Women Really are Different! Gender Differences in Manifestations of CAD

Abstracts & Commentary

Synopsis: Metabolic syndrome, but not obesity alone, was associated with a higher risk of cardiovascular events. The presence of MS in individuals with angiographic CAD at study entry substantially increased the likelihood of death and MACE.

Sources: Kip KE, et al. Circulation. 2004;109:706-713; Marroquin OC, et al. Circulation. 2004;109:714-721.

The Women’s Ischemic Syndrome Evaluation, or WISE program, co-chaired by Noel Bairey-Merz and Robert Bonow, has been making significant contributions to our understanding of differences in ischemia presentation, as well as pathophysiology of chest discomfort in women who may or may not have obstructive coronary artery disease (CAD). In the February 17, 2004, issue of Circulation, 4 WISE studies were published, as well as the conference proceedings from a recent AHA/NHLBI workshop (available on the WISE web site and Circulation electronic pages). Two of these studies are briefly reviewed. One is an examination of the importance of obesity vs the metabolic syndrome (MS) in women relating to cardiovascular risk. In this cohort of 744 women evaluated for suspected myocardial ischemia, it was determined that MS was a much better predictor of CV risk than obesity as assessed by BMI. This was a 3-year follow-up study (range, 2.8-4.7 years) of 83% of the entire WISE study population, representing all women referred for coronary angiography at 4 WISE study sites to evaluate possible myocardial ischemia. There were some interesting differences between obese and normal-weight women (obese women smoked less, had higher triglycerides, were on more antihypertension medications, and were less likely to be white than normal BMI women). They also had higher markers of inflammation (CRP and IL-6). About 30% of women with a normal BMI met MS criteria, 55% of overweight women (BMI 25-30) had MS, and 76% of obese women (BMI > 30) had MS. Confirmation of obstructive coronary artery disease (> 50% lesion) in the absence of MS was 30% in normal-weight women, 25% in overweight women, and 17% in obese women.

However, women in the same weight categories who had MS, 56%, 52%, and 42%, respectfully, had CAD, representing a 2- to 3-fold increased likelihood of significant CAD. When survival and major adverse cardiovascular events (MACE) during follow-up were tabulated, normal metabolic women had a 3-year event-free rate > 96%, even in the obese women. These event-free rates were markedly higher compared to those with a dysmetabolic state, with event-free rates of 87%, 92%, and 92%, respectively, for the 3 weight groups. When BMI alone was evaluated for the relationship to cardiovascular events, there was no association for risk of death or MACE; MS was related to death and MACE with a 2-fold adjusted risk. Thus, MS, but not obesity alone, was associated with a higher risk of cardiovascular events.

Kip and associates’ discussion underlines the findings that obesity, in the absence of MS characteristics, was not associated with adverse outcomes, whereas adverse metabolic status was clearly related to death and cardiovascular events. Women with diabetes were included in this cohort and were classified as dysmetabolic. Of importance, normal-weight women with MS were at increased risk, whereas overweight and obese women with normal metabolism had a relatively low cardiovascular risk. CRP and markers of inflammation appear to be more closely related to metabolic status than body weight. Thus, in women with suspected myocardial ischemia, MS is an adverse prognostic factor for subsequent risk, including death and MACE, whereas high BMI alone without dysmetabolic state does not confer increased risk.

In a related WISE study, it was found that in women with angiographic CAD at baseline, subsequent prognosis is directly related to the presence or absence of MS. In this cohort of 755 women, 25% had MS at entry; they had a more adverse 4-year survival rate than those with a normal metabolic status (94.3% vs 97.8%; P = .03), and 87.8% vs 93.5% event-free survival from MACE (P = .003). Presence of CAD and MS inferred a significantly greater risk for CV events by 5-fold (P = .05). Conversely, there was no increase in 4-year cardiovascular risk in those women without significant CAD, irrespective of metabolic status. As in the first report, markers of inflammation were lower in women with normal metabolic status. The prevalence of significant CAD was 33% in women with MS compared to 22% in those without MS, and 57% in diabetics. Only 23% of the diabetics had no CAD at entry, compared to 45% and 40% of normals and MS, respectively. MS was associated with a decreased survival (94% vs 98%; P = .03) and 4-year MACE was also increased, especially in those with diabetes (survival 93.5% normal metabolic status, 88% MS, and 76% diabetes). In those women who had significant disease at entry, 4-year survival was comparable in the MS and diabetic cohorts at 86% and markedly lower than those with normal metabolic status, who had a 4-year survival of 97%. Thus, the presence of MS in individuals with angiographic CAD at study entry substantially increased the likelihood of death and MACE over 4 years. Conversely, in those women with no CAD at baseline, survival and freedom from MACE were comparable in all cohorts. 

MS in the presence of CAD was associated with a nearly 5-fold increased likelihood of death and MACE vs normal metabolic status. On the other hand, women without CAD at baseline had no increased risk of death, even with MS (40% increase likelihood; P = .65). CRP levels had little influence on risk in normal or MS women. Insulin resistance was higher in women with MS, as expected, but did not predict 4-year risk of death compared to the MS alone. Mortality at 4 years was as follows: normal women 2.2%, MS 7%, and diabetics 10.6%. Marroquin and colleagues conclude that angiographic CAD in women with suspected ischemia associated with metabolic status or diabetes had a substantially lower survival, as well as event-free survival, compared to women with normal metabolic status at baseline. Marroquin et al discussed supportive prior reports and concluded that risk of CAD is intermediate for MS women compared to normal metabolic status and diabetes. Marroquin et al stress that women without CAD at entry had low risk even in the presence of MS and diabetes. They also conclude that measures of insulin resistance are not as powerful predictors of prognosis as features of MS, although they believe that insulin resistance is linked to much of the increased cardiovascular risks in MS, as well as systemic inflammation and a procoagulant state. They recommend aggressive risk-factor modification to all individuals with MS.

Comment by Jonathan Abrams, MD

These 2 reports are of importance by documenting the powerful adverse effect of MS in women with clinical chest discomfort both before and after identification of CAD vs normal coronary arteries. It is reassuring that MS appears to be a powerful predictor of risk and that clinicians do not need to be concerned about obtaining measures of insulin resistance. Markers of inflammation were greater in obese women but appear to have relatively little relationship to clinical outcomes once CAD status was evaluated by angiography. Both reports confirm the well-known fact that diabetic women have the worst prognosis. One conclusion that seems reasonable is that all women with a clinical presentation that suggests myocardial ischemia should be aggressively evaluated for the presence or absence of CAD, as obstructive CAD appears to be a critical prognostic factor. Women with MS, obese or not, with normal angiograms had a comparable 4-year event rate to women with normal metabolic status, confirming the critical importance of significant coronary atherosclerosis.

In conclusion, women are different than men, which of course is no secret. What is surprising, however, is the increased likelihood of chest discomfort, often atypical, in women with or without angiographic CAD, as well as the adverse influence of MS in women who have coronary atherosclerosis. There are also ample data confirming ischemic symptoms in women even in the absence of CAD, which may be related to endothelial dysfunction, or "microvascular angina," a problem that appears to be much more common in females. The WISE study has made and continues to make important contributions. For those interested in cardiac disease and gender differences, these new publications are valuable resources.

Dr. Abrams, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque, is on the editorial board of Clinical Cardiology Alert.