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234 Recent Patents on Cardiovascular Drug Discovery, 2009, 4, 234-240

1574-8901/09 $100.00+.00 2009 Bentham Science Publishers Ltd.

Gender Differences in Ischemic Heart Disease

Ryotaro Wake* and Minoru Yoshiyama

Department of Internal Medicine and Cardiology, Osaka City University, Graduate School of Medicine, Osaka, Japan

Received: January 12, 2009; Accepted: February 13, 2009; Revised: May 4, 2009Abstract: Coronary artery disease (CAD) is a leading cause of mortality and morbidity in most developed countries.

Gender-related differences have been found in the presentation, prevalence, and clinical outcomes of CAD in many

studies. Compared to women, men present with ST-segment elevation myocardial infarction more often and have a higher

prevalence of CAD. These findings indicate that gender may have an important influence on CAD. Appropriate diagnosis,

prevention, recent patent inventions, and treatment will improve the care of all patients. It is therefore necessary to

consider the differences in the features of ischemic heart disease between men and women when examining patients.

Novel drugs for tailor-made therapy based on gender differences should be developed for the treatment of CAD in future.

Keywords: Coronary Artery Disease (CAD), gender difference, ischemic heart disease, risk factor, noninvasive testingprevention & treatment.

INTRODUCTION

Coronary artery disease (CAD) is a leading cause ofmortality and morbidity in most developed countries [1].Many studies have found gender-related differences in thepresentations, prevalence, and clinical outcomes of CAD [2-4]. CAD first presents itself in women approximately 10years later than in men, most commonly after menopause[5]. Compared to women, men present with ST-segmentelevation myocardial infarction (MI) more often and have ahigher prevalence of CAD adjusted for age [6, 7]. However,younger women experience more adverse outcomes after MIand coronary artery bypass grafting surgery than men [8]. Agreater proportion of women than men with MI die ofsudden cardiac arrest before reaching hospital [3, 9].Previous reports have shown a 20% reduction in total

mortality among patients randomized to exercise-basedcardiac rehabilitation compared with controls receiving usualcare [10]. The outcome was however similar between menand women, although only 20% of all participants werewomen in many reports. Women are less likely than men toparticipate in cardiac rehabilitation after acute MI [10].

Next, he prevalence of microvascular angina is higher inwomen than men. Takotsubo cardiomyopathy is more preva-lent in women than in men [11]. These findings indicate thatgender difference may have an important influence oncardiovascular physiology and pathology [12, 13].

In many developing countries, a large budget is expendedfor the treatment of CAD, and it is necessary to minimize the

influence of risk factors. The burden of CAD on women andthe global economy will continue to increase [5]. In additionto population-based and macroeconomic interventions,interventions in individual patients are key to reducing the

*Address correspondence to this author at the Department of InternalMedicine and Cardiology, Osaka City University, Graduate School ofMedicine, Osaka, Japan; 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585,Japan; Tel: +81-79-272-8555; Fax: +81-79-272-8550;

E-mail: ryotaro_wake@yahoo.co.jp

incidence of CAD globally [14]. Prevention of CAD isparamount to the health of every woman and every nation.

There have been numerous clinical trials that have abearing on CAD prevention in women [15]. Women (XXand men (XY) differ in their genetic complement by a singlechromosome out of the 46 that are present in the humanspecies. However, this single chromosomal difference affectboth the expression of disease and the psychosocial andbehavioral characteristics and work environments of individuals, which may reduce or increase the susceptibility tocardiovascular diseases.

In future, novel drugs for tailor-made therapy of CADbased on gender differences may be developed. This reviewdiscusses gender differences in the features of ischemic heardisease and the possibilities of future developments in

treatments.

CLINICAL RISK FACTORS OF CORONARYARTERY DISEASE IN WOMEN

It is important to classify women as being at highintermediate, or low risk for CAD. Classification may bebased on clinical criteria and the Framingham global riskscore [16]. A woman found to have coronary calcification oincreased carotid intimal thickness may be at low risk foCAD on the basis of the Framingham risk score, but she maybe actually at intermediate or high risk for a future CADevent.

We should take several factors into considerationincluding medical and lifestyle histories, Framingham riskscore, family history of CAD, and other genetic condition(e.g., familial hypercholesterolemia), since these affect thedecisions about the aggressiveness of preventive therapyNovel CAD risk factors (e.g., high-sensitivity C-reactiveprotein [17]) and novel screening technologies (e.g.coronary calcium scoring) should help guide preventiveinterventions. Further research is needed on the benefitsrisks, and costs associated with such strategies. There are

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Gender Differences in Ischemic Heart Disease Recent Patents on Cardiovascular Drug Discovery, 2009, Vol. 4, No. 3 235

many unique opportunities for early detection of CAD inwomen; for example, in pregnancy, preeclampsia may be anearly indicator of CAD risk [18, 19]. In addition, maternalplacental syndromes in combination with traditional cardio-vascular risk factors, such as prepregnancy hypertension ordiabetes mellitus, obesity, dyslipidemia, and metabolicsyndrome, may be additive in defining CAD risk in women[18]. Future research should evaluate the potential for events

or medical contact during unique phases in a womans life,such as adolescence, pregnancy, and menopause, to identifywomen at high risk, and determine the effectiveness ofpreventive interventions during critical periods.

The diagnosis of CAD in women presents challenges notobserved in case of men. Differences in the epidemiology ofCAD between men and women show that women aregenerally at a lower risk than their male counterparts untilthe seventh decade of life. For both asymptomatic andsymptomatic women, the choice of initial test is guided byclassification into low, intermediate, or high pretest riskcategories. Asymptomatic intermediate-risk women havelower event rates. In symptomatic women, noninvasive diag-nostic studies (exercise ECG and cardiac imaging studies)are recommended for those who are at an intermediate tohigh pretest likelihood of CAD [20]. Therapeutic decision-making is guided by the extent and severity of inducibleischemia. Thus, referral of low-likelihood women (forexample, premenopausal women with less than one riskfactor and nonanginal/atypical symptoms) will be associatedwith a high rate of false positives.

Smoking is an important risk factor for vascular diseases.Vascular disease risk was most quickly reduced by cessationof smoking compared with other associated factors. Thebeneficial effect of quitting on the risk for death from CHDwas realized within 5 years, whereas the risks for death fromchronic obstructive pulmonary disease and lung cancer did

not approach those of women who had never smoked untilthe age of 20 and 30 years, respectively [21]. It may never be

too late for women to quit smoking in order to reduce therisk for vascular diseases.

A blood pressure-lowering treatment provided similaprotection against major cardiovascular events in men andwomen [22].

FEATURES OF CORONARY ARTERY PATHOLOGYIN WOMEN

Men have a greater burden of atheroma and eccentricatheroma in coronary arteries compared to women. A studyreported that plaque rupture in patients with sudden coronarydeath was more frequent in men than in women [23].

Men have more severe structural and functionaabnormalities in the epicardial coronary arteries than womenThese factors may influence the higher incidence rates oCAD and ST-segment MI in men compared to women. Withregard to the lower cardiac event rate in female patientsseveral mechanisms have been proposed to explain thecardioprotective effect of sex hormones in women [12]. Weshow the effect of sex hormones in ischemic heart disease inTable 1.

Women had lower rates of obstructive CAD at angiography when evaluated for symptoms suggestive of myocardial ischemia [24]. Among angiographic CAD patientsatheroma volume in women is less than that in men, despitethe presence of more cardiovascular risk factors in womenWomen had slightly lower coronary vasodilator reserve evenwith normal coronary angiographic results [25]. Endothelialindependent microvascular dysfunction was an independenpredictor of adverse outcomes in patients with mild CAD[26]. It has been suggested that the mechanism of myocardiaischemia in women may be localized to the microvasculacoronary arteries and that abnormal micro-vascular functionmay have prognostic implications [27].

Takotsubo cardiomyopathy is more prevalent in womenthan in men. Because the onset of this syndrome is often

Table 1. Effect of Estrogen on Atherosclerosis

Favorable Unfavorable

Lipids LDL-cholesterol

HDL-cholesterol

Trigriceride

Coagulation

Fibrinolysis

PAI-1

Fibrinogen

Factor VII

AT III

InflammationAdhesion

Adhesion molecules

CRP

Endothelial Function

Blood Pressure

ACE activity

Nitric oxide

Endothelin-1

Plasminogen 12

VSMC migration, proliferation

Angiotensinogen

PAI-1: Plasminogen Activator Inhibitor-1, AT III: Antithrombin III, ACE: Angiotensinogen Converting Enzyme, VSMC: Vascular Smooth Muscle Cell.

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preceded by emotional or physical stress, catecholamine-mediated multivessel epicardial spasm, microvascularcoronary spasm, or possible direct catecholamine-mediatedmyocyte injury have been advocated as possible patho-physiological mechanisms [11].

DIAGNOSIS AND PROGNOSIS

Electrocardiography

Changes in electrocardiography (ECG) during exercisehave been reported to be of diminished accuracy in womenas a result of more frequent changes in resting ST-T wave,lower ECG voltage, and hormonal factors such as endo-genous estrogen in premenopausal women and hormonereplacement therapy in postmenopausal women [28-30]. In ameta-analysis of exercise ECG studies in women, sensitivitywas 61% and specificity was 70%, compared to 72% and77%, respectively, in men [20]. From a cohort of sympto-matic women who were referred for exercise treadmilltesting followed by coronary angiography, significant coro-nary stenosis (more than 75%) was observed in 19%, 35%,

and 89% of low-, moderate-, and high-risk women, respec-tively, based on Duke treadmill score risk categories [31].

Maximal exercise capacity and heart rate recoverymeasurements can aid in estimation of near- and long-termoutcome in large cohorts of women [32]. Recent reports havenoted that a simple measure such as heart rate recovery (at 1or 2 min after exercise) have substantial prognostic value.

Women engage less often in physical exercise programs,have lower functional capacity, and show a greaterfunctional decline during their menopausal years. Because oftheir lower work capacity on exercise tests (on average 5-7min) as a result of premature peripheral fatigue, it is difficultto provoke myocardial ischemia [33]. Women who exercise

less than 5 metabolic equivalents (METs) are at an increasedrisk for death [34]. Women expected to perform less than 5METs may be better evaluated by pharmacological stressimaging. However, women who have inducible ischemia atlow workloads (less than 5 METs) have a higher likelihoodof obstructive CAD and may be referred for coronaryangiography.

The exercise ECG test has a high negative predictivevalue in women with a low pretest probability of CAD and alow-risk Duke treadmill score [20]. The diagnostic andprognostic accuracy of the exercise ECG stress test insymptomatic women with suspected CAD is increased by theinclusion of additional parameters in the interpretation of theST-segment response to exercise.

Echocardiography

Stress echocardiography can provide information aboutthe presence of left ventricular systolic or diastolic dys-function, valvular heart disease, and the extent of infarctionand stress-induced ischemia. Exercise echocardiography maybe performed with a treadmill or by supine or upright bicycleexercise. Exercise stress echocardiography is a physiologicalinvestigation and the most widely available method forevaluation of CAD. However, exercise capacity is oftenimpaired in aged or diabetic patients and the workload

required to produce stress-induced myocardial ischemiamight not be achieved by such patients.

Stress echocardiography provides significantly highespecificity and accuracy than the standard exercise ECGtesting in women [35].

Stress echocardiography has demonstrated good diagnostic accuracy for detecting or excluding significant CAD

with a mean sensitivity of 81%, specificity of 86%, and anoverall accuracy of 84% [35-38]. There appears to be nosignificant effect of gender on the diagnostic accuracy oexercise echocardiography.

A study of dobutamine stress echocardiography (DSE)revealed an overall sensitivity of 80% and specificity of 84%[36]. Similar to exercise stress echocardiography, DSEappears to have similar diagnostic accuracy in detectingCAD in both women and men.

Cardiac events occur less frequently in women than inmen. This difference is compatible with the lower prevalenceand lesser sensitivity of detection of CAD in women compared to men. No gender differences have been reported in

the prognostic value of exercise stress echocardiography in alarge population.

The low specificity of exercise ECG testing in womenespecially in young and middle-aged women, may lead to ahigher rate of unnecessary angiography and higher expenseparticularly if stress imaging is not used before coronaryangiography in a sequential testing strategy.

Stress echocardiography with exercise or dobutamine isan effective and highly accurate noninvasive means of detecting ischemic heart disease and risk-stratifying symptomaticwomen with an intermediate to high pretest likelihood oCAD. Stress echocardiography provides incremental valueover exercise ECG and clinical variables in women with

suspected or known coronary heart disease. Stress echocardiography is recommended for symptomatic women withan intermediate or high pretest probability of CAD (womenwith suspected CAD must also have an abnormal restingECG). Previous reports demonstrated that pharmacologicastress echocardiography provides independent prognosticinformation in both men and women [39, 40].

Myocardial Perfusion

Gated myocardial perfusion single-photon emissioncomputed tomography (SPECT) is a nuclear-based techniquethat provides a combination of test elements that are used todiagnose and risk-stratify women. Myocardial perfusionimaging, however, has been reported to have technicalimitations in women, including false-positive results due tobreast attenuation and small left ventricular chamber size[41].

The accuracy of 201Tl SPECT imaging, for example, ireduced in patients with small hearts, and these patients aremore likely to be women than men. When 201Tl is used asthe radioisotope in women, false-positive test results mayoccur due to soft tissue attenuation (e.g., breast attenuationin the anterior and anterolateral segments [41].

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For women, the lower-energy isotope 201Tl has beenlargely supplanted by technetium-based imaging agents thatimprove accuracy. In comparing the diagnostic accuracy of201Tl with gated 99mTc-sestamibi SPECT in women, thesensitivity for detecting CAD was 80%, and test specificityimproved dramatically from 67% for 201Tl to 92% for gated99mTc-sestamibi SPECT [42].

Pharmacological stress SPECT also merits consideration,

given the higher incidence of decreased exercise capacityand advanced age for women, as discussed previously [41,43]. Vasodilator pharmacological stress perfusion imaginghas been shown to be more accurate than exercise perfusionimaging in identification of CAD in both men and womenwith left bundle-branch block [43]. Adenosine 99mTc-sestamibi imaging was reported to have 91% sensitivity and86% specificity for detecting significant coronary arterystenoses of more than 50% [44].

Myocardial perfusion imaging has powerful predictivevalue with regard to the development of subsequent cardiacdeath or MI or the need for coronary revascularization [45-47], regardless of sex [33]. Prognosis worsens commensurate

with the number of vascular territories involved, with 3-yearsurvival rates ranging from 99% for women withoutischemia to 85% in women who had three-vessel ischemia[33].

In addition, pharmacological stress was recently shownto be effective in the risk stratification of diabetic womenwith suspected and known CAD. The CAD mortality fornondiabetic women with a moderately abnormal scan was2.8% compared with 4.1% in diabetic women [45].

Cardiac Computed Tomography

The diagnostic accuracy of coronary computed tomo-graphy (CT) angiography is not greater than that of invasive

coronary angiography. Although the risk of adverse eventsfor invasive coronary angiography is generally considered tobe low, significant and potential life-threatening compli-cations can arise, including not only coronary arterydissection, but also arrhythmia, stroke, hemorrhage, MI, anddeath [48].

The negative predictive value at the patient and vessellevels establishes coronary CT angiography as an effectivenon-invasive alternative to invasive coronary angiography inruling out obstructive coronary artery stenosis.

New generation 64-MDCT systems permit acquisition ofcardiac studies in less than 10s, allowing faster contrastinjection rates and lower contrast volume requirements, and

reducing the number of artifacts related to inadequate breath-holding and heart rate variability [49, 50].

Cardiac CT detects and quantifies the amount of coro-nary artery calcium (CAC), a marker of atheroscleroticdisease burden. Calcification does not occur in a normalvessel wall; it therefore indicates the presence of athero-sclerosis, but is not specific for luminal obstruction. CACscores approximate the total atherosclerotic plaque burden.However, the absence of detectable CAC has a negativepredictive value of 100%. Although these findings are con-sistent with the concept that the calcified plaque burden

parallels the overall plaque burden, CAC testing is noappropriate as an alternative for angiographic diseasedetection because of the modest relationship between CACand obstructive CAD [50]. The greatest potential for CACdetection could be as a marker for CAD prognosis inasymptomatic women. The presence and severity of CAChas independent and incremental value when added toclinical or historical data in the estimation of death or

nonfatal MI [51, 52].In case of women, risk-adjusted relative risk ratios for

all-cause mortality were elevated 2.5-, 3.7-, 6.3-, and 12.3fold for calcium scores of 11-100, 101-400, 401-1000, and >1000, respectively (P < 0.0001), compared with a score of