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J Thorac Cardiovasc Surg 2004;127:1247-1252
© 2004 The American Association for Thoracic Surgery

Editorial

Is it important to examine gender differences in the epidemiology and outcome of severe heart failure?

Mariell Jessup, MDa,*, Ileana L. Piña, MDb

a University of Pennsylvania, Philadelphia, Pa, USA
b Case Western Reserve University, Cleveland, Ohio, USA

Received for publication July 29, 2003; accepted for publication September 9, 2003.

* Address for reprints: Mariell Jessup, MD, Heart Failure/Transplant Program, Hospital of the University of Pennsylvania, 6 Penn Tower, 3400 Spruce St, Philadelphia, PA 19104, USA
jessupm{at}uphs.upenn.edu


See related editorials on pages 1245 and 1253.

 

Nearly 5 million Americans have heart failure (HF) today, with an incidence approaching 10 per 1000 population in persons older than 65 years of age; approximately 50% of these patients are women (Figure 1).1 In 2000, 62.3% of all HF mortalities occurred among women; 20% of those patients died within 1 year of their diagnosis, and less than 15% of women survive more than 8 to 12 years after diagnosis.2 These results notwithstanding, the Framingham study recently noted that the age-adjusted rates of HF are higher among men, with no significant change in this rate over a 50-year period.3 Among women, the incidence of HF has decreased by 31% to 40% in the decades after 1950.



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  		Figure 1. Prevalence and mortality of heart failure by gender: A, prevalence of heart failure in the United States, 1988 through 1994, by age group and gender; B, mortality (51,546 total deaths, including Hispanics) in 2000. Percentage of male deaths was 37.6%, and percentage of female deaths was 62.4%.1

 
HF is the reason for at least 20% of all hospital admissions in persons older than 65 years, and over the past decade, hospitalizations for HF have increased by 159%. Women who have been hospitalized with HF have less improvement in physical health status and perceive their quality of care to be lower than that of their male cohorts.4 Of the thousands of patients disabled from HF within 6 years of their diagnosis, 46% are adult women compared with only 22% of men. In 1997, an estimated $5501 was spent for every hospital-discharge diagnosis of HF, and another $1742 per month was required to care for each patient after discharge. Gender has been shown to be an important determinant of hospital length of stay, hospital charges, and mortality during hospitalization.5

The above statistics and countless other graphs, studies, and reports chronicle 2 very important issues: (1) the syndrome of HF has reached epidemic proportions in the United States and throughout the world, and (2) the disease appears to have different characteristics in men and women. It is reasonable to postulate that an elucidation of these sex-specific differences might suggest novel approaches to the prevention of this serious disorder. Moreover, additional insights into gender-specific pathophysiologic mechanisms that lead to HF might be used to develop unique therapies for this relentlessly lethal disease. This review, then, should be regarded as more than a politically expedient exercise but as one part of the larger battle to fight the syndrome of HF in all its forms. We would also like to acknowledge the newer literature on this subject since the outstanding review of Petrie and colleagues6 was published in 1999.

Epidemiology

Elderly patients in the United States represent an increasing proportion of patients with HF. There is the general aging of the population, a progressive increase in the age of onset of HF, and improved treatment of other cardiovascular diseases, such as hypertension and myocardial infarction, to account for these figures.7 Although the overall prevalence of HF is similar in men and women, there is a striking effect of age on the prevalence of the disease. Men have a much higher prevalence of HF when younger than 75 years of age, whereas women surpass the male prevalence when older than 75 years of age. Importantly, these elderly female patients are much more likely to have HF with preserved systolic function,8-11 or "diastolic heart failure," than their younger cohorts.7,12

Over the past 50 years, the incidence of HF has decreased among women but not among men.3 What could account for this differing gender trend? Treatment of hypertension reduces the incidence of HF by about 50%, and important advances have occurred in the awareness, treatment, and control of high blood pressure during this time period.13,14 The risk of HF imparted by hypertension is greater for women than for men: the population-attributable risk effect of hypertension was 59% in women and only 39% in men in an earlier Framingham report.15 Increasing use of antihypertensive medications has led to a decrease in the prevalence of high blood pressure and might have affected the incidence of HF in women more so than in men. In men the greater incidence of HF is partly explained by the greater prevalence and incidence of arteriosclerosis and coronary artery disease. Some data also suggest a sex difference in the cardiac response to increased afterload or hypertension, as discussed subsequently.

Ventricular arrhythmias are thought to be caused by a dispersion of normal conduction through nonhomogeneous myocardial tissue, promoting repetitive ventricular rhythms. The rate of sudden cardiac death among persons with HF is 6 to 9 times that seen in the general population16 and is more common in men than in women.17 One study suggested that women who present with sudden cardiac death are less likely to have a prior history of heart disease than men (37% vs 56%). More recent data revealed that women with cardiac arrest are less likely than men to have ventricular fibrillation as an initial rhythm.18 Albert and colleagues19 prospectively followed a cohort of 121,701 women aged 30 to 55 years at baseline and identified 244 cases of sudden cardiac death between 1976 and 1998. Although the risk of sudden death increased markedly as the women grew older, the percentage of cardiac deaths that were sudden decreased with age. Most (69%) women who had a sudden cardiac death had no history of cardiac disease before their death, but almost all (94%) of the women who died reported at least 1 coronary risk factor. Smoking, hypertension, and diabetes conferred a significantly increased risk of sudden death similar to that seen in men.

Mortality from heart failure

There has been considerable scrutiny of a possible survival advantage of women once they have HF in contrast to men. Two large epidemiologic studies, Framingham20 and NHANES-1,21 both reported an improved survival for women, despite a greater average age in the female cohorts. In contrast, the SOLVD investigators noted a worse outlook, with a 1-year mortality rate of 22% in the women and a 17% rate in the men of the study.22 All patients in SOLVD had a formal measurement of left ventricular ejection fraction (LVEF); entry into the large epidemiologic studies was on the basis of symptoms without an assessment of LVEF. Thus it is probable that the women followed in the earlier studies had a higher incidence of diastolic HF as compared with that in SOLVD, and this might account for their survival advantage. Data from the Italian Network CHF Registry, in which patients were enrolled on the basis of signs and symptoms, reported a similar 1-year mortality in men and women.23 However, the women of the cohort were significantly older, had a worse functional class, and exhibited a higher heart rate and systolic blood pressure with more atrial fibrillation but less ventricular tachycardia. In this study women were more likely to have preserved left ventricular (LV) function than men.

It appears that the underlying cause of HF in women in general is different than that in men, and these baseline risk factors, outside the development of HF, might have an important effect on prognosis. Diabetes, for example, is a stronger risk factor for HF in women than in men, especially in younger women.24 In a Framingham report increased wall thickness and LV mass were found in women but not in men with diabetes mellitus.25 Moreover, LV mass and wall thickness increases with worsening glucose intolerance, an effect that is also more striking in women.26 Thus if one were to examine a given population of patients with HF, the women in the group would more likely be older, have diabetes, and have hypertension. Age, hypertension, and diabetes are powerful determinants of prognosis in other cardiovascular disorders, such as in patients after myocardial infarction or cardiac surgery, and women frequently do less well because of these additional risk factors. Why is it that women with the same comorbid conditions and HF fare better than their male counterparts?

Mortality outcomes become even more muddled as the large randomized clinical trials are examined with regard to this issue. As mentioned earlier, women survived less frequently in SOLVD, a study of patients with LV systolic dysfunction.22 In the FIRST study, which involved patients with far-advanced systolic dysfunction and refractory symptoms, only women without ischemic heart disease had a better prognosis compared with the prognosis of the male patients.27 However, in 2 large trials studying patients with systolic dysfunction and symptomatic HF, MERIT-HF28 and CIBIS-II,29 women had a significantly improved survival, even after adjustment for baseline differences, including ß-blocker treatment and ischemic cause. The mechanisms that determine an enhanced survival for women with HF require elucidation.

Pathophysiology

Numerous studies have shown that the clinical manifestations and prognosis of women with ischemic heart disease differ significantly from those of men. In spite of having preserved LV systolic function more often than men, women have more symptoms of HF.30-32 Mendes and colleagues33 sought to understand more completely the relationship between sex and LV pressure and volume in patients referred for cardiac catheterization. Women comprised 35% of the 1667 patients undergoing catheterization. They also had a higher prevalence of hypertension (41% in women and 31% in men), diabetes (18% in women and 12% in men), and HF (13% in women and 10% in men). At the time of the procedure, women had a higher LVEF, 61% compared with the men's 56%, but had less 3-vessel coronary disease. In a multivariate analysis female sex remained an independent predictor of HF. The LV end-diastolic volume index was smaller in women despite a similar LV end-diastolic pressure. When patients were stratified according to LV end-diastolic pressure, women had a significantly smaller end-diastolic volume. The authors suggested that the response of the left ventricle to the pressure-overload state, such as that seen in hypertension, might be modified by sex. The pressure-volume relationship noted in the study by Mendes and colleagues33 accounts for the diastolic abnormalities seen so often in women with HF and explains the degree of symptoms despite a preserved LVEF.

Other pathophysiologic differences exist in patients with HF that appear to be sex determined. Aronson and Burger34 examined heart rate variability in patients with nonischemic HF and found that women have attenuated sympathetic activation and an attenuated parasympathetic withdrawal. Current understanding about the critical role of the sympathetic nervous system in the progression of HF suggests that the above findings might be advantageous. Likewise, investigators have shown that myocyte necrosis and apoptosis are significantly reduced in women with HF, despite a longer duration of disease compared with that seen in the men in the study populations.35 There are also considerable data to conclude that gender and sex hormones affect the components of the renin-angiotensin system through a number of mechanisms.36

Figure 2 depicts a possible schema of the pathophysiologic response to myocardial injury in men and women derived in part from the above and other studies. The clinical observation that women present with symptoms of HF later in life with more concentric LV hypertrophy might be explained by a gender-specific tendency that confers an improved survival in many instances. Recent reports suggest that the gender response to postinfarction injury favors women in that they have less hypertrophy, a pattern quite different than that observed in nonischemic cardiomyopathy.37



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  		Figure 2. Gender-related survival rates and how they might be influenced by different pathophysiologic mechanisms in men and women. LV, Left ventricle; LVH, left ventricular hypertrophy; RAS, renin-angiotensin system; SNS, sympathetic nervous system.

 
Management of heart failure

Our ability to discern whether women respond to pharmacotherapy for HF in a meaningfully dissimilar manner from men has been impaired by the failure to enroll adequate numbers of women into many of the HF trials, as shown in Table 1.38-54 To be fair, this low enrollment rate is probably caused, in part, by a greater proportion of diastolic HF in women, making them ineligible for the trials outlined in Table 1.55


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  		TABLE 1. Female participants in heart failure trials of left ventricular systolic dysfunction

 
Women might receive less optimal care for a variety of reasons. Harjai and coworkers56 showed that, even after adjusting for age, race, coronary artery disease, and LVEF, there was a higher use of combination therapy by cardiologists in male versus female patients. Improvements in peak exercise capacity might be more pronounced in men than in women with HF after exercise training, and yet women are referred less often to cardiac rehabilitation.57 In addition, the skeletal muscle abnormalities described in the legs of male patients with HF are not as pronounced in women.58 Women had more side effects in the SOLVD trial.59 Most important, however, is the lack of definitive randomized trials in patients with diastolic HF, a group of patients who are predominantly women.60 Some of the differences between men and women at baseline when enrolled in clinical trials are shown in Table 2. 22,27-29,61 Note the greater degree of hypertension and diabetes in women.22,27-29,61,62


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  		TABLE 2. Differences in heart failure: Women compared with men

 
In summary, there is mounting evidence that there are important sex differences in the phenotype of HF as we understand it currently. Women appear to have an overall improved outlook once they become symptomatic with HF. The mechanisms behind this advantage are worthy of further exploration.

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