Guest Editorial: Underdiagnosed, Undertreated, and Understudied: An Epidemic of Cardiovascular Risk in Women

Cardiovascular disease is the leading killer of women,¹ accounting for more than 200,000 deaths in the U.S. each year.² Cardiovascular disease is not simply a disease of older women. Heart attacks afflict one in 90 women ages 45 to 54 years old, exceeding the one in 240 diagnosed with breast cancer.^3,4 Despite these sobering statistics, the burden of cardiovascular disease in women remains vastly underappreciated. In a survey of 2,300 women in the U.S., approximately half correctly identified cardiovascular disease as their leading cause of death; 1 in 2 incorrectly reported cancer as their greatest health risk, and only 1 in 6 reported cardiovascular disease as their leading health risk.⁵ Below we briefly summarize the underdiagnosis and undertreatment, specifically, of atherosclerotic cardiovascular disease risk in women and lend our perspective on potential strategies to bridge the gap.

Ischemic Heart Disease

The diagnosis of ischemic heart disease in women is more elusive than in men. While the predominant symptom in men with acute coronary syndrome is chest pain or pressure, women report chest discomfort less than half of the time.⁶ The most common presentation of acute myocardial infarction in women is sudden cardiac death; followed by back, jaw, and neck pain; dyspnea; indigestion; nausea; and emesis, the latter of which generally are labeled as “atypical,” leading practitioners astray to alternate diagnoses such as gastrointestinal reflux, esophageal spasm, or anxiety.^6-8 Moreover, the afflicted woman may overlook her symptoms and delay seeking medical attention because she is unaware. Retrospective analysis of the Immediate Myocardial Metabolic Enhancement during the Initial Assessment and Treatment in Emergency Care (IMMEDIATE) trial found that women diagnosed with probable acute coronary syndrome took a longer time to call 911 from symptom onset — 73 minutes compared to 45 minutes in men (p<0.01).⁹ It is hypothesized that differences in presentation may be related to gender differences in the pathogenesis of ischemic heart disease.

Striking differences contrast the pathophysiology underlying ischemic heart disease in women and men. Whereas obstructive epicardial stenosis explains the overwhelming majority of coronary disease in men, approximately 25 to 50 percent of women — or from three to five times that of men — who undergo coronary angiography for the evaluation of ischemia have normal or minimal epicardial disease.^10-12 The constellation of angina, objective evidence of ischemia on non- invasive stress testing, and the absence of angiographic epicardial coronary obstruction is referred to as cardiac syndrome X.¹³ Importantly, despite the absence of angiographic disease, angina in women is associated with a significantly worsened outcome. In the Women’s Ischemia Syndrome Evaluation (WISE) study, the five-year annualized event rates for adverse cardiovascular outcomes were 7.9 percent in symptomatic women without angiographic disease and 2.4 percent in asymptomatic controls (p<0.002).^12-16 Vasomotor dysfunction appears to identify a particularly high-risk subgroup of women.^17,18 A WISE sub- study revealed that women with minimal coronary artery disease (defined as 20 to 49 percent stenosis) who had an abnormal intracoronary vasodilator response to acetylcholine had a significantly higher risk of cardiovascular events compared to women with a normal response (hazard ratio 2.8, 95 percent CI 1.26-6.44).¹⁷ The pathogenesis of cardiac syndrome  X remains poorly characterized. In addition to vasomotor dysfunction, other leading hypotheses include abnormal nociception and inflammation.¹³ Evidence- based strategies to treat angina and cardiovascular risk associated with cardiac syndrome X also are lacking.

Assessment of Cardiovascular Risk

Underestimation of cardiovascular risk in women is a significant concern because it leads to missed opportunities in aggressive preventive care. In this regard, limitations of the 10-year Framingham risk score (FRS) for risk prediction in women are well recognized. Systematic variation in risk factor levels revealed that women ages 55 and younger do not exceed a risk of 10 percent, regardless of risk factor burden.¹⁹ Among women ages 65 and older, only the combination of smoking with marked abnormalities in high-density lipoprotein cholesterol (HDL-C), total cholesterol, and systolic blood pressure produces a 10-year predicted risk >10 percent. In fact, according to the National Health and Nutrition Examination Survey, the prevalence of high-risk FRS (>20 percent) among women ages 50 to 69 is 0.3 to 0.4 percent,²⁰ in stark contrast to the actual observed incidence of coronary artery disease.²¹ Although questions linger regarding appropriate calibration, the 2013 Pooled Cohort risk equations better address the underestimation of cardiovascular risk in women, at least in part by the incorporation of stroke.^22-25

In clinical practice, “global” cardiovascular risk assessment of any individual patient incorporates myriad risk factors that are not captured by currently available clinical risk scores. Several additional risk factors that are particularly important to consider in the risk calculus for women are early menopause and features of metabolic syndrome. Most data indicate that early menopause predicts coronary heart disease and possibly stroke. In the Nurses’ Health Study, the relative risks across categories of age at natural menopause (<40, 40-44, 45-49, 50-54, and > or = 55 years) were 1.53, 1.42, 1.10, 1.00, and 0.95 after adjusting for traditional risk factors.²⁶ In the Multi-Ethnic Study of Atherosclerosis (MESA), women with early menopause (either natural menopause or surgical removal of ovaries at an age <46 years) exhibited more than a two-fold higher risk of coronary heart disease and stroke compared to women without early menopause after adjusting for other risk factors.²⁷ In addition, features of metabolic syndrome — namely insulin resistance, dyslipidemia, hypertension, and abdominal obesity — confer greater cardiovascular risk in women. A sub-study of the WISE cohort showed that, compared with women with normal metabolic status, women with metabolic syndrome had a significantly lower four-year survival rate (94.3 percent versus 97.8 percent, P=0.03) and event-free survival from major adverse cardiovascular events (death, nonfatal myocardial infarction, stroke, or congestive heart failure; 87.8 percent versus 93.5 percent, P=0.003).²⁸

Subclinical atherosclerosis imaging in selected women may be useful to refine cardiovascular risk and guide the intensity of preventive therapy above and beyond clinical risk factors or blood tests. Both coronary artery calcium scanning (CACS) and assessment of carotid intima-media thickness and plaque (CIMT) have consistently shown a positive association with coronary heart disease (CHD) risk.²⁹ A meta-analysis  evaluating  24,260 women demonstrated progressively increased risk of myocardial infarction with higher coronary artery calcium scores (CACS 0-10 reference, CACS 11-100 relative risk 3.0, CACS 101-399 RR 5.7, CACS 400-999 RR 9.7, CACS>1000 21.5).³⁰ Among low-risk women (10-year CHD risk <10 percent), an analysis of MESA further demonstrated that CACS was highly associated with CHD events, yielding an adjusted relative risk of 8.3 and an absolute annual risk of 1.8 percent among women with a CAC above 300).³¹ The Atherosclerosis Risk in Communities (ARIC) study evaluated 12,841 people free of clinical CHD at baseline over a median of 5.2 years. Among the 7,289 women, a CIMT of 1 mm or greater was associated with a relative risk for CHD events of 5.1 compared with a CIMT below 1 mm, adjusted for age and race.³² CACS and CIMT improve reclassification and discrimination for CHD above and beyond traditional risk factors, effecting statistically significant increases in the area under the curve (AUC), a rigorous measure of discrimination that fails to improve even with the incorporation of several accepted traditional risk factors.³³ CACS and CIMT may be useful in refining cardiovascular risk in selected women by guiding the intensity of preventive therapies when standard clinical risk assessment yields equivocal results. Notably, randomized trials comparing clinical outcomes and cost-effectiveness of various risk assessment strategies, including those incorporating subclinical atherosclerosis imaging modalities, are lacking.

Treatment of Cardiovascular Risk

Even after women have been diagnosed as being at high risk, with all the pitfalls and perils described above, women — far more frequently than men — fail to receive evidence-based therapies and fail to meet guideline-based targets for primary and secondary prevention.^34-36 In a large, retrospective chart review led by Dr. Dean Karalis examining 9,950 patients with coronary artery disease, women were more likely not to be treated with a statin (16.9 percent versus 11.6 percent, p <0.001) and more likely to be on no lipid-lowering therapy at all (12.8 percent versus 7.8 percent, p <0.001) compared with men. Moreover, compared with men, women on statins were less likely to achieve Adult Treatment Panel III (ATP III) target low-density lipoprotein cholesterol (LDL- C) (30.6 percent versus 38.4 percent, p <0.001) and non-HDL-C (37.1 percent versus 48.2 percent, p <0.001)³⁴ Narrowing the Gaps In 2012, Dr. Nanette Wenger outlined major recommendations to improve coronary heart disease outcomes in women (Table 1).³⁸ Proposed strategies to help implement these recommendations in clinical practice have included: 1) building clinical-decision support embedded in electronic medical records to facilitate the identification and treatment of women at risk, 2) leveraging social media to engage a wider audience, emulating the success of breast cancer campaigns, and 3) identifying local champions — women with atherosclerotic cardiovascular disease — to foster peer-to-peer education. Perhaps the greatest impact we can have in day-to-day patient care is to view each and every encounter as an opportunity to increase awareness. This approach is most obvious for the female patients for whom we care directly, but, for our male patients, do we consider the women in their families? How often do we take a moment to share information about the risk of heart disease in women with the spouses and female relatives who accompany our male patients to their clinic appointments? A brief message highlighting cardiovascular disease risk in women, systematically reinforced by healthcare providers at each clinic visit, may be a simple and practical way to improve awareness, detection, and treatment. 

Disclosure statement: Dr. Mark has no disclosures to report. Dr. deGoma received research honoraria from Aegerion, Pfizer, Regeneron, Sanofi, and Amgen.

References are listed on page 38 of the PDF.