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By Kevin A. Bybee, MD & Tracy L. Stevens, MD

Published in Missouri Medicine, the Journal of the Missouri State Medical Association, January/February 2013

Abstract

Cardiovascular disease is the leading cause of death in United States women and accounts for approximately 500,000 deaths annually.  Over half of cardiovascular disease-related deaths in women result from coronary artery disease including acute coronary syndromes.  This paper reviews gender specific issues in women as they relate to current cardiovascular disease epidemiology, trends in cardiovascular disease epidemiology, coronary artery disease detection, risk factor modification, and prevention of cardiovascular disease-related events.

Epidemiology of Cardiovascular Disease in Women

Cardiovascular disease (CVD) is the leading cause of death in women and men in the United States (U.S.) and in other developed countries.  Cardiovascular disease, which includes hypertension, coronary artery disease, heart failure and stroke accounts for nearly 500,000 deaths in U.S. women every year.  More than half of these CVD-related deaths are due to coronary artery disease.  In 2005, death rates for CVD in the U.S. were 237.1 per 100,000 for all women, 230.4 for white women and 319.7 for black women.¹

The leading causes of death in U.S. women are diseases of the heart, cancer, stroke, and chronic lower respiratory disease.^2-5  CVD is responsible for one death every minute in U.S. women−roughly equivalent to the total number of deaths in females due to cancer, diabetes mellitus, Alzheimer’s disease, accidents, and chronic lower respiratory disease combined.  It is estimated that 3,200,000 U.S. women suffer a myocardial infarction every year, with 213,572 U.S. women dying from coronary artery disease each year. For the first time, U.S. death rates due to cardiovascular disease in women have now surpassed that of men.⁴  Death rates from coronary artery disease in those <55 years of age are still significantly higher in men than women. However death rates for coronary artery disease and acute coronary syndromes after the age of 65 are higher in women than in men (See Figure 1).

Figure 1. Number of myocardial infarctions (new and recurrent) or fatal coronary artery disease events per year in the U.S. by age and gender.  Source: National Heart, Lung and Blood Institute

Trends in Cardiovascular Disease Mortality and Outcomes in Women 

Coronary heart disease-related mortality rates have decreased in the U.S. over the past three decades.  From 1980 to 2002, overall the death rate due to heart disease decreased 49% in women over the age of 65.  Similarly, death rates due to heart disease in men over the age of 65 decreased by 52%.⁴  Disturbingly the rates of heart disease-related mortality appear to be increasing in women ages 35 to 54.   Several factors may increase rates of CVD-related morbidity and mortality in the near future.  These include the rising average female lifespan, the aging baby-boomer population and increasing prevalence of cardiovascular risk factors.  This trend will likely affect women to a greater extent than men given the greater likelihood of heart disease-related mortality in older women. 

Prevalence of Subclinical Atherosclerosis 

Coronary atherosclerosis is a disease process that begins well before the clinical presentation of angina, an ischemic coronary event or death.  Fatty streaks and aortic atheroma have been detected in children.  We can now detect subclinical coronary atherosclerosis through measurement of calcification within the coronary arteries using ECG-gated cardiac computed tomography technology.   The Coronary Artery Risk Development in Young Adults (CARDIA) study evaluated the prevalence of subclinical coronary atherosclerosis in younger adults.⁶  This study found that 5.1% of women between the ages of 33 and 45 and 15.0% of men between these ages had subclinical coronary atherosclerosis identified by the presence of coronary artery calcification.  This finding emphasizes the importance of identifying and treating modifiable risk factors as early in life as possible.

Detection of CAD

Early initial detection of coronary artery disease (CAD) in women at risk is critical for optimal prognosis and management.  Several modalities exist for the non-invasive assessment of CAD.  Non-invasive detection of CAD in women presents gender-specific issues that make the diagnosis more challenging than in men. Women commonly present with CAD at an older age than men and often have limited exercise capacity due to co-morbid conditions. The sensitivity and specificity test characteristics for non-invasive functional testing are less robust in women compared to men.

Risk Stratification of Women at Risk for Coronary Artery Disease

The initial assessment of possible CAD in women begins with risk stratification based on cardiovascular risk factors and symptom status. Testing modalities for detecting CAD in women can be divided into two categories: 1) coronary anatomic assessment using coronary artery calcium scoring, coronary CT angiography, invasive coronary angiography; 2) functional testing using exercise electrocardiography, stress echocardiography, stress radionuclide myocardial perfusion imaging including single photon emission computed tomography (SPECT), positron emission tomography (PET) and stress cardiac magnetic resonance imaging (MRI).

Evaluation for Coronary Artery Disease in Asymptomatic Women

Coronary Artery Calcium Scoring

Coronary artery plaques are complex structures and are composed of multiple components including heterotopic calcium deposits.  Coronary artery calcification is pathopneumonic of coronary artery plaque/CAD.  ECG-gated computed tomography (CT) imaging of the coronary arteries can be performed without the use of intravascular contrast and provides for accurate detection and quantification of coronary artery calcium.  The amount of coronary artery calcification is most commonly quantified utilizing the Agatston scoring technique. The coronary calcium score correlates with risk of cardiac events and independently predicts cardiac risk beyond that of the Framingham Risk Score (FRS).  Current data support the use of CAD screening procedures such as coronary calcium scoring in women with an intermediate risk FRS.  Current guidelines do not advocate CAD screening in woman at low risk for CAD events.  Women with high CAD risk should be treated with proven, aggressive secondary prevention measures to reduce the risk of subsequent ischemic cardiovascular events.

Evaluation for Coronary Artery Disease in Symptomatic Women

Women presenting with symptoms suggesting angina/CAD are commonly referred for functional stress testing for obstructive CAD and for prognostication.  Functional testing for CAD is extremely valuable for diagnosis and management  including identifying patients that would benefit from coronary revascularization. 

Exercise Electrocardiography

Exercise electrocardiography (ECG) is one of the most studied and utilized stress testing modalities.  Numerous studies have demonstrated the ability of the exercise ECG to diagnose and prognosticate suspected CAD.  The current ACC/AHA guidelines recommend exercise ECG in symptomatic women with an intermediate pre-test likelihood of CAD based on cardiovascular risk factors, a normal resting ECG and the capacity to perform maximal exercise testing.  Exercise ECG testing in women has several limitations. ST-segment depression during treadmill testing is a less specific marker of ischemia in women due to hormonal effects on cardiac repolarization.  The menstrual cycle can influence the ischemic threshold in premenopausal women.  Estradiol and progesterone levels are lower during the early follicular phase and as a result myocardial ischemia can be provoked with lesser levels of exercise.  Inducible ischemia develops at higher levels of exercise later in the menstrual cycle when estrogen levels are higher.  A large meta-analysis of previously published exercise ECG studies found that the overall sensitivity and specificity of detecting obstructive CAD by exercise ECG in women was 61% and 70%, respectively.  These test characteristics are significantly less robust compared to exercise ECC performance in men in whom the sensitivity and specificity are 72% and 77%, respectively.  Prognostication of CAD can be improved by utilizing the Duke Treadmill Score using data such as exercise duration, presence of anginal symptoms provoked during the stress test, heart rate recovery and magnitude of ST-segment deviation with exercise.

Stress Echocardiography

It is recommended that stress echocardiography be reserved for the evaluation of CAD in symptomatic women who are at least intermediate risk and do not qualify for exercise ECG.  The test can be performed utilizing exercise stress or pharmacologic stress in those unable to exercise. Stress echocardiography is more accurate than exercise ECG in detecting obstructive CAD in both men and women.  The sensitivity of stress echocardiography in detecting single vessel CAD in women is approximately 81% with a specificity of 86%.  Women with an abnormal stress echocardiogram have higher cardiac event rates compared to women with a normal study. Stress echocardiography provides a more robust risk stratification compared to exercise ECG.

Radionuclide Stress Myocardial Perfusion Imaging

It is currently recommended that stress radionuclide myocardial perfusion imaging (MPI) be reserved for the evaluation and prognostication of suspected CAD in symptomatic women who are at intermediate or high risk for CAD.  Stress single positron emission computed tomography (SPECT) MPI is the most commonly employed imaging stress modality in the U.S. in both men and women. Smaller left ventricular volumes in women, a lesser likelihood of multi-vessel disease and the relatively poor spatial resolution of Tl-201 reduce the accuracy of Tl-201 SPECT imaging in women.  The reported sensitivity and specificity of Tl-201 SPECT in women is approximately 78% and 64%, respectively.  Contemporary analyses have shown a sensitivity and specificity of 99m-technitium based SPECT studies to be approximately 84% to 87% and 91% to 94% respectively.

Stress MPI results have been shown to provide prognostic information in women beyond that of standard clinical and exercise ECG variables.  A normal SPECT MPI study is associated with a very low risk of short-term cardiac events (<1%).  The risk of cardiac events increases when ischemia is present.  There is a continuum of risk based on the size and severity of perfusion defects. Women undergoing pharmacologic stress MPI have higher mortality and cardiac event rates compared to those undergoing exercise MPI for any given perfusion result including those with non-ischemic studies. The annual rate of CAD-related mortality is double in diabetic women with normal MPI studies compared to non-diabetic women with normal MPI studies (0.8% vs. 1.6%).

Cardiac stress MPI utilizing positron emission tomography (PET) is becoming a more widely available modality for assessment of coronary artery disease. PET MPI is much more accurate than SPECT in detecting flow-limiting CAD, especially in women.  Reported sensitivity and specificity for detecting obstructive CAD with PET is 98% to 95%, respectively. 

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