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Usefulness of Peak Oxygen Consumption in Predicting Outcome of Heart Failure in Women Versus Men
Usefulness of Peak Oxygen Consumption in Predicting Outcome of Heart Failure in Women Versus Men David R. Richards, DO, Mandeep R. Mehra, MD, Hector O. Ventura, MD, Carl J. Lavie, MD, Frank W. Smart, MD, Dwight D. Stapleton, MD, and Richard V. Milani, MD he application of cardiopulmonary stress testing in T categorizing the severity of heart failure was first described by Weber and Janicki in 1982. Subse1
2
quently, Szlachcic et al investigated the prognostic utility of cardiopulmonary stress testing for heart failure and found a correlation between peak oxygen consumption and mortality.2 In the past decade, multiple studies have confirmed this association and have found peak oxygen consumption to be a strong independent predictor of mortality2–7. Although women were included in most of these studies, they composed only a small fraction of the study population.2–7 These gender differences have only been sparsely studied and warrant further evaluation. The present study examines whether a genderspecific difference exists in the ability of peak oxygen consumption to risk stratify ambulatory heart failure patients, and analyzes the potentially greater discriminatory ability of percent of predicted maximum oxygen consumption, an age- and gender-adjusted measurement, as a better outcome determinant in women with heart failure. •••
Between November 1992 and August 1994, patients undergoing outpatient heart transplantation evaluation, who were referred to our noninvasive laboratory for cardiopulmonary stress testing, were examined for possible enrollment into this prospective observational study. Entry criteria included moderate to moderately severe heart failure symptoms (New York Heart Association functional classes II to III), left ventricular ejection fraction #40%, no symptomatic change on maximum medical therapy for 6 weeks, and an ability to exercise on a treadmill. Exclusion criteria included unstable ischemic symptoms, uncontrolled severe hypertension, and inability to undergo treadmill exercise testing. Seventy-six patients were enrolled and followed prospectively for a mean period of 12 months (range 9 to 25). An adverse clinical event was defined prospectively as the occurrence of cardiac death or heart transplantation. Ejection fraction was measured within 3 months of the cardiopulmonary stress testing. The etiologic diagnosis of ischemic cardiomyopathy was established by the demonstration of angiographic or nuclear imaging evidence of coronary artery disease. Four of the From the Department of Internal Medicine, Section of Cardiology, Ochsner Medical Institutions, New Orleans, Louisiana. Dr. Milani’s address is: Department of Cardiology, Ochsner Medical Institutions, 1514 Jefferson Highway, New Orleans, Louisiana 70121. Manuscript received April 8, 1997; revised manuscript received and accepted June 26, 1997.
1236
©1997 by Excerpta Medica, Inc. All rights reserved.
cases of non ischemic-dilated cardiomyopathy did not have documentation of their coronary anatomy. Cardiopulmonary stress testing was performed using an individually tailored ramping protocol designed to yield a test duration of 8 to 12 minutes.8 Minute ventilation, oxygen consumption, and carbon dioxide production were recorded using a Medgraphics CPX/D metabolic cart (Vadnais Heights, Minnesota), providing incremental data every 15 seconds. The test was carried out to maximum effort with a goal of reaching a respiratory exchange ratio of .1.0. Percent of predicted maximum oxygen consumption was calculated by the Wasserman et al formula.9 Patients were prospectively followed until May 1995 when their clinical records and cardiopulmonary stress testing data were analyzed. Two groups were formed on the basis of gender and were compared on the basis of demographics, metabolic parameters (peak oxygen consumption and percent of predicted oxygen consumption), and event-free survival. Groups were compared using a student’s t test or chi-square analysis as appropriate. Results were reported as mean 6 1 SD, and a p value #0.05 was considered significant. Event-free survival was computed by the Kaplan-Meier method. Seventy-six patients with New York Heart Association II or III heart failure symptoms were entered into the study. Clinical characteristics are outlined in Table I. Patients were followed for a mean duration of 12 6 3 months (range 9 to 25). There were 55 men (72%) and 21 women (28%) with a mean age of 51 6 11 years (range 16 to 69). Ischemic cardiomyopathy was more prevalent (n 5 12) than dilated cardiomyopathy (n 5 34). Twenty-two of 76 (28.9%) patients were listed for transplantation. Fourteen of these patients were alive at follow-up, 1 patient had died, and 7 patients were transplanted. Of the 54 patients not listed, 10 were deferred for noncardiac reasons, and 44 were deferred because their functional capacity did not meet transplant criteria. Forty-seven of these patients were alive at follow-up and 7 patients died. Five of the 7 who died had been deferred because their functional capacity was above the transplant criteria; the other 2 had been deferred for noncardiac reasons. Sixty-six patients (87%) achieved a respiratory exchange ratio of .1.0, indicating good patient effort. Of the patients who did not reach a respiratory exchange ratio of .1.0 (n 5 10), 6 were men and 4 were women. The mean peak oxygen consumption was 17.6 6 5.0 ml/kg/min, and the mean percent of predicted maximum oxygen consumption was 66.4 6 17.8%. Of the 55 men, there were 30 patients (60%) with 0002-9149/97/$17.00 PII S0002-9149(97)00651-6
tion was examined, it was found to be a more accurate predictor of surAll (n 5 76) Men (n 5 55) Women (n 5 21) vival in women and provided a more refined outcome assessment parameAge (yrs) 51 6 11 51 6 12 49 6 9 ter for women with systolic heart Weight (kg) 86.2 6 16.2 89.1 6 15.5 72.7 6 12.3* Ischemic cardiomyopathy 42 (55%) 33 (60%) 7 (33%)† failure. † Dilated cardiomyopathy 34 (45%) 22 (40%) 14 (67%) Previous studies of the prognostic Ejection fraction 19 6 10 19 6 9 20 6 11 utility of peak oxygen consumption NYHA Class 2.7 6 0.9 2.7 6 0.9 2.6 6 0.9 in heart failure patients have studied Peak VO2 (ml/kg/m) 17.6 6 5.0 18.3 6 5.2 14.5 6 2.3* PPVO2 max (%) 66.4 6 17.8 65.5 6 18.1 75.4 6 16.8‡ predominantly male populations Respiratory exchange ratio 1.14 6 0.17 1.14 6 0.17 1.08 6 0.18 with women comprising only a sparse fraction of the patients in *p 5 0.001; †p ,0.05 (women compared with men); ‡p 5 0.03 between gender. NYHA 5 New York Heart Association; PPVO2 max 5 percent of predicted maximum oxygen these studies (0% to 30%).2–7 Addiconsumption; RER 5 respiratory exchange ratio; VO2 5 oxygen consumption. tionally, much information has been extracted from 2 major studies regarding predictors of mortality in heart failure, yet of the 1,446 patients in these 2 studies, none were women.10,11 Furthermore, information gained from these studies in men is commonly extrapolated to the risk stratification of all heart failure subsets, including women. However, we have learned that conclusions drawn from other types of cardiac studies (i.e., coronary atherosclerosis and hyperlipidemia) in men cannot be successfully extrapolated for women.12–15 Therefore, applying clinical decision trees from heart failure studies performed predominantly in male heart failure patients remains suspect. The event-free survival for men and women in this study was significantly different (p 5 0.01). Ninetyfive percent of the female group and 75% of their FIGURE 1. Event-free actuarial survival by gender. counterparts had an event-free 1-year survival. It is not clear why the women in this study had a survival advantage over men, but it may be related to a differischemic cardiomyopathy and 22 patients (40%) with ent natural history of systolic heart failure in women.16 dilated cardiomyopathy. Fourteen women (67%) had The Framingham data further supports the concept dilated cardiomyopathy (p ,0.05). Gender did not that women enjoy an enhanced survival advantage differ significantly in terms of age or ejection fraction. during heart failure.16,17 Previous studies in healthy men and women have The 2 groups did differ significantly in their peak aerobic capacity (Table I), with a mean peak oxygen demonstrated a gender-based difference in peak aeroconsumption of 18.3 ml/kg/min for men and 14.5 bic capacity. Women are known to achieve lower peak ml/kg/min for women (p 5 0.01). Conversely, the oxygen consumption with exercise compared with gender-specific percent of predicted maximum oxygen healthy men,18,19 and this difference appears to persist consumption was significantly higher in women than even after endurance training.19 The possibilities for these gender differences may be related to a smaller men (75.4% vs 65.5%; p 5 0.03). Women comprised 27% of the patients (6 of 22) degree of stroke volume augmentation and a greater listed for transplantation and 28% of the patients (15 degree of peripheral oxygen extraction in women durof 54) deferred from transplantation, which is similar ing exercise.20 Women also have a higher percent of to the representation of women in the study group. Six non-oxygen consuming body fat than men, and beof 7 transplants (86%) and 8 of 8 deaths were limited cause weight adjusted peak oxygen consumption is to the male cohort. With only 1 clinical event (trans- not adjusted to lean body mass, this may lead to a plant), women in this study had a higher event-free ‘‘pseudo’’ reduction of peak oxygen consumption in survival rate (Figure 1) (95% vs 75%; p 5 0.01) than women. Therefore, criteria for transplantation based men, despite lower mean peak oxygen consumption. on peak oxygen consumption may actually lead to Figure 2 shows the comparison of peak oxygen con- unwarranted advanced therapy of otherwise stable fesumption and percent of predicted oxygen consump- male patients who possess a lower, and possibly ‘‘relatively appropriate,’’ peak oxygen consumption. tion based on gender and clinical events. TABLE I Patient Demographics
•••
Women with heart failure were found to have a better 1-year survival than men, despite demonstrating a lower peak oxygen uptake. Conversely, when gender-adjusted percent of predicted oxygen consump-
In conclusion, this investigation finds that percent of predicted maximum oxygen consumption, an age- and gender-adjusted measure of exercise capacity, describes the degree of functional impairBRIEF REPORTS
1237
FIGURE 2. A, comparison of peak oxygen consumption (VO2) and cardiac event rates by gender. B, comparison of percent of predicted maximum oxygen consumption (PPVO2) and cardiac event rates by gender. Note that despite a lower mean peak oxygen consumption in women, the event rate was significantly lower in men.
ment in women more accurately than peak oxygen consumption. This evidence must be considered when cardiopulmonary metabolic parameters are used for prognostic stratification of women with heart failure. 1. Weber KT, Janicki JS. Cardiopulmonary exercise testing for evaluation of
chronic cardiac failure. Am J Cardiol 1985;55:22A–31A. 2. Szlachchic J, Massie BM, Kramer BL, Topic N, Tubau J. Correlates and
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prognostic implication of exercise capacity in chronic congestive heart failure. Am J Cardiol 1985;55:1037–1042. 3. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH, Wilson JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 1991;83:778 – 86. 4. Cohn JN, Johnson MS, Shabetai R, Loeb H, Tristani F, Rector T, Smith R, Fletcher R. Ejection fraction, peak exercise oxygen consumption, cardiothoracic ratio, ventricular arrhythmias, and plasma norepinephrine as determinants of prognosis in heart failure. Circulation 1993;87(suppl VI):VI-5–VI-16. 5. Willens HJ, Blevins RD, Wrisley D, Antonishen D, Reinstein D, Rubenfire M. The prognostic value of functional capacity in patients with mild to moderate heart failure. Am Heart J 1987;114:377. 6. Cohn JN, Rector TS. Prognosis of congestive heart failure and predictors of mortality. Am J Cardiol 1988;62:25A–30A. 7. Pin˜a IL, Fitzpatrick JT. Exercise and heart failure. A review. Chest 1996;110: 1317–1327. 8. Milani RV, Lavie CJ, Spiva H. Limitations of estimating metabolic equivalents in exercise assessment in patients with coronary artery disease. Am J Cardiol 1995;75:940 – 42. 9. Wasserman K, Hansen JE, Sue DY, Whipp BJ. Principles of Exercise Testing and Interpretation. Philadelphia: Lea & Febiger, 1986:73. 10. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, Dunkman WB, Jacobs W, Florh KH, Goldman S, Cobb FR, Shah PM, Saunders R, Fletcher RD, Loeb HS, Hughes VC, Baker B. Veterans administration cooperative study on vasodilator therapy of heart failure: influence of prerandomization variables on the reduction of mortality by treatment with hydralazine and isosorbide dinitrate. Circulation 1987;75(suppl IV):IV-49 –IV-54. 11. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wong M, Bhat G, Goldman S, Fletcher RD, Doherty J, Hughes CV, Carson P, Cintron G, Shabetai R, Haakenson C. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303–310. 12. La Rosa JC. Lipids and Cardiovascular Disease: Do the findings and therapy apply equally to men and women? Women’s Health Issues 1992;2:102–11. 13. Cannel WB, Wilson PWF. Risk factors that attenuate the female coronary disease advantage. Arch Intern Med 1995;155:57– 61. 14. Kuhn FE, Rackley CE. Coronary artery disease in women: risk factors, evaluation, treatment, and prevention. Arch Intern Med 1993;153:2626 –2636. 15. Wenger NK, Speroff L, Packard B. Cardiovascular health and disease in women. N Engl J Med 1993;329:247–256. 16. Ho KKL, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol 1993;22(suppl A):6A–13A. 17. Johnson MR. Heart failure in women: a special approach? J Heart Lung Transplant 1994;13(4):S130 –134. 18. Toth MJ, Gardner AW, Ades PA, Poehlman ET. Contribution of body composition and physical activity to age-related decline in peak VO2 in men and women. J Appl Physiol 1994;77:647– 652. 19. Spina RJ, Ogawa T, Kohrt WM, Martin WH, Holloszy JO, Ehsani AA. Differences in cardiovascular adaptations to endurance exercise training between older men and women. J Am Physiol 1993;75:849 – 855. 20. Fagard RH, Thijs LB, Amery AK. The effect of gender on aerobic power and exercise hemodynamics in hypertensive adults. Med Sci Sports Exerc 1995;27:29 –34.
NOVEMBER 1, 1997
2
quently, Szlachcic et al investigated the prognostic utility of cardiopulmonary stress testing for heart failure and found a correlation between peak oxygen consumption and mortality.2 In the past decade, multiple studies have confirmed this association and have found peak oxygen consumption to be a strong independent predictor of mortality2–7. Although women were included in most of these studies, they composed only a small fraction of the study population.2–7 These gender differences have only been sparsely studied and warrant further evaluation. The present study examines whether a genderspecific difference exists in the ability of peak oxygen consumption to risk stratify ambulatory heart failure patients, and analyzes the potentially greater discriminatory ability of percent of predicted maximum oxygen consumption, an age- and gender-adjusted measurement, as a better outcome determinant in women with heart failure. •••
Between November 1992 and August 1994, patients undergoing outpatient heart transplantation evaluation, who were referred to our noninvasive laboratory for cardiopulmonary stress testing, were examined for possible enrollment into this prospective observational study. Entry criteria included moderate to moderately severe heart failure symptoms (New York Heart Association functional classes II to III), left ventricular ejection fraction #40%, no symptomatic change on maximum medical therapy for 6 weeks, and an ability to exercise on a treadmill. Exclusion criteria included unstable ischemic symptoms, uncontrolled severe hypertension, and inability to undergo treadmill exercise testing. Seventy-six patients were enrolled and followed prospectively for a mean period of 12 months (range 9 to 25). An adverse clinical event was defined prospectively as the occurrence of cardiac death or heart transplantation. Ejection fraction was measured within 3 months of the cardiopulmonary stress testing. The etiologic diagnosis of ischemic cardiomyopathy was established by the demonstration of angiographic or nuclear imaging evidence of coronary artery disease. Four of the From the Department of Internal Medicine, Section of Cardiology, Ochsner Medical Institutions, New Orleans, Louisiana. Dr. Milani’s address is: Department of Cardiology, Ochsner Medical Institutions, 1514 Jefferson Highway, New Orleans, Louisiana 70121. Manuscript received April 8, 1997; revised manuscript received and accepted June 26, 1997.
1236
©1997 by Excerpta Medica, Inc. All rights reserved.
cases of non ischemic-dilated cardiomyopathy did not have documentation of their coronary anatomy. Cardiopulmonary stress testing was performed using an individually tailored ramping protocol designed to yield a test duration of 8 to 12 minutes.8 Minute ventilation, oxygen consumption, and carbon dioxide production were recorded using a Medgraphics CPX/D metabolic cart (Vadnais Heights, Minnesota), providing incremental data every 15 seconds. The test was carried out to maximum effort with a goal of reaching a respiratory exchange ratio of .1.0. Percent of predicted maximum oxygen consumption was calculated by the Wasserman et al formula.9 Patients were prospectively followed until May 1995 when their clinical records and cardiopulmonary stress testing data were analyzed. Two groups were formed on the basis of gender and were compared on the basis of demographics, metabolic parameters (peak oxygen consumption and percent of predicted oxygen consumption), and event-free survival. Groups were compared using a student’s t test or chi-square analysis as appropriate. Results were reported as mean 6 1 SD, and a p value #0.05 was considered significant. Event-free survival was computed by the Kaplan-Meier method. Seventy-six patients with New York Heart Association II or III heart failure symptoms were entered into the study. Clinical characteristics are outlined in Table I. Patients were followed for a mean duration of 12 6 3 months (range 9 to 25). There were 55 men (72%) and 21 women (28%) with a mean age of 51 6 11 years (range 16 to 69). Ischemic cardiomyopathy was more prevalent (n 5 12) than dilated cardiomyopathy (n 5 34). Twenty-two of 76 (28.9%) patients were listed for transplantation. Fourteen of these patients were alive at follow-up, 1 patient had died, and 7 patients were transplanted. Of the 54 patients not listed, 10 were deferred for noncardiac reasons, and 44 were deferred because their functional capacity did not meet transplant criteria. Forty-seven of these patients were alive at follow-up and 7 patients died. Five of the 7 who died had been deferred because their functional capacity was above the transplant criteria; the other 2 had been deferred for noncardiac reasons. Sixty-six patients (87%) achieved a respiratory exchange ratio of .1.0, indicating good patient effort. Of the patients who did not reach a respiratory exchange ratio of .1.0 (n 5 10), 6 were men and 4 were women. The mean peak oxygen consumption was 17.6 6 5.0 ml/kg/min, and the mean percent of predicted maximum oxygen consumption was 66.4 6 17.8%. Of the 55 men, there were 30 patients (60%) with 0002-9149/97/$17.00 PII S0002-9149(97)00651-6
tion was examined, it was found to be a more accurate predictor of surAll (n 5 76) Men (n 5 55) Women (n 5 21) vival in women and provided a more refined outcome assessment parameAge (yrs) 51 6 11 51 6 12 49 6 9 ter for women with systolic heart Weight (kg) 86.2 6 16.2 89.1 6 15.5 72.7 6 12.3* Ischemic cardiomyopathy 42 (55%) 33 (60%) 7 (33%)† failure. † Dilated cardiomyopathy 34 (45%) 22 (40%) 14 (67%) Previous studies of the prognostic Ejection fraction 19 6 10 19 6 9 20 6 11 utility of peak oxygen consumption NYHA Class 2.7 6 0.9 2.7 6 0.9 2.6 6 0.9 in heart failure patients have studied Peak VO2 (ml/kg/m) 17.6 6 5.0 18.3 6 5.2 14.5 6 2.3* PPVO2 max (%) 66.4 6 17.8 65.5 6 18.1 75.4 6 16.8‡ predominantly male populations Respiratory exchange ratio 1.14 6 0.17 1.14 6 0.17 1.08 6 0.18 with women comprising only a sparse fraction of the patients in *p 5 0.001; †p ,0.05 (women compared with men); ‡p 5 0.03 between gender. NYHA 5 New York Heart Association; PPVO2 max 5 percent of predicted maximum oxygen these studies (0% to 30%).2–7 Addiconsumption; RER 5 respiratory exchange ratio; VO2 5 oxygen consumption. tionally, much information has been extracted from 2 major studies regarding predictors of mortality in heart failure, yet of the 1,446 patients in these 2 studies, none were women.10,11 Furthermore, information gained from these studies in men is commonly extrapolated to the risk stratification of all heart failure subsets, including women. However, we have learned that conclusions drawn from other types of cardiac studies (i.e., coronary atherosclerosis and hyperlipidemia) in men cannot be successfully extrapolated for women.12–15 Therefore, applying clinical decision trees from heart failure studies performed predominantly in male heart failure patients remains suspect. The event-free survival for men and women in this study was significantly different (p 5 0.01). Ninetyfive percent of the female group and 75% of their FIGURE 1. Event-free actuarial survival by gender. counterparts had an event-free 1-year survival. It is not clear why the women in this study had a survival advantage over men, but it may be related to a differischemic cardiomyopathy and 22 patients (40%) with ent natural history of systolic heart failure in women.16 dilated cardiomyopathy. Fourteen women (67%) had The Framingham data further supports the concept dilated cardiomyopathy (p ,0.05). Gender did not that women enjoy an enhanced survival advantage differ significantly in terms of age or ejection fraction. during heart failure.16,17 Previous studies in healthy men and women have The 2 groups did differ significantly in their peak aerobic capacity (Table I), with a mean peak oxygen demonstrated a gender-based difference in peak aeroconsumption of 18.3 ml/kg/min for men and 14.5 bic capacity. Women are known to achieve lower peak ml/kg/min for women (p 5 0.01). Conversely, the oxygen consumption with exercise compared with gender-specific percent of predicted maximum oxygen healthy men,18,19 and this difference appears to persist consumption was significantly higher in women than even after endurance training.19 The possibilities for these gender differences may be related to a smaller men (75.4% vs 65.5%; p 5 0.03). Women comprised 27% of the patients (6 of 22) degree of stroke volume augmentation and a greater listed for transplantation and 28% of the patients (15 degree of peripheral oxygen extraction in women durof 54) deferred from transplantation, which is similar ing exercise.20 Women also have a higher percent of to the representation of women in the study group. Six non-oxygen consuming body fat than men, and beof 7 transplants (86%) and 8 of 8 deaths were limited cause weight adjusted peak oxygen consumption is to the male cohort. With only 1 clinical event (trans- not adjusted to lean body mass, this may lead to a plant), women in this study had a higher event-free ‘‘pseudo’’ reduction of peak oxygen consumption in survival rate (Figure 1) (95% vs 75%; p 5 0.01) than women. Therefore, criteria for transplantation based men, despite lower mean peak oxygen consumption. on peak oxygen consumption may actually lead to Figure 2 shows the comparison of peak oxygen con- unwarranted advanced therapy of otherwise stable fesumption and percent of predicted oxygen consump- male patients who possess a lower, and possibly ‘‘relatively appropriate,’’ peak oxygen consumption. tion based on gender and clinical events. TABLE I Patient Demographics
•••
Women with heart failure were found to have a better 1-year survival than men, despite demonstrating a lower peak oxygen uptake. Conversely, when gender-adjusted percent of predicted oxygen consump-
In conclusion, this investigation finds that percent of predicted maximum oxygen consumption, an age- and gender-adjusted measure of exercise capacity, describes the degree of functional impairBRIEF REPORTS
1237
FIGURE 2. A, comparison of peak oxygen consumption (VO2) and cardiac event rates by gender. B, comparison of percent of predicted maximum oxygen consumption (PPVO2) and cardiac event rates by gender. Note that despite a lower mean peak oxygen consumption in women, the event rate was significantly lower in men.
ment in women more accurately than peak oxygen consumption. This evidence must be considered when cardiopulmonary metabolic parameters are used for prognostic stratification of women with heart failure. 1. Weber KT, Janicki JS. Cardiopulmonary exercise testing for evaluation of
chronic cardiac failure. Am J Cardiol 1985;55:22A–31A. 2. Szlachchic J, Massie BM, Kramer BL, Topic N, Tubau J. Correlates and
1238
THE AMERICAN JOURNAL OF CARDIOLOGYT
VOL. 80
prognostic implication of exercise capacity in chronic congestive heart failure. Am J Cardiol 1985;55:1037–1042. 3. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH, Wilson JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 1991;83:778 – 86. 4. Cohn JN, Johnson MS, Shabetai R, Loeb H, Tristani F, Rector T, Smith R, Fletcher R. Ejection fraction, peak exercise oxygen consumption, cardiothoracic ratio, ventricular arrhythmias, and plasma norepinephrine as determinants of prognosis in heart failure. Circulation 1993;87(suppl VI):VI-5–VI-16. 5. Willens HJ, Blevins RD, Wrisley D, Antonishen D, Reinstein D, Rubenfire M. The prognostic value of functional capacity in patients with mild to moderate heart failure. Am Heart J 1987;114:377. 6. Cohn JN, Rector TS. Prognosis of congestive heart failure and predictors of mortality. Am J Cardiol 1988;62:25A–30A. 7. Pin˜a IL, Fitzpatrick JT. Exercise and heart failure. A review. Chest 1996;110: 1317–1327. 8. Milani RV, Lavie CJ, Spiva H. Limitations of estimating metabolic equivalents in exercise assessment in patients with coronary artery disease. Am J Cardiol 1995;75:940 – 42. 9. Wasserman K, Hansen JE, Sue DY, Whipp BJ. Principles of Exercise Testing and Interpretation. Philadelphia: Lea & Febiger, 1986:73. 10. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, Dunkman WB, Jacobs W, Florh KH, Goldman S, Cobb FR, Shah PM, Saunders R, Fletcher RD, Loeb HS, Hughes VC, Baker B. Veterans administration cooperative study on vasodilator therapy of heart failure: influence of prerandomization variables on the reduction of mortality by treatment with hydralazine and isosorbide dinitrate. Circulation 1987;75(suppl IV):IV-49 –IV-54. 11. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wong M, Bhat G, Goldman S, Fletcher RD, Doherty J, Hughes CV, Carson P, Cintron G, Shabetai R, Haakenson C. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303–310. 12. La Rosa JC. Lipids and Cardiovascular Disease: Do the findings and therapy apply equally to men and women? Women’s Health Issues 1992;2:102–11. 13. Cannel WB, Wilson PWF. Risk factors that attenuate the female coronary disease advantage. Arch Intern Med 1995;155:57– 61. 14. Kuhn FE, Rackley CE. Coronary artery disease in women: risk factors, evaluation, treatment, and prevention. Arch Intern Med 1993;153:2626 –2636. 15. Wenger NK, Speroff L, Packard B. Cardiovascular health and disease in women. N Engl J Med 1993;329:247–256. 16. Ho KKL, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol 1993;22(suppl A):6A–13A. 17. Johnson MR. Heart failure in women: a special approach? J Heart Lung Transplant 1994;13(4):S130 –134. 18. Toth MJ, Gardner AW, Ades PA, Poehlman ET. Contribution of body composition and physical activity to age-related decline in peak VO2 in men and women. J Appl Physiol 1994;77:647– 652. 19. Spina RJ, Ogawa T, Kohrt WM, Martin WH, Holloszy JO, Ehsani AA. Differences in cardiovascular adaptations to endurance exercise training between older men and women. J Am Physiol 1993;75:849 – 855. 20. Fagard RH, Thijs LB, Amery AK. The effect of gender on aerobic power and exercise hemodynamics in hypertensive adults. Med Sci Sports Exerc 1995;27:29 –34.
NOVEMBER 1, 1997