Dr Nabil Alama MD FRCPC Head of Cardiology

Dr. Nabil Alama (MD. FRCPC) Head of Cardiology Unit King Abudlaziz University Hospital

Ø CVD is the number one cause 1 death for women Ø Each year 500, 000 women have MI and more than 250, 000 die of CAD Ø Combined with stroke, hypertension and other vascular disease, more than 500, 000 women die normally of CAD

Ø Although virtually all women can readily quote lifetime incidence of breast cancer (1 in 9), few realise that 50% (1 in 2) all women will die of CVD. Ø 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 less Information about optimal primary & secondary. Presentation strategies, diagnostic modalities and responses to medical & surgical Treatment is available for women than for men.

This lack of data reflects several factors, exclusion of women From 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 predominately Effect women, including menopause status, hormone replacement therapy. Oral controceptives & pregnancy related heart diease

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

The concern has been raised that women are evaluated less Intensively, under referred and not treated as aggressively as 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 symptom Of cardiac disease. But more men who have angina go on to have MI 25% vs 14%). This led to erroneous conclusion that angina is benign condion In 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 approximately 50% compared with less than 20% in men.

In Framingham study angina has defined clinically without Angiography, (women are more likely to have non Ischaemic cause of chest pain that has benign prognosis. Reexamining date, showed prognosis for older women with Probably true ischemic was activity worse than for man in Framingham study.

Presenting Symptoms On average, women with CAD present with symptoms cardiac Events or sudden death 10 years later than man. It is largely Protective effects & endogenous oestrogen in premenopaul in men. Most men & women present with typical symptoms CAD however Disproportinately more women present atypically with dyspnea, Fatigue and referred pain. Because of late presentation, women are less likely to be eligible For emergency PTCA – Thrombolysis for acute MI & often have Advanced 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 to Men (Lower prevalence (CAD) until 70 years. Lower specificity is related to gender specific autonomic and sex Hormone effects for ECG. In older women, failure to achieve an adequate stress level due to Deconditioning or orthopaedic limitation may adversely affect Sensitivity of exercise test. Normal finding of stress ECG at adequate work load in women Are 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 is Defined as a lack of increase in ejection fraction with exercise. In men increase stroke volume in response to exercise is caused By an increase in ejection fraction. Whereas in women, it is caused by an increase in end-diastolic Volume so 1/3 of women with normal coronary arteries do not Have 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 99 m (Tc 99)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 for Diagnosis dobutamine echo is safe in women. Until more studies, no firm guidelines can be offered about Specific stress testing modalities in women, because no approach Or 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 likelihoood Of CAD is low, no stress test is very accurte. Women with Intermediate probability of CAD and normal ECG standard test ECG 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 probability Of CAD argument can be made to proceed directly to angiography. Coronary Angiography is safe in women Most studies have demonstrated despite gender differences of Rates of referral to angiography, after anatomy is defined women Are 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 after Myocardial 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 death But 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 and Myocardial 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 left Ventricular 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 angioplasty Or surgery ASA, Blocker, ACE. More less likely to have invasive & therapeutic procedures when Hospitalized with ACS. This relative “undertreatment” is not Benign. Women in these studies who have revascularization procedure Had a better prognosis than those who did not.

Coronary Angiography Female gender is independent predictor of a lower likelihood Of receiving coronary angiography. After little difference found in subsequent use of angiography And bypass surgery, decisions made primarily on severity of Disease 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 comorbid Conditions, women have same rate of vessel patency, LVEF and Short - and long term martality as men. Women receive Thrombolysis much less frequently at least partly because they Are more likely to be ineligible at the time of evaluation, because Of 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

Coronaryartery and Surgery 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.

PHARMACOLOGIC THERAPY ASA, B-blcoker, ACEI under utilized ineligible patients With acute MI or left venticular dysfunction. ISIS I & ISIS II, demonstrated that improved survival in women Receiving 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 be used

NONCORONARY CARDIOVASCULAR DISEASE (CVD) Framingham and other reported markedly prevalence of MVP Diagnosed clinically or by M-mode. In women but men with MVP 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 have Not found any gender difference in prevalence of mitral valve Prolapse.

AORTIC VALVE DISEASE Calcific AS is disease of elderly Women with aortic stenosis have different pattern of LV Adaptation to pressure load of AS then man, with better preservation of LV systolic function and concentric pattern of LVH. Men more frequently have eccentric hypertrophy And lower systolic function. The classic criteria (LV EDD >70, LV ESD >50 for timing AVR for severe AR has been questioned recently. Women With even advanced severe AR rarely meet established LVD Surgical 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 operating Late in the clinical course, with poor outcomes. Female gender Appears independent risk factor for poor outcome and optimal Criteria is not clear for surgical timing for asymptomatic chronic Aortic regurgitation. Surgery should be considered in men and women with more than mild symptoms or with an ejection fraction less than 55%.

CONGESTIVE HEART FAILURE Rate of hospitalization for CHF has increased steadily in Last 20 years. CHF affects 20% of population over 45. Framingham study found incidence rate of CHF are higher In men but that of prevalence of CHF is nearly equal except In 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 function Than men with similar heart failure symptoms. In women Have 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 interpreted Carefuly, CONSENSUS, SOLVD, and SAVE heart failure Trials women received less benefit from ACE than men. Fewer than 20% of cardiac transplantation operations are Performed on women, and there appears to be a gender effect On outcome after cardiac transplantation. Women may be at increased risk of death and rejection spisodes, (small date) one possible cause frequency of autoimmune Disease 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 fewer Premonitory symptoms, have better LVF, and are less likely To have cardiac cause of syncope identified subsequently Have fewer cardiac events. Female survivors of cardiac arrest tend to have better LV Function and are less likely to have CAD as underlying cause. They are more likely to have dilated cardiomyopathy, valvular Heart disease, long QT syndrome, RV dysplasia, Coronary vasospasms or structurally Normal heart. Despite these differences, long-term survival appears to be similar. Benefit of defibrillator therapy are less well defined mainly because Of 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 are Women. More women than men have atrial because of greater number Of elderly women. Paroxysmal SVT more common in women than men. Some Investigations have described cyclical variation in the frequency And duration of PSVT in premenopausal women, with highest Frequency occurring in the luteal phase of the menstrual cycle When estrogen levels are lowest. Mechanism may be cyclic body Temperature changes, direct or indirect actions of estrogen or Progesterone effects.

RISK FACTORS Men & women have the same risk factors for CAD, but relative Weight of a given risk may be more or less significant in women. DM is more powerful risk factor for CAD and heart failure in Women than in men and completely negates the protective effect Of female gender, even in premenopausal women. Metabolic derangements accompanying diabetes adversely Contribute to obesity, lower levels of high-density lipoprotein And TG abnormal endothelial and coagulation function and Increased risk of hypertension. DM acts synergistically with Other risk factors especially smoking, increase cardiac risk. DM is independent risk for subsequent cardiac events and Poor outcome after PTCA in women.

TOBACCO Cigarette smoking is a significantly stronger risk factor in Women than in men. Even women who smoke fewer than 5 cigarette per day have double the risk of CAD than non. Smokers Smoking cessation is associated with a significant reduction Of risk. Women with CAD who continue to smoke have significant Progression of atherosclerosis and are at risk for recurrent Events 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 than Women until age 60. In Black and Hispanic persons older than 60 and white people Older than 70. Age specific hypertension rate is higher in women Tha in man. With women older than 80 have rates 14% higher Than men. BP tend to increase throughout life in men and women, but before Age 60, women have lower systolic and diastolic BP than men. Subsequently systolic BP increases more steeply in women and Surpasses 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 a Strong female preponderance (8: 1) and should be considered When hypertension occurs in women less than 40 difficult To control or occurs in pregnancy complicated by severe Hypertension. Ingestion of currently available oral contraceptive agents is Associated with and increase in BP, although not commonly As first generation agents.

Hypertension and LVH both are stronger risk factors for stroke And CHF in women than in men. Framingham (LVH removes survival advantage of female gender. No real gender differences exist in relative risk reduction for Stroke and CHF from the treatment of hypertension. Absolute Risk reduction are lower in women because the baseline risk Of events is lower. Current guidelines from the Joint National Committee on the Treatment of Hypertenstion VI (JNC-VI) are not gender Specific and it appears that women with hypertension benefit From therapy and should e treated as aggressively as men.

HYPERLIPIDEMIA Serum levels of toal cholesterol in women increase steadily From mid-30 s to age 55 – 60. LDL remain lower than in men until 50 age, which levels in men stabilize and are surpassed by those in women.

This coincides with the average of menopause and likely Contributes to observed increase in cardiac events in older Women younger than 65 with T-cholesterol level greater 240 mg/d. L LDL greater 160 mg/d. L have relative risk of cardiac Event is 2 -3 times that of women without hyperlipidemia HDL cholesterol remains a strong risk factor in women older than 65. Relationship of total cholesterol and LDL Ch. & CAD in older Women is not as strong. Conflicting data about triglyceride as independent risk factors. This appear similar to those of men.

Primary prevention hyperlipidemia trials excluded women And elderly; therefore little information on which to base Therapeutic 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 to Recommend early or aggressive pharmacologic therapy unless Multiple risks are present. Postmenopausal women without CAD and hypercholesterolemia Or a low HDL cholesterol may be considered for estrogen Replcement therapy, which may obviate additional pharmacologic Therapy.

AFCAPS / TEXT CAPS) 1000 postmenopausal women with no known vascular disease Average TC, Low average HDL Ch. to placebo or treatment With lovastatin and found 46% reduction in CV events in Treated women. Study not powered to detect treatment differences In mortality but showed similar or greater reduction events in Women than in men and demonstrated risk reduction from Lipid modification in relatively low risk group that otherwise Not treated in current NCEP- ATP-II guidelines.

There is strong evidence from well-designed randomized Trials to support aggressive treatment of increased cholesterol Levels in women with CAD. CARE randomized men and women with recent myocardial Infarction and normal LDL cholesterol levels (115 -174 m/d. L) To treatment pravastatin or placebo. Treated men and women both had a significant reduction in all end points including cardiac death, MI & revascularization.

Subgroup analysis demonstrated an even greater reduction In 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 coronary Events 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 prevention Of CAD with goal LDL cholesterol of less than 100 mg/d. L. No study has suggested significant gender differences in dietary Intervention or lipid lowering drugs.

RISK FACTORS UNIQUE TO WOMEN Oral Contraceptives One of the most effective methods for pregnancy prevention But women who took first generation high-dose agents has Increased 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 increased In nonsmoking women taking oral contraceptive and no inceased Risk 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 relatives Risk. The risk of pregnancy related thromboembolic events and stroke Is as much as 3 times than that associated with oral contaceptives.

Menopause and Hormone Replacement Therapy Estrogen at menopause associated with several adverse effects On cardiac risk factors, include: é TC é LDL Ch. é LP 9 a) LP (a) é Circulating procoagulants And homocysteine Decreased HDL cholesterol These changes responsible at least partly for the observed Acceleration of cardiovascular events afer menopause.

Premenopausal women who have had bilaeral oophonatomy And do not receive estrogen have more than twice the risk of MI than those receive estrogen replacement has been associated With cardiovascular risk. Primary epidemiological data and meta-analysis, including Lipid Research Clinic and Nurse Health Study. Indicate risk Reductions of 40% - 50% for CAD in women who choose to Take postmenopausal HRT. The data for stroke reduction by estrogen is less but similar risk Reduction has been showb. These data are observational and not from prospective randomized trials but has remarkable uniformity and consistency in results

Estroen reverses many of the unfavorable physiologic changes That occur at menopause. Lipid effects are prominent, but the mechanism are incompletely Understood. Oral administered estrogen decreased LDL cholesterol by 10%-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 effect On lipoprotein levels, suggesting that the liver effects of Estrogen absorbed through the gut are responsible for these Changes. These favorable effects are also seen when estrogen is combined With progestational agents, but increase in HDL levels is often Blunted. Limited data suggest that the use of micronized pro. Gesterone, comapred with medroxyprogesterone, blunts the Estrogen induced increase in HDL cholesterol less, while Maintaining protection against endometrial hyperplasia.

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

Despite the impressive benefits reported for coronary artery Disease risk in these observational trials, . The first randomized, blinded, placebo-controlled trial of Estrogen for secondary prevention of coronary events did not Show any significant reduction in cardiac risk

The Heart and Estrogen/Progesterone Replacement Study( HERS) Enrolled 2763 postmenopausal women younger than 80 years With definite coronary artery disease and intact uterus to receive Continuous-combined estrogen and medroxyprogesterone or Placebo. Average follow-up 4. 1 years and was 100% complete. No Signifidant differnece were observed for any of the CV Outcome. That is combination hormone replacement therapy(HRT) did Not reduce cardiovascular events as expected from result of Previous 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 progestrone Which blunts beneficial lipid effect • Selection bias or healthy user. Results trial should not be extropaleted to other patient poplation Patient without CAD Without uterus Other Hr. T formulation Several 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 hormonal Status assessed as a risk factors. Decision to start hormone Replacement therapy must be individdual and based on risk of CAD breast cancer and fracture and on hysterectomy status, Life expectancy, and side effects.

Non cardiac beneficial oesgtrogen replacement therapy decreased postmenopausal symptoms decreased osteoprotic fracture decreased Colon Ca decreased Urinary incontinence of Alzheimer dieses Cancer Breast Estrogen therapy for more 5 – 10 years associated With an increased relative risk 1. 2 to 1. 5 which is similar to early Menanrche and mulliparity. Breast cancer must be put into perspective because CVD kills More women that breast cancer at all ages.

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

Venous thromboembolism and pulmonary embolus have Been associated with estrogen replacement. The increae In relative risk of various thromboembolism appears to be 2 to 4 (2. 9 in HERS_. This risk appears higher during the First year of treatment and affects those currently receiving Treatment but not those who formerly received it. The Women affected may have unidentified coagulapathies or Other predisposing risk factors, because no consistent adverse Effects on the clotting system have been identified. The Absolute incidenc is low, but women experiencing venous thromboembolism while receiving hormone replacement therapy Should be evaluated for the presence of coagulapathy.

Selective estrogen receptor modulators (SERMS) are a class Of synthetic tissue-specific estrogens(“designer estrogens”) Formulated to provide the beneficial action of estrogen without The risks and side effects Tarnoxifen (used for prevention and Treatment 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 significant Beneficial effects on HDL cholesterol, and the observed Improvements in the lipid profile are less than those observed with oral estrogen. Currently, the role of SERMs in preventing Cardiovascular disease is unclear.

Hrmone Replacement Therapy Recommendations Currently, no consensus exists about the role of postmenopausal Hormone replacement therapy in the prevention of coronary artery Disease. Recommendations are evolving as now data published. Hypercholesterolemia The National Choelsterol Education Program (NCEP II) gudelines Now 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 low Cost. It has complemented effects on the lipid profile when Combined with statins should be given as initial therapy for hype Lipdema in women with vascular disease.

Secondary Preventions HRT should not be recommended to women with documented CAD solely for cardio protection if noncardiac indications exist, Hormone replacement may be prescribed but the inceased risk of Venous trhomboembolism should be discussed. All other proved Rx (aspirin, beta-blocker, statisn, ACE inhibitors used Maximal. Primary Preventions Adeauate data to support widespreade use of estrogen replacement Therapy in postmenopausal women for primary precaution of CAD do not exist.