraction with exercise.In men increase stroke volume in response to exercise is causedBy an increase in ejection fraction.

Whereas in women, it is caused by an increase in end-diastolicVolume so 1/3 of women with normal coronary arteries do notHave an increase in ejection fraction.

Stress Thallium Scintegraphy Improres

Diagnostic accuracy in women

-Breast tissue attenuates radioactivity and may produce a false positive study as a result of artifactual defects in anterior wall and septum.

-Use of technetium 99m (Tc99)sestamibi imaging higher energy radioactivity, reduce breast tissue attenuation artifact.

-Limited studies suggested that thallium and sestamibi have similar test sensitivity by specificity may be enhanced by sestamibi imaging.

-Pharmacologic stress using dypyridamole, adenosine, or dobutamine is limited but suggests that diagnostic accuracy is similar for men and women.

Exercise echo may improve accuracy of exercise testing forDiagnosis dobutamine echo is safe in women.

Until more studies, no firm guidelines can be offered aboutSpecific stress testing modalities in women, because no approachOr technique has been shown to be clearly superior. As in men,Pretest probability of disease is likely more important in deter-Mining diagnosis accuracy than specific type of test. If likelihooodOf CAD is low, no stress test is very accurte. Women with Intermediate probability of CAD and normal ECG standard testECG has acceptable sensitivity and specificity. If result are normal,There is a high negative predictive value regarding absence of CAD and prognosis is good.

Women with worrisome symptoms and high pretest probabilityOf CAD argument can be made to proceed directly to angiography.

Coronary Angiography is safe in women

Most studies have demonstrated despite gender differences ofRates of referral to angiography, after anatomy is defined womenAre revascularized at a rate similar to men.

Myocardial Infarction

•Numerous studies have demonstrated greater early and late mortality and more compliclations in women than in men afterMyocardial infarction. However, analysis of several studies(GUSTO-I, ISIS-11, TIMI IIIB)

•After baselise differences have been accounted for especially age and cardiac risk factors, gender is no longer an independent risk factor for death.

•Women with MI are older and have more comorbid conditions and have increase of all cardiac risk factors except smoking.

•DM is more common in women and may account for increased frequency of silent ischaemic

Women may be slightly less likely to present with sudden deathBut more likely than men to have non-Q-myocardial infarction.Also, women are morel likely to delay receiving Rx.

Risk of inhospital complications (reinfarction, stroke andMyocardial rupture) has been reported to be higher in women.But some of these differences may be related to older age.

Women have more heart failure despite better residual leftVentricular systolic function, presumably because of diastolic Abnormalities.

Women are less likely to be referred to cardiac rehabilitation

All therapies and interventions for RX of MI have been Beneficial revascularization by thrombolysis, direct angioplastyOr surgery ASA, Blocker, ACE.

More less likely to have invasive & therapeutic procedures whenHospitalized with ACS. This relative “undertreatment” is notBenign.

Women in these studies who have revascularization procedureHad a better prognosis than those who did not.

Coronary Angiography

Female gender is independent predictor of a lower likelihoodOf receiving coronary angiography.

After little difference found in subsequent use of angiographyAnd bypass surgery, decisions made primarily on severity ofDisease and not gender.

Thrombolysis decreased 30% overall reduction in mortality. No difference in fundamental mechanism of action of Thrombolysis agents. After adjustment for age and comorbidConditions, women have same rate of vessel patency, LVEF andShort - and long term martality as men. Women receiveThrombolysis much less frequently at least partly because theyAre more likely to be ineligible at the time of evaluation, becauseOf age, comorbid conditions and late presentation.

Intracerebral hemorrhage is more common in women than in men,Smaller size and lack of dose adjustment.

CETHETER BASED REVASCUAFSTIN

Early in interventional era procedural success for PTCA in women was lower then man because large non stearable catheters and balloons and generaly smaller coronaly alteries in women currently no gender difference in the procedure success or restenosis date have been document all report series show that women more severe angina and more contaminant illness including DM, Hypertention, Heart failer at the time of persentation

When age and these base lines charteristics are consider there minmal or no genger difference in short or long term servival or rate of MI CABG wheter interventional proccdure is perform for UA, acute MI, Elective stable angina

Women more likely to have residual angina and to take anti angina medication after PTCA this difference observed also after CABG

Microsvasculaer disease and abnormalities in coronary flow reseved associated with LVH or DM may contribute this observation

Earlear women who had CABG have greative operative short and long mortality then man (smaller body size more advanced desisae at the time of operation and refferial bias) however studies cass, bari trials reported similar graft patency and loge term servival benefit.

Rate of the peri operative death and compications (MI, Strocks and heart failer) are greater for women this disparty disappear when the base line factors such as age heart falier are considered

Women are more likely to have residual angina that requires theropy also women have more likely to have emergency by pass which is lndepently assoated higher morbiatity and mortality CABE proides Excellent Relief of symptomes and comprarable survival benefits in women.

Coronaryartery and Surgery

PHARMACOLOGIC THERAPY

ASA, B-blcoker, ACEI under utilized ineligible patientsWith acute MI or left venticular dysfunction.

ISIS I & ISIS II, demonstrated that improved survival in womenReceiving b-blocker & ASA was comparale to that of men.

Trials involving ACEI & generally have sown beneficial effects in women, but less than those in men so should beused

NONCORONARY CARDIOVASCULAR DISEASE (CVD)

Framingham and other reported markedly prevalence of MVPDiagnosed clinically or by M-mode. In women but men withMVP more likely to develop progressive MR and other Complications.

More recent studies with two-dimensional echocardiography(which may be less likely to overcall the diagnosis of MVP haveNot found any gender difference in prevalence of mitral valveProlapse.

AORTIC VALVE DISEASE

Calcific AS is disease of elderly

Women with aortic stenosis have different pattern of LVAdaptation to pressure load of AS then man, with better preservation of LV systolic function and concentric pattern of LVH. Men more frequently have eccentric hypertrophyAnd lower systolic function.

The classic criteria (LV EDD >70, LV ESD >50 for timing AVR for severe AR has been questioned recently. WomenWith even advanced severe AR rarely meet established LVDSurgical criteria (which traditionally has not been adjusted for Body size.

Even after sgnificant symptoms develop, ventricular Dimension tend to be smaller than those of the criteria.

Thus, using these criteria for women results in operatingLate in the clinical course, with poor outcomes. Female genderAppears independent risk factor for poor outcome and optimalCriteria is not clear for surgical timing for asymptomatic chronicAortic regurgitation.

Surgery should be considered in men and women with more thanmild symptoms or with an ejection fraction less than 55%.

CONGESTIVE HEART FAILURE

Rate of hospitalization for CHF has increased steadily inLast 20 years. CHF affects 20% of population over 45.

Framingham study found incidence rate of CHF are higherIn men but that of prevalence of CHF is nearly equal exceptIn very elderly.

•5 year suvival was better in women than in men.• Hypertension, DM and valvular heart disease tend to be more common in women with CHF whereas CAD and smoking are more common in men.

Women are more likely to have better LV systolic functionThan men with similar heart failure symptoms. In womenHave been ascribed to higher rate of diastolic dysfunction(more symptomatic with similar EF) Many of major heart failure Trials did not include women or so conclusion must be interpretedCarefuly, CONSENSUS, SOLVD, and SAVE heart failureTrials women received less benefit from ACE than men.

Fewer than 20% of cardiac transplantation operations arePerformed on women, and there appears to be a gender effectOn outcome after cardiac transplantation.

Women may be at increased risk of death and rejection spisodes,(small date) one possible cause frequency of autoimmuneDisease for in women and multiparity, which exposes women to Additional antibodies to foreign material.

Arrhythmias, Syncope, and Sudden Death

Women presenting with syncope tend to be older, have fewerPremonitory symptoms, have better LVF, and are less likely To have cardiac cause of syncope identified subsequentlyHave fewer cardiac events.

Female survivors of cardiac arrest tend to have better LVFunction and are less likely to have CAD as underlying cause.They are more likely to have dilated cardiomyopathy, valvularHeart disease, long QT syndrome, RV dysplasia, Coronary vasospasmsor structurally Normal heart. Despite these differences, long-term survival appears to be similar.

Benefit of defibrillator therapy are less well defined mainly becauseOf small number.

Prevalence of atrial fib is higher at all ages in men than in women.It has been estimated athat 50% to 55% of all persons and 60%Of those older than 75 years who have atrial fibrillation areWomen.

More women than men have atrial because of greater numberOf elderly women.

Paroxysmal SVT more common in women than men. SomeInvestigations have described cyclical variation in the frequencyAnd duration of PSVT in premenopausal women, with highestFrequency occurring in the luteal phase of the menstrual cycleWhen estrogen levels are lowest. Mechanism may be cyclic bodyTemperature changes, direct or indirect actions of estrogen orProgesterone effects.

RISK FACTORS

Men & women have the same risk factors for CAD, but relativeWeight of a given risk may be more or less significant in women.

DM is more powerful risk factor for CAD and heart failure inWomen than in men and completely negates the protective effectOf female gender, even in premenopausal women.

Metabolic derangements accompanying diabetes adverselyContribute to obesity, lower levels of high-density lipoprotein And TG abnormal endothelial and coagulation function andIncreased risk of hypertension. DM acts synergistically with Other risk factors especially smoking, increase cardiac risk.DM is independent risk for subsequent cardiac events andPoor outcome after PTCA in women.

TOBACCO

Cigarette smoking is a significantly stronger risk factor inWomen than in men. Even women who smoke fewer than5 cigarette per day have double the risk of CAD than non-Smokers

Smoking cessation is associated with a significant reductionOf risk.

Women with CAD who continue to smoke have significantProgression of atherosclerosis and are at risk for recurrentEvents and repeat revascularization.

HYPERTENTION

Women make up 60% of all those in the US who have hyper-Tention. Prevalence of hypertension is greater in men thanWomen until age 60.

In Black and Hispanic persons older than 60 and white peopleOlder than 70. Age specific hypertension rate is higher in womenTha in man. With women older than 80 have rates 14% higherThan men.

BP tend to increase throughout life in men and women, but beforeAge 60, women have lower systolic and diastolic BP than men.Subsequently systolic BP increases more steeply in women andSurpasses that of men.

As result older women more likely to have isolated systolic hypertention.

SEVERAL TYPES OF HYPERTENSION AFFECT WOMEN

Renal artery stenosis caused by fibromuscular dysplasia has aStrong female preponderance (8:1) and should be consideredWhen hypertension occurs in women less than 40 difficultTo control or occurs in pregnancy complicated by severe Hypertension.

Ingestion of currently available oral contraceptive agents isAssociated with and increase in BP, although not commonly As first generation agents.

Hypertension and LVH both are stronger risk factors for strokeAnd CHF in women than in men. Framingham (LVH removessurvival advantage of female gender.

No real gender differences exist in relative risk reduction forStroke and CHF from the treatment of hypertension. AbsoluteRisk reduction are lower in women because the baseline riskOf events is lower.

Current guidelines from the Joint National Committee on theTreatment of Hypertenstion VI (JNC-VI) are not genderSpecific and it appears that women with hypertension benefitFrom therapy and should e treated as aggressively as men.

HYPERLIPIDEMIA

Serum levels of toal cholesterol in women increase steadilyFrom mid-30s to age 55 – 60.

LDL remain lower than in men until 50 age, which levels in menstabilize and are surpassed by those in women.

This coincides with the average age of menopause and likelyContributes to observed increase in cardiac events in olderWomen.

Women younger than 65 with T-cholesterol level greater 240mg/dL LDL greater 160mg/dL have relative risk of cardiacEvent is 2-3 times that of women without hyperlipidemia

HDL cholesterol remains a strong risk factor in women olderthan 65.

Relationship of total cholesterol and LDL Ch. & CAD in olderWomen is not as strong.

Conflicting data about triglyceride as independent risk factors. This appear similar to those of men.

Primary prevention hyperlipidemia trials excluded womenAnd elderly; therefore little information on which to baseTherapeutic decisions.

1993 NCEP, ATP II acknowledged gender differences and Estrogen status in calculating the risk for CAD for premeno-Pausal women with out CAD, there are insufficient data toRecommend early or aggressive pharmacologic therapy unlessMultiple risks are present.

Postmenopausal women without CAD and hypercholesterolemiaOr a low HDL cholesterol may be considered for estrogenReplcement therapy, which may obviate additional pharmacologicTherapy.

AFCAPS / TEXT CAPS)

1000 postmenopausal women with no known vascular diseaseAverage TC, Low average HDL Ch. to placebo or treatmentWith lovastatin and found 46% reduction in CV events in Treated women. Study not powered to detect treatment differencesIn mortality but showed similar or greater reduction events in Women than in men and demonstrated risk reduction fromLipid modification in relatively low risk group that otherwiseNot treated in current NCEP- ATP-II guidelines.

There is strong evidence from well-designed randomizedTrials to support aggressive treatment of increased cholesterol Levels in women with CAD.

CARE randomized men and women with recent myocardialInfarction and normal LDL cholesterol levels (115-174 m/dL)To treatment pravastatin or placebo.

Treated men and women both had a significant reduction in allend points including cardiac death, MI & revascularization.

Subgroup analysis demonstrated an even greater reductionIn risk for coronary events in women than in men (46% vs. 20%)and benerfit was observed much earlier the follow-up period.

4 S Study randomly assigned hyperlipidemic patients wth CAD to treatment a placebo. The risk reduction for major coronaryEvents were similar in men and women (34% vs. 35%, Respectively).

These studies provide evidence to support the use of the Current NCEP-ATP-II guidelines for secondary preventionOf CAD with goal LDL cholesterol of less than 100mg/dL.

No study has suggested significant gender differences in dietaryIntervention or lipid lowering drugs.

RISK FACTORS UNIQUE TO WOMEN

Oral Contraceptives

One of the most effective methods for pregnancy preventionBut women who took first generation high-dose agents hasIncreased rate of MI and thrombotic events.

There was a clear synergy with cigarette smoking believed Thrombotic rather than atherosclerotic currently oral contra-Ceptives with markedly lower estrogen content have been Lower rates MI and appears that there is little or no increasedIn nonsmoking women taking oral contraceptive and no inceasedRisk in those who previously took them.

Small excess risk of ischemic stroke cannot be excluded

Large risk appears unlikely

Smokers specially older than 35 years shout quit smoking, and If unable to do so, should use an alternative birth control method.Oral contraceptives are associated with increased BP, some Become overtly hypertensive (if happened should discontinue).

Increased incidence of DVT & PE has been associated with Taking oral contraceptive (less with current pills with relativesRisk.

The risk of pregnancy related thromboembolic events and strokeIs as much as 3 times than that associated with oral contaceptives.

Menopause and Hormone Replacement Therapy

Estrogen at menopause associated with several adverse effectsOn cardiac risk factors, include:

TC LDL Ch. LP9a) LP (a) Circulating procoagulants And homocysteine Decreased HDL cholesterol

These changes responsible at least partly for the observedAcceleration of cardiovascular events afer menopause.

Premenopausal women who have had bilaeral oophonatomyAnd do not receive estrogen have more than twice the risk ofMI than those receive estrogen replacement has been associatedWith cardiovascular risk.

Primary epidemiological data and meta-analysis, includingLipid Research Clinic and Nurse Health Study. Indicate riskReductions of 40% - 50% for CAD in women who choose toTake postmenopausal HRT.

The data for stroke reduction by estrogen is less but similar riskReduction has been showb. These data are observational and notfrom prospective randomized trials but has remarkable uniformity and consistency in results

Estroen reverses many of the unfavorable physiologic changesThat occur at menopause.

Lipid effects are prominent, but the mechanism are incompletelyUnderstood.

Oral administered estrogen decreased LDL cholesterol by10%-20%, increased HDL cholesterol by 10%-30%And lowers LP(a) by 25% - 50%Triglycerides are increased 20% or more

Transdermal administration of estrogen has little or no effectOn lipoprotein levels, suggesting that the liver effects of Estrogen absorbed through the gut are responsible for theseChanges.

These favorable effects are also seen when estrogen is combinedWith progestational agents, but increase in HDL levels is oftenBlunted. Limited data suggest that the use of micronized pro-Gesterone, comapred with medroxyprogesterone, blunts theEstrogen induced increase in HDL cholesterol less, whileMaintaining protection against endometrial hyperplasia.

Balance of the effects estrogen is likely due to severalDirect and indirect vascular and hemostatic effects.

Despite the impressive benefits reported for coronary arteryDisease risk in these observational trials,.

The first randomized, blinded, placebo-controlled trial ofEstrogen for secondary prevention of coronary events did notShow any significant reduction in cardiac risk

The Heart and Estrogen/Progesterone ReplacementStudy( HERS)

Enrolled 2763 postmenopausal women younger than 80 yearsWith definite coronary artery disease and intact uterus to receiveContinuous-combined estrogen and medroxyprogesterone orPlacebo.

Average follow-up 4.1 years and was 100% complete. No Signifidant differnece were observed for any of the CVOutcome.

That is combination hormone replacement therapy(HRT) didNot reduce cardiovascular events as expected from result ofPrevious observational trials.

Most previous studies, conjugated equine estrogen (Premarin)Was only estrogen formulation used

•Doses was higher than currently recommended• Use of progestational agent in women was not routine (Not practice now)•Addition of progestins antagonies part on the beneficial of estrogen. Women in HERS, received continuous progestroneWhich blunts beneficial lipid effect•Selection bias or healthy user.

Results trial should not be extropaleted to other patient poplationPatient without CADWithout uterusOther HrT formulationSeveral study are on going for bot Pri + Sec includes women Health study.

NONCARDIAC RISK AND BENEFITS OF HORMONE

All women with suspected CAD should have their hormonalStatus assessed as a risk factors. Decision to start hormone Replacement therapy must be individdual and based on risk ofCAD breast cancer and fracture and on hysterectomy status,Life expectancy, and side effects.

Non cardiac beneficial oesgtrogen replacement therapy

decreased postmenopausal symptomsdecreased osteoprotic fracturedecreased Colon Cadecreased Urinary incontinence of Alzheimer dieses

Cancer BreastEstrogen therapy for more 5 – 10 years associatedWith an increased relative risk 1.2 to 1.5 which is similar to earlyMenanrche and mulliparity.

Breast cancer must be put into perspective because CVD killsMore women that breast cancer at all ages.

Unopposed estrogen is associated with significantly increasedRisk of endometrial hyperplasia and cancer. Excess risk of Cancer is eliminated with addition of progestrin; therefore,Unopposed estrogen is recommended only for women who hadA hysterectomy.

Venous thromboembolism and pulmonary embolus haveBeen associated with estrogen replacement. The increaeIn relative risk of various thromboembolism appears to be2 to 4 (2.9 in HERS_. This risk appears higher during the First year of treatment and affects those currently receivingTreatment but not those who formerly received it. TheWomen affected may have unidentified coagulapathies orOther predisposing risk factors, because no consistent adverseEffects on the clotting system have been identified. The Absolute incidenc is low, but women experiencing venousthromboembolism while receiving hormone replacement therapyShould be evaluated for the presence of coagulapathy.

Selective estrogen receptor modulators (SERMS) are a classOf synthetic tissue-specific estrogens(“designer estrogens”)Formulated to provide the beneficial action of estrogen withoutThe risks and side effects Tarnoxifen (used for prevention andTreatment of breast cance) and raloxifene (approved for the treatment of osteoporosis) are the most commonly used SERMs,And both of them have favorable effects on lipoprotein and Homocysteine levels. These drugs do not have significantBeneficial effects on HDL cholesterol, and the observed Improvements in the lipid profile are less than those observedwith oral estrogen. Currently, the role of SERMs in preventingCardiovascular disease is unclear.

Hrmone Replacement Therapy Recommendations

Currently, no consensus exists about the role of postmenopausalHormone replacement therapy in the prevention of coronary arteryDisease. Recommendations are evolving as now data published.

Hypercholesterolemia

The National Choelsterol Education Program (NCEP II) gudelinesNow include postmenopausal status as CAD risk factor in the Assessment for hyperlipidemia. Estrogen replacement therapy Considered as athe initial/primariy therapy of hyperterolemia in Postmenopausal women because of the efficacy and relatively lowCost. It has complemented effects on the lipid profile when Combined with statins statins should be given as initial therapy for hyper-Lipdema in women with vascular disease.

Secondary Preventions

HRT should not be recommended to women with documentedCAD solely for cardio protection if noncardiac indications exist,Hormone replacement may be prescribed but the inceased risk ofVenous trhomboembolism should be discussed. All other provedRx (aspirin, beta-blocker, statisn, ACE inhibitors usedMaximal.

Primary Preventions

Adeauate data to support widespreade use of estrogen replacementTherapy in postmenopausal women for primary precaution ofCAD do not exist.