GENDER DIFFERENCES: Heart Disease in Women: Where are we now?

Ann Kao, MD

During the 1960s, the American Heart Association sponsored a conference titled “How Can I Help My Husband Cope with Heart Disease?” Half a century later, substantial progress has been achieved in debunking the myth that cardiovascular disease is a “man’s disease.” Cardiovascular disease (CVD) is the leading cause of mortality in both women and men, responsible for one-third of all deaths.

Coronary Heart Disease

Dr. Bernadine Healy introduced the concept of the “Yentl syndrome” in a 1991 article,[1] suggesting gender bias in the recognition and management of coronary heart disease (CHD). Since then, sex-exclusive scientific and clinical research is no longer the norm. Multiple studies in the past two decades with conflicting information about rates of CHD mortality among women compared to men have fueled the debate of whether gender differentially modulates CHD mortality and why. It is now generally recognized that the sex-based differences in CHD can be largely explained by different clinical characteristics.[2-5] Women, as a group, are older when they present with disease, and have more comorbidities, including hypertension, hyperlipidemia, diabetes and heart failure. In addition, there is gender difference in angiographic severity, with women having fewer obstructive lesions and less frequent two- and three-vessel coronary artery disease.[4]

A large cohort analysis of data from the National Registry of Myocardial Infarction (NRMI), published in 1999, demonstrated a higher risk of early death after myocardial infarction for younger women compared with younger men, but no gender-related mortality difference in the older population. The younger the age of the patients, the higher the risk of hospital mortality among women compared to men. This interaction between sex and age raises the possibility that coronary atherosclerosis in younger women may have a unique pathophysiology which manifests in more aggressive disease.[5]

An analysis reported in 2009 of a cohort of 136,247 patients (28% women) pooled from 11 international trials, suggested that while sex-based differences in 30-day mortality exist in acute coronary syndrome (ACS) and vary depending on the type of syndrome, the differences are markedly attenuated after adjustment of clinical and angiographic differences.[6] In this analysis, no interaction between sex and age was detected, but a significant correlation between sex and the type of ACS was observed. The higher 30-day mortality rate among women compared to men appears to be limited primarily to ST-segment elevation myocardial infarction (STEMI), while a lower 30-day mortality risk was seen in non-STEMI and unstable angina. It is possible that the intrinsic sex-based differences in the type of culprit lesion, the degree of angiogenesis and collateralization, and the extent of angiographic disease burden can partly explain these findings.

A more recent NRMI evaluation of outcomes from 1994 to 2006, published in 2009,[7] showed that women, particularly younger women, compared to men, experienced a larger decrease in hospital mortality after an acute MI. The absolute reduction for the cohorts <55 years old was three times larger in women than men (2.7% vs 0.9%). Over 90% of this decreased mortality in younger women compared with men was attributed to a greater improvement of risk factors. Thus, the difference in MI mortality for younger women as compared to younger men has markedly narrowed in the decade between NRMI reports.

Heart Failure

The focus of public education on heart disease in the past two decades has been on coronary heart disease, which is the largest contributor to CVD and accounts for nearly 50% of the female CVD mortality. Heart failure (HF), despite its contribution to 35% of that death toll, has received much less public attention. The prevalence of HF increases with age in both genders. Of the 5.3 million Americans afflicted with HF, nearly 50% are women, with more women than men having HF after the age of 79. Studies have shown that women with HF have lower quality of life, more functional impairment, more hospital stays and higher incidence of depression. Nonetheless, HF survival appears better for women.

The sex difference in HF survival is not entirely explained by LV systolic function or by etiology. Several experimental studies point to sex-related fundamental differences in the nature and degree of myocardial remodeling, which may contribute to the female survival advantage. About one-half of patients with HF have preserved ejection fraction (HFpEF), which is often described as “diastolic dysfunction.” The pathophysiology of HFpEF is poorly understood, and there is ongoing debate about whether it is part of the HF spectrum or a distinct pathophysiologic entity fundamentally different from the much better understood HF with reduced ejection fraction (HFrEF).

The HFpEF patient population is older, more likely to be hypertensive and more often female.[8] The “preserved” systolic function does not denote good prognosis. In prospective studies of HFpEF, the mortality is comparable to HFrEF. Therapies such as ACE inhibitors and beta blockers that have demonstrated unequivocal benefit in HFrEF have not shown consistent efficacy in HFpEF. Diuretics are effective in relieving HF symptoms in both HFpEF and HFrEF, but there is scant evidence showing their effect on clinical outcome. Diagnosis of HFpEF is frequently challenging, relying on careful clinical evaluation, echo-Doppler cardiography and invasive hemodynamic monitoring. Many outpatients with chronic unexplained dyspnea attributed to deconditioning or overweight may have HFpEF. A higher level of awareness and a better understanding of this disease entity are needed since its prevalence is on the rise.

CVD in Pregnancy

Normal pregnancy is associated with a 30-50% increase in blood volume. About 40-100% plasma volume expansion is reached at 32-34 weeks, along with 20-30% increase in the red cell mass, thus creating a “physiologic anemia” that reduces the impact of blood loss during delivery, typically 300-500 cc for a vaginal delivery and 750-1000 cc for a C-section. An augmented cardiac output parallels the increase in blood volume, accomplished by a 35% increase in the stroke volume and a small rise in the basal heart rate.

Cardiovascular diseases are the most common cause of maternal death during pregnancy in the Western industrialized world, and occur in approximately 0.4% to 4% of all pregnancies.[9] While not routinely anticipated, incipient cardiac diseases such as peripartum cardiomyopathy (PPCM), spontaneous coronary dissection and aortic dissection are among

the “must not miss” diagnoses in late pregnancy. Shortness of breath at that stage may either reflect increased minute ventilation due to mechanical interference with diaphragmatic expansion by the gravid uterus, or the possibility of a serious and pathologic cardiopulmonary process.

PPCM presents in the last month of pregnancy or within 5 months postpartum. It is estimated to occur in 1 of 4,000 pregnancies in the U.S.[10] Risk factors include high parity, advanced maternal age, usage of tocolytics, African descent and twin pregnancy. The etiology is unknown, but experimental data have identified inflammation, autoimmune processes, apoptosis and impaired cardiac microvasculature as some pathophysiologic features. Recent data have shown that pregnancy-related imbalance of oxidative stress is linked to proteolytic cleavage of the nursing hormone prolactin, and produces a potent anti-angiogenic, pro-apoptotic and pro-inflammatory factor.[11]

Bromocriptine, a dopamine D2 receptor agonist that inhibits prolactin secretion, has been shown to improve recovery from PPCM in pilot studies.[12] There is enthusiasm about this new therapy, but large clinical studies are needed to validate the result. Currently, about one-half of PPCM patients recover normal systolic function within 6 months. On the other hand, 20% of PPCM patients deteriorate and either die or require heart transplantation.

Spontaneous coronary artery dissection is rare. In comparison with the usual myocardial infarction population, it occurs in relatively young people, with a striking predilection for women. Eighty percent of all spontaneous coronary artery dissections occur in women,[13] and one-third of these occur during pregnancy or the postpartum period. A variation in hormonal levels is thought to play an etiologic role.

During pregnancy, altered endocrine status may cause changes in the arterial wall, including fragmentation of reticulin fibers, loosening of ground substance, and smooth-muscle hypertrophy. These changes may participate in the pathogenesis of spontaneous coronary dissection.[14] Seventy-eight percent of women with peripartum coronary dissection have no risk factors for coronary artery disease, and 84% of the lesions involve the left anterior descending artery.[15] Early intervention with either percutaneous coronary intervention or bypass surgery may be associated with better outcomes than conservative management,[16] but the studies to date are not conclusive, and no guidelines have been established.

Acute aortic dissection may occur in pregnancy in the setting of severe hypertension due to preeclampsia, coarctation of the aorta, bicuspid aortic valve, or connective tissue diseases such as Marfan’s syndrome.[17] The main predisposing factor is degeneration of the collagen and elastin in the intima and media. On the basis that 50% of all aortic dissections in women under age 40 occur during pregnancy or the puerperium, it is often stated that pregnancy is a risk factor for aortic dissection. The most common site of pregnancy-associated aortic dissection is the proximal aorta, and aortic rupture usually occurs during the third trimester or the first stage of labor.

In general, pregnant women tolerate valvular insufficiency better than stenosis because the reduced systemic vascular resistance improves forward flow and limits the effects of regurgitation. The dramatic physiologic demands make pregnancy highly risky for women with certain conditions, including Marfan syndrome with dilated aortic root (>4cm), pulmonary hypertension (pulmonary vascular resistance >6 Wood units), moderate to severe left ventricular outflow obstruction (>30 mmHg), and left ventricular ejection fraction <30%.

Primary pulmonary hypertension is a rare disease that particularly affects young women of child-bearing age. It is characterized by medial thickening and intimal fibrosis. The mortality of pregnant mothers with primary pulmonary hypertension has been reported to be 30%. Secondary pulmonary hypertension has a perinatal mortality as high as 60%.[18]

Stroke

The third leading cause of death in women and men in the U.S is stroke. When compared to men, women have a relatively greater proportion of stroke than of myocardial infarction. Each year, approximately 55,000 more women than men suffer a stroke. Data from the Women’s Health Study showed the ratio of stroke to MI to be 1.4 to 1 among women in their placebo group, whereas among men of similar age in the Physician’s Health Study, the ratio was 0.4 to 1.[19,20] Even after adjustment for older age of stroke onset, women have poorer outcomes, greater disability, a higher likelihood for admission to nursing facilities, and greater mental impairment than men.

Hypertension is the most important modifiable risk factor for stroke. Although women and men have nearly equal percentage of hypertension (one in three adults), the prevalence is higher in women older than 65, with the highest rate found among black women, at 44% and increasing.[21]

Any discussion of stroke and CVD prevention inevitably leads to the role of aspirin. In secondary prevention, low-dose aspirin (75-150 mg daily) clearly reduces the risk of cardiovascular events, myocardial infarction and ischemic stroke in both men and women.[22] However, aspirin’s utility in primary prevention shows a sex-based difference. Aggregate data from six trials with a total of 95,456 individuals showed that aspirin therapy in women was associated with a 17% reduction in stroke but no significant effect on myocardial infarction. In contrast, there was a 32% reduction in the risk of myocardial infarction in men and no significant impact on the risk of stroke.[23] Analysis of data from the Women’s Health Study showed that in women 65 and older, aspirin use was associated with a significant risk reduction in ischemic stroke and a small risk reduction in MI. Among women younger than 65, there was no benefit in MI and a small benefit in reduction of stroke risk.[20]

The American Heart Association (AHA) suggests that aspirin therapy can be useful in primary prevention in women 65 and older if blood pressure is controlled and benefit for the prevention of ischemic stroke and myocardial infarction is deemed to outweigh risks of gastrointestinal bleeding and hemorrhagic stroke. The AHA also suggests that aspirin use may be reasonable in women younger than 65 for prevention of ischemic stroke, but recommends against its routine use in healthy women younger than 65 for the purpose of MI prevention.[24]

For the same primary prevention population, the U.S. Preventive Services Task Force (USPSTF) recommends the use of aspirin for women age 55 to 79 when the potential benefit of a reduction in ischemic stroke outweighs the potential harm of an increased risk of gastrointestinal hemorrhage, and the task force recommends against the use of aspirin for stroke prevention in women younger than 55.[25] For men in the age group 45 to 79, the USPSTF recommends aspirin use when the potential benefit of reducing the risk of myocardial infarction, not ischemic stroke, outweighs the potential harm from an increase in gastrointestinal bleed.

 

The age group 80 years and older has not been well represented in the many studies used to formulate the guideline recommendations. While the incidence of MI and stroke is high in persons 80 years and older, the relationship between increased age and bleeding is also well established. Current evidence is insufficient to evaluate the balance of benefits and harms of aspirin for cardiovascular disease prevention in this older age group. The easy availability of aspirin, with its direct marketing to patients without the context of age and gender differences in risks and benefits, complicates the issue of aspirin chemoprevention and underscores the importance of individual counseling.

Atrial fibrillation requires separate emphasis as a stroke risk. This arrhythmia is independently associated with a four- to five-fold increase in the risk of ischemic stroke, and is responsible for 15-20% of all ischemic strokes.[26,27] Women with non-valvular atrial fibrillation have nearly double the chance of stroke compared to men with the same risk profile. Use of warfarin anticoagulation for thromboembolic prophylaxis substantially lowers the risk of stroke in both men and women, by 60% and 84% respectively. No sex-related differences in the risk of bleeding were found in a recent systematic review of bleeding complications, but use of warfarin has been reported to be less common in women than in men.[28] Appropriately, the expert panel for AHA’s 2011 updated guideline for the Prevention of Cardiovascular Disease in Women included a recommendation for the pharmacologic prevention of stroke among women with atrial fibrillation.

Other stroke risk factors unique to women include pregnancy and the use of exogenous hormones for menopausal symptoms. The major physiologic changes that occur during pregnancy may “unmask” a predisposition to vascular pathology. Although cerebrovascular complications occur in a very small proportion of women with preeclampsia (<1%), they carry devastating morbidity and mortality. Primary care physicians and ob-gyns should be aware that a history of preeclampsia is associated with a future risk for hypertension, stroke and heart disease. In a way, pregnancy serves as a natural stress test and provides a unique opportunity to identify women at risk for cardiovascular disease.

Hormone Replacement Therapy

Since its approval by the FDA in 1942, estrogen has been used to alleviate the vasomotor symptoms of menopause and has been advocated for a variety of perceived health benefits, including CHD risk reduction. By the 1990s, the most compelling argument for hormone replacement therapy (HRT) in heart disease prevention came from observational studies. In 1998, the Heart and Estrogen/Progesterone Replacement Study--the first large, randomized, blinded, placebo-controlled secondary prevention trial--showed no cumulative difference of CHD events between HRT and placebo, with an increased risk of MI in the first year after initiation of hormone therapy, and an increased risk of venous thromboembolism.[29] This study was followed in 2002 by the release of data on primary prevention from the Women’s Health Initiative (WHI) showing that HRT did not prevent incident CHD and actually increased the risk of stroke and invasive breast cancer in apparently healthy women.[30]

These results led the FDA and the AHA to recommend against the use of HRT for either primary or secondary prevention of CVD in women. However, HRT remains the most effective treatment available for the disruptive symptoms of menopause. Controversy and interest in this powerful drug continue to spark energetic debate and research. The concept of “time trend”--which postulates an immediate pro-thrombotic and pro-arrhythmic effect of estrogen that is later outweighed by its beneficial effect on the vascular endothelial function--was forwarded to explain the finding of increased CHD events in the first year and decreased risk in subsequent years.

Another concept relates to the “timing” of HRT. The WHI enrolled women with a mean age of 63, who were on average 12 years post menopause. The “timing” hypothesis argues that significant vascular disease may have already been present in the study population at the initiation of HRT, so estrogen may not reverse established pathological atherosclerosis. A subset analysis of WHI women aged 50 to 59 post-hysterectomy who received only estrogen suggested lower heart disease risk. This finding lends support to the concept that with proper “timing,” estrogen given in low doses early in the menopausal transition may be cardioprotective. The ongoing Kronos Early Estrogen Prevention Study is investigating estrogen and intermittent progestin on atherosclerosis in a younger population, and its pending result may shed some light on this complex area.

CVD Prevention

A crucial aspect of contemporary cardiovascular medicine is the appreciation that much of CVD is preventable, which increases the need for timely identification of younger women at risk. The most established tool of risk assessment has been the Framingham Risk Score, which consists of criteria used to develop the National Cholesterol Education Program guidelines for lipid therapy.[31]

The Framingham score focuses on the short-term 10-year risk, and only on MI and CHD deaths. Since women develop CVD 5-10 years later than men, and their risks for stroke and heart failure through middle and older age typically exceed their risk for CHD, the Framingham score traditionally underestimates the risk in younger women and hence their need for preventive interventions.[32] For example, women with poor exercise capacity or unhealthy lifestyles have a broad range of risk for CVD, but may have a relatively low Framingham score.

The lifetime risk for CVD is high in almost all women and approaches 1 in 2 on average. Focus on a woman’s lifetime risk underscores the importance of a healthy lifestyle and may also better communicate future risk. For example, a 25-year-old woman with hypertension, diabetes and adverse lipid profile might be more likely to adopt the necessary lifestyle modification upon hearing that her 30-year risk of CVD is higher than 1 in 4, than when she is told that her 10-year risk is 1 in 40.[33]

Women also need to be better educated about the ineffectiveness of certain practices, such as supplementation with antioxidants and folic acid,[34] and focus their energy on effective preventive measures, including healthy diet, weight management, regular physical activity and abstinence from smoking. While certain impediments in clinical practice (such as time pressure, complex comorbidities and socioeconomic issues) undermine delivery of successful preventive care, the reality remains that physician-led, multidimensional interactions provide the most impact on the patients’ adoption of healthy behavior.

Over time, the barriers to implementation must be tackled systematically to give physicians the ability to effect behavioral changes and monitor adherence to therapy. By doing so, we will achieve the goal of greater longevity and better quality of life for all our patients--both women and men.

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Dr. Kao is a board certified cardiologist at Cardiovascular Associates of Marin in Larkspur.

Email: akao@camsf.com

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