VIEWPOINT
Women, Ischemic Heart Disease, Revascularization, and the Gender Gap
What Are We Missing?
Alice K. Jacobs, MD*
Section of Cardiology, Boston University Medical Center, Boston, Massachusetts
Manuscript received November 1, 2004;
accepted December 21, 2004.
* Reprint requests and correspondence: Dr. Alice K. Jacobs, Section of Cardiology, Boston University Medical Center, 88 East Newton Street, Boston, Massachusetts 02118-2308 (Email: alice.jacobs{at}bmc.org).
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Abstract
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During the past three decades, numerous reports from single-center databases, multicenter registries, and a few randomized trials in patients with ischemic heart disease (IHD) undergoing revascularization with both coronary artery bypass grafting and percutaneous coronary intervention have noted remarkably consistent gender differences in clinical, angiographic, and procedural factors and an increased morbidity and mortality in women. Explanations such as alternative markers of atherosclerosis and novel risk factors in women, gender-specific measures of left ventricular function, and the relationship between disorders more common in women with IHD and adverse cardiovascular outcomes are beginning to unfold.
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Abbreviations and Acronyms
| | CABG = coronary artery bypass grafting | | CASS = Coronary Artery Surgical Study | | IHD = ischemic heart disease | | LV = left ventricular | | PCI = percutaneous coronary intervention | | WISE = Women’s Ischemia Syndrome Evaluation |
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This year, an estimated 150,000 women will undergo coronary artery bypass grafting (CABG) and 360,000 women will undergo percutaneous coronary intervention (PCI) for treatment of ischemic heart disease in the U.S. (1). Based upon numerous previous studies (2–4), it is anticipated that periprocedural mortality and morbidity will be significantly higher in women in than in men. Most of this difference in outcomes following revascularization has been attributed to the older age in women and to the underlying gender differences in clinical, angiographic, and procedural factors.
In fact, much of what we have learned about the gender differences in patients with IHD has been gleaned from the numerous studies of patients undergoing coronary revascularization during the past three decades. Single-center databases, multicenter registries, and fewer randomized trials have all reported that when compared with men, women have a higher prevalence of risk factors, acute coronary syndromes, (angina) symptoms, and a higher prevalence of congestive heart failure, despite preservation of left ventricular (LV) systolic function, but a similar (or lesser) extent of epicardial coronary disease (5,6). Based upon emerging data from investigations such as the Women’s Ischemia Syndrome Evaluation (WISE) study (7), explanations for these seemingly paradoxic observations between the sexes are beginning to unfold.
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Have we been looking at the wrong measures of coronary atherosclerosis in women?
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The Coronary Artery Surgical Study (CASS) registry most clearly demonstrated that for a given extent of coronary artery disease (single, double, or triple vessel) measured by angiography, women were more symptomatic, had more functional (Canadian Cardiovascular Society) impairment, and more unstable symptoms than men (8). Initial skepticism about altered pain threshold and psychologic factors operative in women has gained credence, and appropriate evaluation and treatment options are currently being evaluated (9). In addition, increased appreciation for syndrome X (chest pain, abnormal (ischemic) stress test, and normal coronary arteries) is based on the finding of abnormal coronary flow velocity reserve suggestive of microvascular dysfunction in women (10). Interestingly, endothelial dysfunction due to a higher prevalence of hypertension and hypercholesterolemia has been implicated as the basis for the increased chest discomfort in women and for the presence of chest pain in the absence of significant coronary artery disease (3). However, aging is associated with progressive endothelial dysfunction in both sexes, and this occurs, in fact, later in women than in men although there is a steep decline in endothelial function around menopause (11,12). These findings suggest a gender difference in the pattern of age-related vascular injury.
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Have we been looking at the wrong risk factors for coronary disease in women?
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Despite a higher prevalence of traditional risk factors in women undergoing coronary revascularization, the extent of epicardial disease is similar to that seen in men (2–6). In fact, in many series, women have a lower prevalence of multivessel disease and fewer significant coronary stenoses. Whether the traditional risk factors are less potent in women (perhaps based on a protective effect of estrogen) or whether women have more diffuse coronary atherosclerosis is unclear. However, these findings have prompted the evaluation of other potential risk factors or markers of disease in women.
Reports form the WISE study investigators have noted that the metabolic syndrome but not obesity (defined by body mass index) is associated with significant coronary artery disease (13), that apolipoprotein E polymorphism is an independent risk factor for the presence and severity of coronary atherosclerosis (14), and that serum amyloid A is independently associated with coronary disease measured by angiography in women (15). Additionally, in patients with acute coronary syndromes, there is a differential expression of cardiac biomarkers by gender (16). Specifically, men are more likely to have elevated creatine kinase MB and troponins, whereas women are more likely to have elevated C-reactive protein and brain natriuretic peptide. These data suggest that there may be gender differences in the pathophysiologic mechanisms associated with acute coronary syndromes. Atherosclerotic plaque rupture, platelet-rich thrombus, and microembolization may be operative more often in men, whereas small-vessel disease, vascular inflammation, and congestive heart failure may be operative more often in women (16).
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Have we been looking at the wrong measure of LV function in women with heart failure?
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The higher prevalence (and incidence) of congestive heart failure despite a lower prevalence of LV systolic dysfunction (consistent with fewer previous myocardial infarctions) in women in comparison to men undergoing both CABG and PCI has been attributed to diastolic dysfunction and hypertensive heart disease in women (3). In fact, a steeper LV pressure-volume relationship in women has been reported (17). It is noteworthy that heart failure is an independent predictor of mortality following revascularization in both genders (6). Although difficult to study because women are under-represented in trials of heart failure, owing to older age and preserved LV function serving as exclusions for enrollment (18), several observations have increased our understanding of issues specific to women. In elderly patients hospitalized with (all-cause) heart failure, female gender is an independent predictor of preserved LV systolic function (19). Hypertension, diabetes, and obesity all impart a higher risk, although myocardial infarction appears to impart a lower risk of heart failure in women than in men (20). Furthermore, gender differences in postinfarction hypertrophy and cellular remodeling in end-stage failing hearts have been reported, with women exhibiting reduced hypertrophy (21).
Is there a relationship between the issues specific to women with IHD and outcome following coronary revascularization?.
Although our understanding of the gender differences in outcomes following coronary revascularization has increased, what is missing is a clear concept of how these gender paradoxes translate into increased morbidity and mortality in women. Recent reports suggest that impaired coronary vasomotor response to acetylcholine is independently linked to adverse cardiovascular outcomes regardless of the severity of coronary atherosclerosis (22), that the metabolic syndrome modifies the risk associated with coronary artery disease measured by angiography (23), and that lower hemoglobin levels are associated with a higher risk for adverse outcomes in women undergoing evaluation for ischemic heart disease (24) and in patients undergoing PCI (with anemia more frequent in women) (25). It is also noteworthy that in patients with acute coronary syndromes (16), gender differences in the relationship between elevated biomarkers and outcomes have been noted. Elevated biomarkers are associated with a benefit from early coronary revascularization (compared with early conservative therapy) in both genders. However, the absence of at least one positive biomarker is associated with an increased incidence of adverse outcomes in the invasive compared with conservatively treated group of women, whereas there is no difference in outcomes between the two strategies in men. Finally, LV hypertrophy has been shown to be an independent predictor of mortality in patients with coronary artery disease. Although the relative risk of LV hypertrophy does not vary by race or gender, the attributable risk is greater in black patients and in women (26).
Whether our increasing appreciation of the issues and novel risk factors operative in women will result in continued improvement in outcomes following both PCI and CABG remain speculative. What is clear, however, is that the gender gap in mortality in patients undergoing PCI with stable coronary disease (27), acute coronary syndromes (28), ST-segment elevation myocardial infarction (29), and cardiogenic shock complicating acute myocardial infarction (30) has narrowed and that the outcomes in women following both PCI and CABG have improved (4,27,31). Whether the remaining gender difference in outcomes is related to our inability to completely and correctly account for the inherent biologic differences between the genders has yet to be defined. The fact that stents (32,33) and newer surgical techniques, including minimal access approaches (34), have not eliminated the gender difference in mortality following these procedures suggests that periprocedural complications are not the major determinant of survival. Certainly, observations concerning risk-benefit ratios in women with acute coronary syndromes where the benefits of revascularization have been most apparent in those at high risk (28), in ST-segment elevation myocardial infarction where the benefit of primary PCI in comparison to fibrinolytic therapy has been demonstrated (35), and in cardiogenic shock where the benefit of revascularization was similar to that in men (30) will influence the recommendation of these therapies to women.
What is missing is a clear understanding of the relationship between symptoms and microvascular ischemia, of the gender differences in novel risk factors and particularly how they relate to the pathophysiology of acute coronary syndromes, of the independent relationship between heart failure and mortality following revascularization, and of the small but persistent gender difference in (adjusted) outcomes following both CABG and PCI. Fortunately, what is apparent is that the increasing awareness of the burden of cardiovascular disease in women has resulted in ongoing studies such as those by the WISE study investigators that will address what is missing in our understanding of the gender gap and ultimately improve the care and outcomes in women with IHD.
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Abstract
Have we been looking...
