What is responsible for heart disease being the leading cause of death in the United States?

Mo Med. 2013 Jan-Feb; 110(1): 65–70.

Kevin A. Bybee, MD

Kevin A. Bybee, MD, is with Saint Luke’s Cardiovascular Consultants and the Saint Luke’s Mid America Heart Institute in Kansas City, and an Associate Professor of Medicine at the University of Missouri-Kansas City School of Medicine

Tracy L. Stevens, MD

Tracy L. Stevens, MD, is with the Saint Luke’s Cardiovascular Consultants and the Saint Luke’s Mid America Heart Institute in Kansas City and the Julia Irene Kauffman Endowed Chair for Women’s Cardiovascular Health and Professor of Medicine, UMKC School of Medicine

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).

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.

Traditional and Nontraditional Risk Factors for Cardiovascular Disease in Women

Although women’s awareness about their number one health threat has increased over the past ten years, the percentage remains low. Even “aware” women often feel exempt and personally not at risk. It is imperative to educate all women on their personal responsibility to know and manage their individual risk factors. These include traditional risk factors and those that are gender specific. Finally all women must understand that all women are at risk.7

Hypertension

The overall prevalence of hypertension is greater in women than men, especially those with a history of hypertension during pregnancy. Black and Hispanic women are twice as likely to have hypertension. Diastolic elevation is more common in younger women and favorably responds to exercise. Oral contraceptives and hormone replacement therapy may increase blood pressure. Reno-vascular hypertension from fibromuscular dysplasia and autoimmune disorders such as systemic lupus erythematosus are contributing factors.8,9

Angiotensin converting enzyme inhibitors or angiotensin receptor blockers are first to be considered in patients with diabetes and may be preferred in postmenopausal women with hypertension.7 This is supported by the theory of menopause being associated with a fall in nitric oxide from lack of estrogen receptor stimulation with resultant rise in aldosterone. Studies suggest this mechanism may account in part for diastolic dysfunction observed in post menopausal women. Interestingly, women are more likely to experience the ACE inhibitor cough than men as well as develop edema from the vasodilatory effects of calcium channel blockers.

Diabetes

Diabetes is a more powerful risk factor in women than men.7 Abnormal lipid profiles are more likely to be present in diabetic women than diabetic men. Women with a history of gestational diabetes are at greater risk for developing diabetes later in life. Metabolic syndrome risk factors, including polycystic ovary syndrome, increases the likelihood of developing diabetes and warrants aggressive screening. As women transition through menopause, a common occurrence is weight gain and increase in abdominal girth compromising the ability of insulin receptors to govern blood glucose.

Dyslipidemia

While studies have reported statin therapy to be effective in women, dyslipidemia is less likely to be treated in women than men. Changes in cholesterol are associated with menopausal status. Total and LDL cholesterol levels are lower in premenopausal women than in age matched men; following menopause they exceed that of men. A common false assumption is that women can ignore elevated total and LDL cholesterol if their HDL cholesterol and total cholesterol to HDL ratio are ideal.7 As with anti-hypertension medication prescriptions, women are less likely to fill and use a prescription for cholesterol lowering therapy.

Nicotine Abuse

Women who smoke are more likely than men to suffer a myocardial infarction and this occurs twenty years earlier than in women who do not smoke. The most common reason women won’t stop smoking is related to their fear of gaining weight. Nicotine and supplemental hormones, either in the form of contraception or hormone replacement, are a deadly combination and the leading cause of myocardial infarction in young women.

Obesity

Obesity is an independent risk factor for cardiovascular disease, most prevalent in black women, followed by Hispanic and white women. Those with abdominal obesity and increased waist to hip ratio carry an even greater risk of cardiovascular disease even among women of normal weight. This suggests that maintaining a normal waist size may be as or even more important as weight control. Excess adipose tissue results in overproduction of adipokines which are potent mediators of inflammatory factors that are associated with increased cardiovascular risks.

Family History

History of myocardial infarction in primary family members is an independent risk factor for cardiovascular disease. There is evidence to suggest a history of maternal myocardial infarction, regardless of age, carries an increased risk for cardiovascular events.

Oral Hygiene

Evidence correlates periodontal disease with atherosclerosis. Gingivitis becomes more prevalent in the post-menopausal woman and should be aggressively treated.

Depression

The Nurses Health Study reported that physically healthy women with symptoms of depression had an increased risk of future cardiovascular events.10 Young women, less than sixty years of age, have the highest prevalence of depression following myocardial infarction and may account for the lowest attendance in cardiac rehabilitation and poorer outcomes. C-reactive protein is increased in patients with depression and down regulates endothelial nitric oxide production. Associated abnormal serotonin levels may lead to platelet aggregation and prescription of selective serotonin reuptake inhibitors has been shown to reduce cardiovascular mortality.

Immune System Disorders

Autoimmune disorders, including rheumatoid arthritis and systemic lupus erythematosus, carry an increased risk of premature coronary artery disease. Young women with lupus have a fifty time greater risk of myocardial infarction compared to healthy women in the same age group. These inflammatory states are associated with spontaneous plaque rupture and therapies that reduce inflammation reduce cardiac risk. Considering lupus as a coronary artery disease equivalent has recently been proposed, placing these women in the high risk category.

Cancer Therapies

Doxorubicin (Adriamycin) and trastuzumab (Herceptin), chemotherapy agents administered for treatment of breast cancer, have potential cardiotoxic effects which can result in cardiomyopathy and congestive heart failure. Radiation to the chest can cause myocardial restriction and pericardial constriction. Radiation-induced coronary artery and valvular disease may require surgical intervention. Cardiac complications manifest clinically ten or more years following radiation therapy and may be more likely to occur in those receiving therapy for left sided breast cancer.

Hormonal status

Menopause, whether it is natural or surgical, is a risk factor all women share and is associated with accelerating risk for cardiovascular disease.7 Estrogen receptors are present throughout the cardiovascular system. As estrogen circulates and binds to these receptors, vasodilation via nitric oxide occurs. This relationship creates a healthy vasculature, promoting relaxation with antioxidant properties. As circulating hormonal levels fluctuate, whether related to hormone therapy, menstrual cycle, pregnancy, perimenopause, natural or surgical menopause, variable physiologic responses occur. This can result in a multitude of symptoms including palpitations, chest discomfort and account for potential increased risk of cardiovascular events. Fluctuations in circulating reproductive hormones can trigger endothelial dysfunction. Women with vasomotor disorders such as migraine headaches and Raynaud’s Disease may note exacerbation of their symptoms depending on the stage of menstrual cycle. Chest discomfort just prior to menses may be related to coronary artery spasm. Spontaneous dissection and acute coronary syndromes are more likely to occur in this phase of the menstrual cycle.

The post-menopausal woman with hypertension and diabetes is most likely to experience symptomatic diastolic dysfunction. Shortness of breath, especially with quick acceleration and climbing stairs is commonly reported. Women may experience microvascular angina with abnormal coronary flow reserve. Diastolic dysfunction is a trigger for atrial fibrillation. Strict risk factor control and exercise have favorable effects on diastolic function. Congestive heart failure is the most common diagnosis for adult hospitalization and diastolic rather than systolic congestive heart failure is more common in women.

Recent studies suggest hormone replacement therapy should not be used with the expectation of cardiovascular protection. Rather, women should consider hormone therapy for relief of menopausal symptoms and to use the lowest dose for the shortest duration.11-14

Summary

Cardiovascular disease is the number one health threat to women. (See book review above.) Women of all ages and ethnic cultures need to proactive about their own heart health and take responsibility to reduce their risk factors. In addition to traditional risk factors, women need to be aware of other clinical conditions that can impact their cardiovascular health.

Biography

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Kevin A. Bybee, MD, is with Saint Luke’s Cardiovascular Consultants and the Saint Luke’s Mid America Heart Institute in Kansas City, and an Associate Professor of Medicine at the University of Missouri-Kansas City School of Medicine. Tracy L. Stevens, MD, is with the Saint Luke’s Cardiovascular Consultants and the Saint Luke’s Mid America Heart Institute in Kansas City and the Julia Irene Kauffman Endowed Chair for Women’s Cardiovascular Health and Professor of Medicine, UMKC School of Medicine.

Contact: gro.sekul-tnias@eebybek

Footnotes

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