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Coronary artery disease: Are men and women created equal?
GENDER MEDICINE/VOL. 6, NO. 3, 2009
Coronary Artery Disease: Are Men and Women Created Equal? Arnon Blum, MD1; and Nava Blum, PhD2 1Department
of Internal Medicine, Baruch-Padeh Poria Medical Center, Lower Galilee, Israel; and 2Faculty of Social Welfare and Health Sciences, School of Public Health, Haifa University, Haifa, Israel
ABSTRACT Background: Ischemic heart disease in women is a difficult issue in cardiovascular medicine, mainly because of our lack of understanding of the early-stage mechanisms and symptoms. A better and earlier understanding of the pathophysiology of coronary artery disease (CAD) in women will enable us to detect ischemic heart disease earlier and prevent adverse clinical outcomes. Objectives: The aims of this article were to describe the phenomenon of ischemic heart disease in women, increase awareness of the difference between men and women in relation to ischemic heart disease, improve our understanding of the mechanisms that cause this difference, and identify new approaches for better and earlier detection and treatment of CAD in women. Methods: We conducted a search of the PubMed database for double-blind studies on the mechanistic pathways of CAD in women published in English within the past 10 years and epidemiologic studies published since 1970. Search terms included women and coronary artery disease and ischemic heart disease in women. Results: The literature search revealed 30 peer-reviewed articles pertaining to this issue. The incidence of CAD was markedly lower in women <60 years of age than in older women. After 60 years of age, the rate of CAD increased and reached the rate seen among men by the 8th decade of life. The gender difference in atherosclerosis in the coronary tree was particularly large in patients <55 years of age and remained large at older ages. The gender difference in the coronary bed was strikingly larger than in other vascular beds. Intensive risk-factor modification had a similar effect on plaque progression in both men and women. Coronary endothelial dysfunction appeared to be related to cardiovascular morbidity and mortality in women as well as in men, and because endothelial dysfunction could be modified, it appeared that the prognosis could be improved by appropriate management. A strong association was found between body mass index (BMI) and metabolic status, but only the metabolic syndrome was associated with CAD. Physical activity was independently associated with fewer risk factors, less CAD, and fewer adverse events in women; however, obesity was not associated with these outcomes. Conclusions: Results of the identified studies suggest that reduction of risk factors is a common approach to fighting heart disease in both sexes. It appears that for women, weight and BMI are not as important as previously thought, but physical exercise and fitness are very important and can change risk factors and clinical outcomes more than any other known intervention. Data suggest that global inflammation may play an important role in women and may predict cardiovascular outcome in women much better than the traditional risk factors that have been used and proved for men. (Gend Med. 2009;6:410–418) © Excerpta Medica Inc. Key words: ischemic heart disease in women, metabolic syndrome, BMI, exercise, endothelial progenitor stem cells. Accepted for publication April 21, 2009. © 2009 Excerpta Medica Inc. All rights reserved.
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doi:10.1016/j.genm.2009.09.005 1550-8579/$ - see front matter
A. Blum and N. Blum
INTRODUCTION
Epidemiologic Studies
Ischemic heart disease in women is a difficult issue in cardiovascular medicine, mainly because of our lack of understanding of the early-stage mechanisms and symptoms. Heightened awareness of women at risk for coronary artery disease (CAD) is needed to allow early diagnosis. Inflammation and endothelial dysfunction are key elements, and both are linked to adverse outcomes, but nonendothelialdependent microvascular dysfunction is involved as well. A better and earlier understanding of the pathophysiology of CAD in women will enable earlier detection of ischemic heart disease and prevention of adverse clinical outcomes. The aims of this article were to describe the phenomenon of ischemic heart disease in women, increase awareness of the difference between men and women in relation to ischemic heart disease, improve our understanding of the mechanisms that cause this difference, and identify new approaches for better and earlier detection and treatment of CAD in women.
The incidence of CAD was markedly lower in women <60 years of age than in older women.1 The predicted probability of having an acute myocardial infarction (MI) at <60 years of age was higher among men than among women (60.6% vs 33.0%, respectively).1 After 60 years of age, the rate of CAD in women increased and reached the rate seen among men by the 8th decade of life.1,2 Based on data from the INTERHEART study,3 a global case–control study conducted in 6787 women in 52 countries, it appears that the lower MI burden among women at younger ages is largely explained by a lower risk-factor burden. The reasons for this decreased burden in younger women compared with men require further study.1,2 The Framingham study4 described risk factors for CAD in women (eg, high levels of LDL-C, smoking, high blood pressure, diabetes mellitus [DM], overweight, lack of physical activity), but was unable to explain the later age of first occurrence of MI among women compared with men. The INTERHEART study,5 designed to determine whether differences in risk factors existed between men and women across various age categories to help understand why acute MIs develop later in life in women than in men, found modifiable risk factors that could explain >90% of acute MIs in young and older individuals, both women and men, across all ethnic groups. The risk factors included abnormal lipid levels, current smoking, abdominal obesity, hypertension, DM, regular alcohol use, “unhealthy” diet, and psychological stress. This international study reported that women experienced their first acute MI 9 years later in life than did men (P < 0.01). The modifiable risk factors that were associated with acute MI in both men and women included abnormal lipid levels, smoking, abdominal obesity, dietary intake, and mental stress. However, hypertension, DM, physical activity, alcohol use, and former smoking differed between the sexes. The lower MI burden among women at younger ages appeared to be explained by the lower risk-factor burden, but the reason for such a difference is not understood. The INTERHEART study found that treating risk factors could be a common
METHODS We conducted a search of the PubMed database. We sought double-blind studies on the mechanistic pathways of CAD in women published in English within the past 10 years (with emphasis on the past 4 years) and epidemiologic studies published since 1970. The search terms included women and coronary artery disease and ischemic heart disease in women. For inclusion in this review, studies had to either be double-blind and compare objective data (eg, volume of coronary artery lesions) or be large epidemiologic studies that were published in peer-reviewed journals. Letters to the editor, case reports, and other types of studies were not included. Only studies that met the inclusion/exclusion criteria for selection were included in this review.
RESULTS The literature search identified 30 peer-reviewed articles that met the inclusion/exclusion criteria. All these papers served as the basis of this review, including the basic science mechanistic studies and the clinically oriented epidemiologic studies.
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goal for both women and men to prevent acute MIs. To better understand CAD in women, a prospective study6 compared degrees of coronary, carotid, peripheral, and aortic atherosclerosis in men and women aged >55 years from the population-based Rotterdam Study. In that study, 2013 participants had both coronary calcification and evidence of extracoronary atherosclerosis, including an increased intima-media thickness (IMT), a denser carotid plaque, a decreased ankle-arm index, and aortic calcification. The prospective study was the first to compare gender differences in atherosclerosis at different sites in the vascular tree. The investigators reported that the coronary calcium score (≥1000) was higher in men than in women in all age categories (>55 years); male:female odds ratios (ORs) were 7.8 (95% CI, 3.2–19.3), 5.4 (95% CI, 2.8–10.2), and 3.0 (95% CI, 1.7–5.2) in the lowest, middle, and highest age tertiles, respectively. A less-pronounced pattern was found for IMT and carotid plaque scores. For aortic calcification scores, the pattern was more heterogeneous, with less-obvious differences between men and women (male:female OR, 1.3).The gender difference in atherosclerosis in the coronary tree was particularly large (male:female OR, 6.9; 95% CI, 3.4–13.9) in patients 61 to 67 years of age and remained large (male:female OR, 2.7; 95% CI, 1.8–4.0) in patients 74 to 85 years of age. The gender difference was reported to be strikingly larger in the coronary bed than in other vascular beds (OR of 4.4 compared with 2.6 in the carotid arteries and 1.3 in the peripheral arteries). The ORs for IMT, carotid plaques, and aortic calcification did not show an obvious decline with increasing age; the age-adjusted ORs were 2.6, 2.7, and 1.3, respectively. Another study explored the effects of diet and lifestyle on primary prevention in women.7 The 84,129 women who participated in the Nurses’ Health Study were free of diagnosed CAD, cancer, or DM when they were enrolled in the follow-up study in 1980. Women in the low-risk group (3% of the population) had a relative risk of coronary events of 0.17 compared with all the other women. Eighty-two percent of coronary events in the study
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cohort could be attributed to lack of adherence to the low-risk lifestyle guidelines. The investigators concluded that, in women, adherence to lifestyle guidelines involving diet, exercise, and abstinence from smoking was associated with a very low risk of CAD. Why is there such a difference in the progression of coronary atherosclerosis between women and men? Which are the important prognostic factors that affect CAD in women?
Mechanistic Insights Rate of Atherosclerosis Progression and Prognosis The relationship between gender and the extent of coronary atherosclerosis was assessed by intravascular ultrasound in 978 women who participated in serial studies of atheroma progression.8 The parameters that were examined included the extent of the coronary atheroma and the change in response to therapy. It is important to mention that, compared with men, women had a lower prevalence of obstructive disease: women had less plaque in terms of mean (SD) percent atheroma volume (33.9% [10.2%] vs 37.8% [10.3%]; P < 0.01) and total atheroma volume (148.7 [66.6]3 vs 194.7 [84.3] mm3; P < 0.001)2,9–11 but tended to have a higher incidence of chest pain, and their clinical outcome after an event tended to be worse,10,12–14 a discrepancy that was accentuated with age.15 Women were more likely than men to have a history of hypertension; greater body mass index (BMI) (mean, 30.5 vs 29.0 kg/m2; P < 0.01); higher levels of LDL-C (mean, 137.0 vs 127.4 mg/dL; P = 0.01), HDL-C (mean, 46.3 vs 38.6 mg/dL; P < 0.01), triglycerides (mean, 180 vs 158 mg/dL; P = 0.02), and C-reactive protein (CRP) (mean, 4.8 vs 2.6 mg/L; P < 0.01); and increased systolic and diastolic blood pressures (80.5% of women, 63.5% of men). Despite the greater prevalence of risk factors in women than in men, women harbored less plaque. The mean percent atheroma volume was 33.3% in women and 37.4% in men (P < 0.01). Furthermore, intensive risk-factor modification had a similar effect on plaque progression in both men and women. Female subjects were as likely as male subjects to undergo substantial regression in lower-
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ing LDL-C levels (26.0% vs 25.0%), lowering systolic blood pressure (20.4% vs 21.9%), and inhibiting CRP (19.2% vs 22.1%), although none of these differences were statistically significant.8 It could be that women are affected less than men by the traditional risk factors in the coronary tree and are affected by inflammation-related risk factors (eg, exercise, metabolic state, levels of CRP and other proinflammatory cytokines and peptides) much more than are men.
Can We Predict Coronary Artery Disease? Coronary vascular dysfunction is believed to be a precursor for atherosclerosis and a predictor of cardiovascular events.16–18 Impaired coronary reactivity to acetylcholine was found to predict poor outcome in patients with documented CAD. However, most of the studies were done in men, and it was not clear whether these data were relevant to women. To explore this question, 163 women were referred for coronary angiography, with quantitative coronary angiography and intracoronary Doppler flow measurements taken before and after intracoronary administration of acetylcholine, adenosine, and nitroglycerin. This trial was part of the Women’s Ischemia Syndrome Evaluation (WISE) study.19 All women who were referred for angiography had chest pain; however, 75.0% of the women had mild CAD. Over a median followup of 48 months, 58 of the 163 women (35.6%) had cardiovascular events. On bivariate analysis, women with an event had significantly less change in coronary cross-sectional area in response to acetylcholine (mean, –7.9%; P < 0.01) and to nitroglycerin (mean, 14.2%; P = 0.04) than did women without an event. Women with abnormal coronary response to acetylcholine had significantly less time free from cardiovascular events (P = 0.04). Apparently, after controlling for age, hypertension, DM, dyslipidemia, tobacco use, and CAD severity (using multivariate analysis), the change in coronary cross-sectional area with acetylcholine was the only independent factor that predicted cardiovascular events (P = 0.01).19 Coronary endothelial dysfunction appeared to be related to cardiovascular morbidity and mortality in women as well as in men, and because endothe-
lial dysfunction could be modified, it appeared that the prognosis could be improved by appropriate management.
Which Parameters Predict Clinical Outcome in Women? Traditional risk factors such as family history and hormonal state were found to be more prevalent in women with chest pain than in women without chest pain or in men with chest pain, without a direct correlation with CAD severity.8 The question was whether other nontraditional risk factors could predict clinical outcome in women. To explore this question, several clinical trials were designed to examine nontraditional risk factors. One study included 15,048 healthy, nondiabetic women >45 years of age who had participated in the Women’s Health Study20 and were followed up for 10 years. High-sensitivity CRP (hs-CRP) made a relative contribution to the global risk, similar to that provided by HDL-C, LDL-C, age, smoking, and elevated blood pressure. A global risk prediction model that included hs-CRP improved cardiovascular risk classification in women, particularly among those with a 10-year risk of 5% to 20%. In the analysis adjusted for age, systolic blood pressure, and smoking, the likelihood ratio statistic indicated that either hs-CRP or HDL-C improved goodness of fit more than did total or LDL-C. For both the model used by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP-III)21 and the final Women’s Health Study model,20 the likelihood ratio test for the inclusion of hs-CRP was statistically significant (P < 0.01). In models that included age, blood pressure, and smoking status, hs-CRP improved prediction at least as much as lipid measures. In another trial22 (part of the WISE study), 580 women were followed for 4.7 years after undergoing coronary angiography. Blood was drawn for detection of “proinflammatory” cytokines (interleukin-6, CRP, and serum amyloid type A), “anti-inflammatory” cytokines (interleukin-18 and tumor necrosis factor-α), and an “immunosuppressive” cluster (transforming growth factor-β). Scores for the proinflammation cluster were not
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associated with the extent of angiographic CAD, but were strongly associated with risk of death over a median of 4.7 years of follow-up. Forty-four (7.6%) of the 580 women died; 21 (47.7%) of the 44 women who died had at least 2 of the 3 proinflammatory cytokines in the upper quartile, compared with 103 (19.2%) of the 536 surviving women. Quartile increases of the proinflammatory cluster yielded death rates of 2.6%, 7.2%, 13.1%, and 26.6%, respectively (P < 0.001). These data suggest that the principal adverse contribution of the inflammatory cascade may not be the result of direct promotion of atherogenesis, but through other mechanisms such as destabilization of vulnerable plaques and plaque erosions. Another report from the WISE study evaluated the contribution of obesity to cardiovascular risk in women.21 BMI and the presence of the metabolic syndrome were studied in 780 women who were referred for coronary angiography to evaluate suspected myocardial ischemia. The prevalence of CAD and 3-year risk of developing a cardiovascular event were studied using BMI and metabolic status. It was found that BMI and metabolic status were strongly associated, but only the metabolic syndrome was associated with CAD. Compared with normal-weight women with normal metabolic status, dysmetabolic women who were normal weight, overweight, or obese had ~3.1 (P = 0.002), 2.6 (P < 0.001), and 1.9 (P = 0.01) times higher adjusted odds of having clinically significant angiographic CAD, respectively. Metabolic status conferred ~2-fold adjusted risks for death and major cardiovascular events.The 3-year survival rate was significantly higher in women with normal metabolic status than in those who were dysmetabolic (97.2% vs 91.5%; P = 0.003). Moreover, within levels of metabolic status, obese and overweight women appeared to have a better 3-year, eventfree survival than did those with normal BMI. The present data suggest that abnormal metabolism, manifested by the metabolic syndrome or DM, may explain this observation. Therefore, in addition to BMI, metabolic status should be evaluated in all women according to the NCEP ATP-III guidelines.
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Mechanisms That May Explain the Difference Three mechanisms may explain the difference in clinical outcomes between men and women: Nitric oxide pathway—Nitric oxide (NO) bioavailability and responsiveness were found to be greater in women with sickle cell disease than in their male counterparts.23 A large sex difference in mean blood flow responses was observed between female and male patients (340% [46%] vs 173% [41%]; P = 0.035).23 Similarly, basal NO bioactivity, as measured by the percent decrease in flow induced by L-NG-monomethyl arginine (L-NMMA), was depressed in men compared with women (–17% [5%] vs –34% [4%]; P = 0.01), as was the response to nitroprusside (86% [21%] vs 171% [22%]; P = 0.008). L-NMMA reduced the blood flow response to acetylcholine in women, but not in men. Sex differences in vascular cell adhesion molecule-1 (VCAM-1) were appreciated, with significant correlations between levels of soluble VCAM-1 and blood flow responses to L-NMMA and nitroprusside (r = 0.53, P = 0.004; and r = –0.66, P < 0.001, respectively). Endothelium-dependent blood flow was largely non-NO mediated in men. These results could provide a possible mechanism for sex differences in morbidity and mortality. Energy metabolism—Phosphorus-31 nuclear magnetic resonance spectroscopy is a noninvasive technique that can directly measure high-energy phosphates in the myocardium and identify metabolic evidence of ischemia. One study24 found that 7 of 35 women with chest pain and no angiographically significant coronary stenosis had decreases in the phosphocreatine:adenosine triphosphate ratio during handgrip exercise that were >2 SDs below the mean value in the control subjects without chest pain. No other significant differences were observed between the 2 groups, including brachial artery flow during the infusion of acetylcholine. These results provide direct evidence of an abnormal metabolic response to handgrip exercise in at least some women with chest pain and are consistent with the occurrence of myocardial ischemia but no angiographically significant coronary stenosis.
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Estrogen beneficial effects—Consecutive eligible subjects with CAD admitted for cardiac catheterization were studied.25 The groups that were evaluated included men, postmenopausal women receiving estrogen replacement therapy, postmenopausal women not receiving estrogen, and premenopausal women. Measurements of cell adhesion molecules like E-selectin, VCAM-1, and intercellular adhesion molecule-1 (ICAM-1) were performed. Levels of cell adhesion molecules were higher in men with CAD and postmenopausal women with CAD than in postmenopausal women with CAD who were receiving estrogen. In addition, statistically significant increases in E-selectin, ICAM-1, and VCAM-1 occurred in postmenopausal women with CAD who were not receiving estrogen compared with postmenopausal women with CAD who were receiving estrogen (all, P < 0.05). Thus, estrogen was associated with a decrease in all cell adhesion molecule levels in postmenopausal women with CAD (all, P < 0.05). A possible mechanism by which estrogen exerts one of its cardioprotective effects is limiting the inflammatory response to injury by modulating the expression of cell adhesion molecules from the endothelium.
Can Women at Risk Change Their Clinical Outcome? In the INTERHEART study,5 women experienced their first acute MI a mean of 9 years later in life than did men all over the world. As stated previously, the modifiable risk factors that were associated with acute MI in both women and men included abnormal lipid levels, smoking, abdominal obesity, dietary intake, and mental stress. However, hypertension, DM, physical activity, alcohol use, and former smoking differed between the sexes. Overall, significantly fewer women than men had abnormal lipid levels (24.3% vs 36.2%, respectively), were current (9.2% vs 33.0%) or former smokers (11.6% vs 24.7%), consumed a highrisk diet (17.9% vs 23.3%), performed regular physical activity (16.5% vs 20.3%), and drank alcohol (11.2% vs 29.1%) (all, P < 0.05). It appears that the lower MI burden among women at younger ages (two thirds of women with MI were >60 years of age compared with 40% of men) is
explained by the lower risk-factor burden, but it remains unclear why such a difference in risk factors exists. This study found that treating risk factors could be a common goal for both women and men to prevent acute MIs.5,26 To investigate the relationship between obesity and physical fitness, 936 women were enrolled in a trial27 (part of the WISE study) after undergoing clinically indicated coronary angiography and were then followed up for 3.9 years for adverse events. Overweight women were more likely than normal-weight women to have risk factors for CAD (P = 0.05), but neither BMI nor abdominal obesity was significantly associated with obstructive CAD or adverse cardiovascular events after adjusting for other risk factors. Conversely, women with lower Duke Activity Status Index (DASI) scores had more cardiovascular risk factors and obstructive coronary disease at baseline compared with women who had higher scores. A low DASI score was associated with a >2-fold risk of having obstructive CAD (hazard ratio, 2.21; 95% CI, 1.62–3.01; P = 0.01). Each 1-MET increase in the DASI score was associated with an 8% decrease in the risk of major adverse cardiovascular events during follow-up. From this study, we learned that physical activity is independently associated with fewer risk factors, less CAD, and fewer adverse events in women; however, obesity was not associated with these outcomes. Two recent clinical trials studied the issue of physical fitness and cardiovascular risk. In the first trial,28 brachial endothelial function and treadmill stress testing with gas-exchange analysis were performed in 90 consecutive women. Using multiple regression analysis, peak oxygen consumption (VO2) was the best predictor of brachial artery reactivity (P = 0.01). Even in the absence of routine exercise, cardiorespiratory fitness (but not conventional risk factors or BMI) was the dominant predictor of endothelial function and suggests a modifiable approach to risk. In the second trial,29 the effects of exercise on the endothelium (as a biomarker of risk) and the relationships between endothelial function and weight loss, lipid changes, and circulating endothelial progenitor stem cells (EPCs) were studied.
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Seventy-two subjects (58 women and 14 men) completed 3 months of participation in the National Heart, Lung, and Blood Institute’s “Keep the Beat” program, with determination of both peak VO2 during exercise and brachial artery function. Brachial artery endothelium was tested by flowmediated dilation (FMD), which was inversely associated with the Framingham risk score at baseline (r = –0.35; P = 0.01). EPCs were quantified by colony assay and by flow cytometry methods. After a mean of 98 minutes of exercise weekly, significant improvements in FMD and peak VO2 were noted (both, P < 0.05). Multiple regression analysis revealed that, taken together, lower baseline FMD, older age, reductions in total and LDL-C, and increases in EPC colonies and peak VO2 were predictors of change in FMD. Results were similar when modeling was performed for women only. Neither adiposity at baseline nor change in weight could predict the improved endothelial function.
Which Mechanism of Endothelial Function Is Improved by Exercise? Exercise may cause repetitive shear stress on the endothelium, with increased transcription or phosphorylation of the primary enzyme for NO synthesis, endothelial NO synthase.30 Exercise may also mobilize bone-marrow–derived EPCs into the circulation with attachment to arteries in the circulation and replacement of dysfunctional endothelium.31–33 The increase in EPC colonies made a small but statistically significant contribution to the improvement in endothelial function (P < 0.05).29
CONCLUSIONS Ischemic heart disease in women was and still is an enigma. The incidence gap for myocardial and vascular events between men and women is not well understood. However, we have learned from recent studies that women share the same risk factors as men, but are affected differently. Reduction of risk factors appears to be a common approach to fighting heart disease in both sexes. For women, weight and BMI are not as important as previously thought, but physical exercise and fitness are very
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important and can change risk factors and clinical outcomes more than any other known intervention. Data suggest that global inflammation may play an important role in women and may predict cardiovascular outcome in women much better than the traditional risk factors that have been used and proved for men.
ACKNOWLEDGMENT The authors have indicated that they have no conflicts of interest regarding the content of this article.
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8. Nicholls SJ, Wolski K, Sipahi I, et al. Rate of progression of coronary atherosclerotic plaque in women. J Am Coll Cardiol. 2007;49:1546–1551. 9. Shaw LJ, Heller GV, Travin MI, et al. Cost analysis of diagnostic testing for coronary artery disease in women with stable chest pain. Economics of Noninvasive Diagnosis (END) Study Group. J Nucl Cardiol. 1999;6:559–569. 10. Vaccarino V, Parsons L, Every NR, et al. Sex-based differences in early mortality after myocardial infarction. National Registry of Myocardial Infarction 2 Participants. N Engl J Med. 1999;341:217– 225. 11. Shaw LJ, Lewis JF, Hlatky MA, et al, for the National Heart, Lung and Blood Institute; American College of Cardiology Foundation. Women’s Ischemic Syndrome Evaluation: Current status and future research directions: Report of the National Heart, Lung and Blood Institute workshop: October 2– 4, 2002: Section 5: Gender-related risk factors for ischemic heart disease. Circulation. 2004;109:e56– e58. 12. Alter DA, Nayler CD, Austin PC, Tu JV. Biology or bias: Practice patterns and long-term outcomes for men and women with acute myocardial infarction. J Am Coll Cardiol. 2002;39:1909–1916. 13. Heart disease and stroke statistics—2005 update. Dallas, Tex: American Heart Association; 2004. 14. Vaccarino V, Krumholz HM, Yarzebski J, et al. Sex difference in 2-year mortality after hospital discharge for myocardial infarction. Ann Intern Med. 2001;134:173–181. 15. Pinsky JL, Jette AM, Branch LG, et al. The Framingham Disability Study: Relationship of various coronary heart disease manifestations to disability in older persons living in the community. Am J Public Health. 1990;80:1363–1367. 16. Suwaidi JA, Hamasaki S, Higano ST, et al. Longterm follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation. 2000;101:948–954. 17. Schächinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000;101:1899–1906. 18. Heitzer T, Schlinzig T, Krohn K, et al. Endothelial dysfunction, oxidative stress, and risk of cardio-
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Address correspondence to: Arnon Blum, MD, Department of Internal Medicine, Baruch-Padeh Poria Medical Center, Lower Galilee 15208, Israel. E-mail: [email protected]
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Coronary Artery Disease: Are Men and Women Created Equal? Arnon Blum, MD1; and Nava Blum, PhD2 1Department
of Internal Medicine, Baruch-Padeh Poria Medical Center, Lower Galilee, Israel; and 2Faculty of Social Welfare and Health Sciences, School of Public Health, Haifa University, Haifa, Israel
ABSTRACT Background: Ischemic heart disease in women is a difficult issue in cardiovascular medicine, mainly because of our lack of understanding of the early-stage mechanisms and symptoms. A better and earlier understanding of the pathophysiology of coronary artery disease (CAD) in women will enable us to detect ischemic heart disease earlier and prevent adverse clinical outcomes. Objectives: The aims of this article were to describe the phenomenon of ischemic heart disease in women, increase awareness of the difference between men and women in relation to ischemic heart disease, improve our understanding of the mechanisms that cause this difference, and identify new approaches for better and earlier detection and treatment of CAD in women. Methods: We conducted a search of the PubMed database for double-blind studies on the mechanistic pathways of CAD in women published in English within the past 10 years and epidemiologic studies published since 1970. Search terms included women and coronary artery disease and ischemic heart disease in women. Results: The literature search revealed 30 peer-reviewed articles pertaining to this issue. The incidence of CAD was markedly lower in women <60 years of age than in older women. After 60 years of age, the rate of CAD increased and reached the rate seen among men by the 8th decade of life. The gender difference in atherosclerosis in the coronary tree was particularly large in patients <55 years of age and remained large at older ages. The gender difference in the coronary bed was strikingly larger than in other vascular beds. Intensive risk-factor modification had a similar effect on plaque progression in both men and women. Coronary endothelial dysfunction appeared to be related to cardiovascular morbidity and mortality in women as well as in men, and because endothelial dysfunction could be modified, it appeared that the prognosis could be improved by appropriate management. A strong association was found between body mass index (BMI) and metabolic status, but only the metabolic syndrome was associated with CAD. Physical activity was independently associated with fewer risk factors, less CAD, and fewer adverse events in women; however, obesity was not associated with these outcomes. Conclusions: Results of the identified studies suggest that reduction of risk factors is a common approach to fighting heart disease in both sexes. It appears that for women, weight and BMI are not as important as previously thought, but physical exercise and fitness are very important and can change risk factors and clinical outcomes more than any other known intervention. Data suggest that global inflammation may play an important role in women and may predict cardiovascular outcome in women much better than the traditional risk factors that have been used and proved for men. (Gend Med. 2009;6:410–418) © Excerpta Medica Inc. Key words: ischemic heart disease in women, metabolic syndrome, BMI, exercise, endothelial progenitor stem cells. Accepted for publication April 21, 2009. © 2009 Excerpta Medica Inc. All rights reserved.
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doi:10.1016/j.genm.2009.09.005 1550-8579/$ - see front matter
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INTRODUCTION
Epidemiologic Studies
Ischemic heart disease in women is a difficult issue in cardiovascular medicine, mainly because of our lack of understanding of the early-stage mechanisms and symptoms. Heightened awareness of women at risk for coronary artery disease (CAD) is needed to allow early diagnosis. Inflammation and endothelial dysfunction are key elements, and both are linked to adverse outcomes, but nonendothelialdependent microvascular dysfunction is involved as well. A better and earlier understanding of the pathophysiology of CAD in women will enable earlier detection of ischemic heart disease and prevention of adverse clinical outcomes. The aims of this article were to describe the phenomenon of ischemic heart disease in women, increase awareness of the difference between men and women in relation to ischemic heart disease, improve our understanding of the mechanisms that cause this difference, and identify new approaches for better and earlier detection and treatment of CAD in women.
The incidence of CAD was markedly lower in women <60 years of age than in older women.1 The predicted probability of having an acute myocardial infarction (MI) at <60 years of age was higher among men than among women (60.6% vs 33.0%, respectively).1 After 60 years of age, the rate of CAD in women increased and reached the rate seen among men by the 8th decade of life.1,2 Based on data from the INTERHEART study,3 a global case–control study conducted in 6787 women in 52 countries, it appears that the lower MI burden among women at younger ages is largely explained by a lower risk-factor burden. The reasons for this decreased burden in younger women compared with men require further study.1,2 The Framingham study4 described risk factors for CAD in women (eg, high levels of LDL-C, smoking, high blood pressure, diabetes mellitus [DM], overweight, lack of physical activity), but was unable to explain the later age of first occurrence of MI among women compared with men. The INTERHEART study,5 designed to determine whether differences in risk factors existed between men and women across various age categories to help understand why acute MIs develop later in life in women than in men, found modifiable risk factors that could explain >90% of acute MIs in young and older individuals, both women and men, across all ethnic groups. The risk factors included abnormal lipid levels, current smoking, abdominal obesity, hypertension, DM, regular alcohol use, “unhealthy” diet, and psychological stress. This international study reported that women experienced their first acute MI 9 years later in life than did men (P < 0.01). The modifiable risk factors that were associated with acute MI in both men and women included abnormal lipid levels, smoking, abdominal obesity, dietary intake, and mental stress. However, hypertension, DM, physical activity, alcohol use, and former smoking differed between the sexes. The lower MI burden among women at younger ages appeared to be explained by the lower risk-factor burden, but the reason for such a difference is not understood. The INTERHEART study found that treating risk factors could be a common
METHODS We conducted a search of the PubMed database. We sought double-blind studies on the mechanistic pathways of CAD in women published in English within the past 10 years (with emphasis on the past 4 years) and epidemiologic studies published since 1970. The search terms included women and coronary artery disease and ischemic heart disease in women. For inclusion in this review, studies had to either be double-blind and compare objective data (eg, volume of coronary artery lesions) or be large epidemiologic studies that were published in peer-reviewed journals. Letters to the editor, case reports, and other types of studies were not included. Only studies that met the inclusion/exclusion criteria for selection were included in this review.
RESULTS The literature search identified 30 peer-reviewed articles that met the inclusion/exclusion criteria. All these papers served as the basis of this review, including the basic science mechanistic studies and the clinically oriented epidemiologic studies.
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goal for both women and men to prevent acute MIs. To better understand CAD in women, a prospective study6 compared degrees of coronary, carotid, peripheral, and aortic atherosclerosis in men and women aged >55 years from the population-based Rotterdam Study. In that study, 2013 participants had both coronary calcification and evidence of extracoronary atherosclerosis, including an increased intima-media thickness (IMT), a denser carotid plaque, a decreased ankle-arm index, and aortic calcification. The prospective study was the first to compare gender differences in atherosclerosis at different sites in the vascular tree. The investigators reported that the coronary calcium score (≥1000) was higher in men than in women in all age categories (>55 years); male:female odds ratios (ORs) were 7.8 (95% CI, 3.2–19.3), 5.4 (95% CI, 2.8–10.2), and 3.0 (95% CI, 1.7–5.2) in the lowest, middle, and highest age tertiles, respectively. A less-pronounced pattern was found for IMT and carotid plaque scores. For aortic calcification scores, the pattern was more heterogeneous, with less-obvious differences between men and women (male:female OR, 1.3).The gender difference in atherosclerosis in the coronary tree was particularly large (male:female OR, 6.9; 95% CI, 3.4–13.9) in patients 61 to 67 years of age and remained large (male:female OR, 2.7; 95% CI, 1.8–4.0) in patients 74 to 85 years of age. The gender difference was reported to be strikingly larger in the coronary bed than in other vascular beds (OR of 4.4 compared with 2.6 in the carotid arteries and 1.3 in the peripheral arteries). The ORs for IMT, carotid plaques, and aortic calcification did not show an obvious decline with increasing age; the age-adjusted ORs were 2.6, 2.7, and 1.3, respectively. Another study explored the effects of diet and lifestyle on primary prevention in women.7 The 84,129 women who participated in the Nurses’ Health Study were free of diagnosed CAD, cancer, or DM when they were enrolled in the follow-up study in 1980. Women in the low-risk group (3% of the population) had a relative risk of coronary events of 0.17 compared with all the other women. Eighty-two percent of coronary events in the study
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cohort could be attributed to lack of adherence to the low-risk lifestyle guidelines. The investigators concluded that, in women, adherence to lifestyle guidelines involving diet, exercise, and abstinence from smoking was associated with a very low risk of CAD. Why is there such a difference in the progression of coronary atherosclerosis between women and men? Which are the important prognostic factors that affect CAD in women?
Mechanistic Insights Rate of Atherosclerosis Progression and Prognosis The relationship between gender and the extent of coronary atherosclerosis was assessed by intravascular ultrasound in 978 women who participated in serial studies of atheroma progression.8 The parameters that were examined included the extent of the coronary atheroma and the change in response to therapy. It is important to mention that, compared with men, women had a lower prevalence of obstructive disease: women had less plaque in terms of mean (SD) percent atheroma volume (33.9% [10.2%] vs 37.8% [10.3%]; P < 0.01) and total atheroma volume (148.7 [66.6]3 vs 194.7 [84.3] mm3; P < 0.001)2,9–11 but tended to have a higher incidence of chest pain, and their clinical outcome after an event tended to be worse,10,12–14 a discrepancy that was accentuated with age.15 Women were more likely than men to have a history of hypertension; greater body mass index (BMI) (mean, 30.5 vs 29.0 kg/m2; P < 0.01); higher levels of LDL-C (mean, 137.0 vs 127.4 mg/dL; P = 0.01), HDL-C (mean, 46.3 vs 38.6 mg/dL; P < 0.01), triglycerides (mean, 180 vs 158 mg/dL; P = 0.02), and C-reactive protein (CRP) (mean, 4.8 vs 2.6 mg/L; P < 0.01); and increased systolic and diastolic blood pressures (80.5% of women, 63.5% of men). Despite the greater prevalence of risk factors in women than in men, women harbored less plaque. The mean percent atheroma volume was 33.3% in women and 37.4% in men (P < 0.01). Furthermore, intensive risk-factor modification had a similar effect on plaque progression in both men and women. Female subjects were as likely as male subjects to undergo substantial regression in lower-
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ing LDL-C levels (26.0% vs 25.0%), lowering systolic blood pressure (20.4% vs 21.9%), and inhibiting CRP (19.2% vs 22.1%), although none of these differences were statistically significant.8 It could be that women are affected less than men by the traditional risk factors in the coronary tree and are affected by inflammation-related risk factors (eg, exercise, metabolic state, levels of CRP and other proinflammatory cytokines and peptides) much more than are men.
Can We Predict Coronary Artery Disease? Coronary vascular dysfunction is believed to be a precursor for atherosclerosis and a predictor of cardiovascular events.16–18 Impaired coronary reactivity to acetylcholine was found to predict poor outcome in patients with documented CAD. However, most of the studies were done in men, and it was not clear whether these data were relevant to women. To explore this question, 163 women were referred for coronary angiography, with quantitative coronary angiography and intracoronary Doppler flow measurements taken before and after intracoronary administration of acetylcholine, adenosine, and nitroglycerin. This trial was part of the Women’s Ischemia Syndrome Evaluation (WISE) study.19 All women who were referred for angiography had chest pain; however, 75.0% of the women had mild CAD. Over a median followup of 48 months, 58 of the 163 women (35.6%) had cardiovascular events. On bivariate analysis, women with an event had significantly less change in coronary cross-sectional area in response to acetylcholine (mean, –7.9%; P < 0.01) and to nitroglycerin (mean, 14.2%; P = 0.04) than did women without an event. Women with abnormal coronary response to acetylcholine had significantly less time free from cardiovascular events (P = 0.04). Apparently, after controlling for age, hypertension, DM, dyslipidemia, tobacco use, and CAD severity (using multivariate analysis), the change in coronary cross-sectional area with acetylcholine was the only independent factor that predicted cardiovascular events (P = 0.01).19 Coronary endothelial dysfunction appeared to be related to cardiovascular morbidity and mortality in women as well as in men, and because endothe-
lial dysfunction could be modified, it appeared that the prognosis could be improved by appropriate management.
Which Parameters Predict Clinical Outcome in Women? Traditional risk factors such as family history and hormonal state were found to be more prevalent in women with chest pain than in women without chest pain or in men with chest pain, without a direct correlation with CAD severity.8 The question was whether other nontraditional risk factors could predict clinical outcome in women. To explore this question, several clinical trials were designed to examine nontraditional risk factors. One study included 15,048 healthy, nondiabetic women >45 years of age who had participated in the Women’s Health Study20 and were followed up for 10 years. High-sensitivity CRP (hs-CRP) made a relative contribution to the global risk, similar to that provided by HDL-C, LDL-C, age, smoking, and elevated blood pressure. A global risk prediction model that included hs-CRP improved cardiovascular risk classification in women, particularly among those with a 10-year risk of 5% to 20%. In the analysis adjusted for age, systolic blood pressure, and smoking, the likelihood ratio statistic indicated that either hs-CRP or HDL-C improved goodness of fit more than did total or LDL-C. For both the model used by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP-III)21 and the final Women’s Health Study model,20 the likelihood ratio test for the inclusion of hs-CRP was statistically significant (P < 0.01). In models that included age, blood pressure, and smoking status, hs-CRP improved prediction at least as much as lipid measures. In another trial22 (part of the WISE study), 580 women were followed for 4.7 years after undergoing coronary angiography. Blood was drawn for detection of “proinflammatory” cytokines (interleukin-6, CRP, and serum amyloid type A), “anti-inflammatory” cytokines (interleukin-18 and tumor necrosis factor-α), and an “immunosuppressive” cluster (transforming growth factor-β). Scores for the proinflammation cluster were not
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associated with the extent of angiographic CAD, but were strongly associated with risk of death over a median of 4.7 years of follow-up. Forty-four (7.6%) of the 580 women died; 21 (47.7%) of the 44 women who died had at least 2 of the 3 proinflammatory cytokines in the upper quartile, compared with 103 (19.2%) of the 536 surviving women. Quartile increases of the proinflammatory cluster yielded death rates of 2.6%, 7.2%, 13.1%, and 26.6%, respectively (P < 0.001). These data suggest that the principal adverse contribution of the inflammatory cascade may not be the result of direct promotion of atherogenesis, but through other mechanisms such as destabilization of vulnerable plaques and plaque erosions. Another report from the WISE study evaluated the contribution of obesity to cardiovascular risk in women.21 BMI and the presence of the metabolic syndrome were studied in 780 women who were referred for coronary angiography to evaluate suspected myocardial ischemia. The prevalence of CAD and 3-year risk of developing a cardiovascular event were studied using BMI and metabolic status. It was found that BMI and metabolic status were strongly associated, but only the metabolic syndrome was associated with CAD. Compared with normal-weight women with normal metabolic status, dysmetabolic women who were normal weight, overweight, or obese had ~3.1 (P = 0.002), 2.6 (P < 0.001), and 1.9 (P = 0.01) times higher adjusted odds of having clinically significant angiographic CAD, respectively. Metabolic status conferred ~2-fold adjusted risks for death and major cardiovascular events.The 3-year survival rate was significantly higher in women with normal metabolic status than in those who were dysmetabolic (97.2% vs 91.5%; P = 0.003). Moreover, within levels of metabolic status, obese and overweight women appeared to have a better 3-year, eventfree survival than did those with normal BMI. The present data suggest that abnormal metabolism, manifested by the metabolic syndrome or DM, may explain this observation. Therefore, in addition to BMI, metabolic status should be evaluated in all women according to the NCEP ATP-III guidelines.
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Mechanisms That May Explain the Difference Three mechanisms may explain the difference in clinical outcomes between men and women: Nitric oxide pathway—Nitric oxide (NO) bioavailability and responsiveness were found to be greater in women with sickle cell disease than in their male counterparts.23 A large sex difference in mean blood flow responses was observed between female and male patients (340% [46%] vs 173% [41%]; P = 0.035).23 Similarly, basal NO bioactivity, as measured by the percent decrease in flow induced by L-NG-monomethyl arginine (L-NMMA), was depressed in men compared with women (–17% [5%] vs –34% [4%]; P = 0.01), as was the response to nitroprusside (86% [21%] vs 171% [22%]; P = 0.008). L-NMMA reduced the blood flow response to acetylcholine in women, but not in men. Sex differences in vascular cell adhesion molecule-1 (VCAM-1) were appreciated, with significant correlations between levels of soluble VCAM-1 and blood flow responses to L-NMMA and nitroprusside (r = 0.53, P = 0.004; and r = –0.66, P < 0.001, respectively). Endothelium-dependent blood flow was largely non-NO mediated in men. These results could provide a possible mechanism for sex differences in morbidity and mortality. Energy metabolism—Phosphorus-31 nuclear magnetic resonance spectroscopy is a noninvasive technique that can directly measure high-energy phosphates in the myocardium and identify metabolic evidence of ischemia. One study24 found that 7 of 35 women with chest pain and no angiographically significant coronary stenosis had decreases in the phosphocreatine:adenosine triphosphate ratio during handgrip exercise that were >2 SDs below the mean value in the control subjects without chest pain. No other significant differences were observed between the 2 groups, including brachial artery flow during the infusion of acetylcholine. These results provide direct evidence of an abnormal metabolic response to handgrip exercise in at least some women with chest pain and are consistent with the occurrence of myocardial ischemia but no angiographically significant coronary stenosis.
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Estrogen beneficial effects—Consecutive eligible subjects with CAD admitted for cardiac catheterization were studied.25 The groups that were evaluated included men, postmenopausal women receiving estrogen replacement therapy, postmenopausal women not receiving estrogen, and premenopausal women. Measurements of cell adhesion molecules like E-selectin, VCAM-1, and intercellular adhesion molecule-1 (ICAM-1) were performed. Levels of cell adhesion molecules were higher in men with CAD and postmenopausal women with CAD than in postmenopausal women with CAD who were receiving estrogen. In addition, statistically significant increases in E-selectin, ICAM-1, and VCAM-1 occurred in postmenopausal women with CAD who were not receiving estrogen compared with postmenopausal women with CAD who were receiving estrogen (all, P < 0.05). Thus, estrogen was associated with a decrease in all cell adhesion molecule levels in postmenopausal women with CAD (all, P < 0.05). A possible mechanism by which estrogen exerts one of its cardioprotective effects is limiting the inflammatory response to injury by modulating the expression of cell adhesion molecules from the endothelium.
Can Women at Risk Change Their Clinical Outcome? In the INTERHEART study,5 women experienced their first acute MI a mean of 9 years later in life than did men all over the world. As stated previously, the modifiable risk factors that were associated with acute MI in both women and men included abnormal lipid levels, smoking, abdominal obesity, dietary intake, and mental stress. However, hypertension, DM, physical activity, alcohol use, and former smoking differed between the sexes. Overall, significantly fewer women than men had abnormal lipid levels (24.3% vs 36.2%, respectively), were current (9.2% vs 33.0%) or former smokers (11.6% vs 24.7%), consumed a highrisk diet (17.9% vs 23.3%), performed regular physical activity (16.5% vs 20.3%), and drank alcohol (11.2% vs 29.1%) (all, P < 0.05). It appears that the lower MI burden among women at younger ages (two thirds of women with MI were >60 years of age compared with 40% of men) is
explained by the lower risk-factor burden, but it remains unclear why such a difference in risk factors exists. This study found that treating risk factors could be a common goal for both women and men to prevent acute MIs.5,26 To investigate the relationship between obesity and physical fitness, 936 women were enrolled in a trial27 (part of the WISE study) after undergoing clinically indicated coronary angiography and were then followed up for 3.9 years for adverse events. Overweight women were more likely than normal-weight women to have risk factors for CAD (P = 0.05), but neither BMI nor abdominal obesity was significantly associated with obstructive CAD or adverse cardiovascular events after adjusting for other risk factors. Conversely, women with lower Duke Activity Status Index (DASI) scores had more cardiovascular risk factors and obstructive coronary disease at baseline compared with women who had higher scores. A low DASI score was associated with a >2-fold risk of having obstructive CAD (hazard ratio, 2.21; 95% CI, 1.62–3.01; P = 0.01). Each 1-MET increase in the DASI score was associated with an 8% decrease in the risk of major adverse cardiovascular events during follow-up. From this study, we learned that physical activity is independently associated with fewer risk factors, less CAD, and fewer adverse events in women; however, obesity was not associated with these outcomes. Two recent clinical trials studied the issue of physical fitness and cardiovascular risk. In the first trial,28 brachial endothelial function and treadmill stress testing with gas-exchange analysis were performed in 90 consecutive women. Using multiple regression analysis, peak oxygen consumption (VO2) was the best predictor of brachial artery reactivity (P = 0.01). Even in the absence of routine exercise, cardiorespiratory fitness (but not conventional risk factors or BMI) was the dominant predictor of endothelial function and suggests a modifiable approach to risk. In the second trial,29 the effects of exercise on the endothelium (as a biomarker of risk) and the relationships between endothelial function and weight loss, lipid changes, and circulating endothelial progenitor stem cells (EPCs) were studied.
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Seventy-two subjects (58 women and 14 men) completed 3 months of participation in the National Heart, Lung, and Blood Institute’s “Keep the Beat” program, with determination of both peak VO2 during exercise and brachial artery function. Brachial artery endothelium was tested by flowmediated dilation (FMD), which was inversely associated with the Framingham risk score at baseline (r = –0.35; P = 0.01). EPCs were quantified by colony assay and by flow cytometry methods. After a mean of 98 minutes of exercise weekly, significant improvements in FMD and peak VO2 were noted (both, P < 0.05). Multiple regression analysis revealed that, taken together, lower baseline FMD, older age, reductions in total and LDL-C, and increases in EPC colonies and peak VO2 were predictors of change in FMD. Results were similar when modeling was performed for women only. Neither adiposity at baseline nor change in weight could predict the improved endothelial function.
Which Mechanism of Endothelial Function Is Improved by Exercise? Exercise may cause repetitive shear stress on the endothelium, with increased transcription or phosphorylation of the primary enzyme for NO synthesis, endothelial NO synthase.30 Exercise may also mobilize bone-marrow–derived EPCs into the circulation with attachment to arteries in the circulation and replacement of dysfunctional endothelium.31–33 The increase in EPC colonies made a small but statistically significant contribution to the improvement in endothelial function (P < 0.05).29
CONCLUSIONS Ischemic heart disease in women was and still is an enigma. The incidence gap for myocardial and vascular events between men and women is not well understood. However, we have learned from recent studies that women share the same risk factors as men, but are affected differently. Reduction of risk factors appears to be a common approach to fighting heart disease in both sexes. For women, weight and BMI are not as important as previously thought, but physical exercise and fitness are very
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important and can change risk factors and clinical outcomes more than any other known intervention. Data suggest that global inflammation may play an important role in women and may predict cardiovascular outcome in women much better than the traditional risk factors that have been used and proved for men.
ACKNOWLEDGMENT The authors have indicated that they have no conflicts of interest regarding the content of this article.
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Address correspondence to: Arnon Blum, MD, Department of Internal Medicine, Baruch-Padeh Poria Medical Center, Lower Galilee 15208, Israel. E-mail: [email protected]
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