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Circulation. 1999;99:2334-2341

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(Circulation. 1999;99:2334-2341.)
© 1999 American Heart Association, Inc.

Current Perspective

Failure of Women's Hearts

Mark C. Petrie, BSc, MRCP; Nuala F. Dawson, MRCP; David R. Murdoch, BMS, MRCP; Andrew P. Davie, BSc, MRCP; John J. V. McMurray, MD, FRCP, FESC

From the Medical Research Council Clinical Research Initiative in Heart Failure, Wolfson Building, University of Glasgow, and Department of Cardiology, Western Infirmary, Glasgow, Scotland.

Correspondence to Prof John J.V. McMurray, Medical Research Council Clinical Research Initiative in Heart Failure, Wolfson Building, University of Glasgow, Glasgow G11 6 NT, Scotland. E-mail J.McMurray{at}bio.gla.ac.uk


Key Words: women • heart failure • sex • epidemiology • prognosis


*    Introduction
up arrowTop
 *Introduction
down arrowEpidemiology
 down arrowEtiology
 down arrowDiagnosis
 down arrowPatient Management
 down arrowMorbidity
 down arrowMortality
 down arrowWomen in Clinical Trials...
 down arrowHeart Transplantation
 down arrowConclusions
 down arrowReferences
 
Recently, differences in the management of men and women with ischemic heart disease have been highlighted.1 Although at least as great, sex differences in heart failure have received little attention. In this article, we review the evidence that men and women with heart failure may differ with respect to epidemiology, etiology, diagnosis, prognosis, and treatment.


*    Epidemiology
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 up arrowIntroduction
 *Epidemiology
down arrowEtiology
 down arrowDiagnosis
 down arrowPatient Management
 down arrowMorbidity
 down arrowMortality
 down arrowWomen in Clinical Trials...
 down arrowHeart Transplantation
 down arrowConclusions
 down arrowReferences
 
To date, most studies of the prevalence and incidence of heart failure have identified cases on clinical grounds and, in some instances, with the aid of an ECG and chest radiograph. Thus, the precise type of heart failure (eg, left ventricular systolic dysfunction, or valvular disease) is unclear in most reports. This is important in view of the evidence that left ventricular systolic dysfunction is less common in women than in men with suspected heart failure (see the "Diagnosis" section below).

Prevalence
With these caveats in mind, the major epidemiological surveys of heart failure (see the FigureDown)2 3 4 5 show that the overall prevalence rate of heart failure is similar in men and women. This balance, however, reflects a much lower female prevalence <70 to 75 years of age and a higher prevalence in older women than in older men. Overall, within the population, there appear to be more women than men with heart failure.6 7 8 Although age-adjusted rates for both sexes have decreased from 1988–1995, rates for women have fallen less than those for men.8B



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  		Figure 1. Sex differences in prevalence of heart failure and left ventricular systolic dysfunction in major epidemiological studies. *Based on clinical criteria; **based on echocardiography.

Incidence
Although the absolute incidence rate is lower than the prevalence rate, the effect of age on sex incidence is similar.3


*    Etiology
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 up arrowIntroduction
 up arrowEpidemiology
 *Etiology
down arrowDiagnosis
 down arrowPatient Management
 down arrowMorbidity
 down arrowMortality
 down arrowWomen in Clinical Trials...
 down arrowHeart Transplantation
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Risk factors for heart failure appear to differ markedly between the sexes.

Hypertension
The risk of heart failure imparted by hypertension is greater for women than for men. In the Framingham study, the hazard in a proportional hazards regression model (adjusting for age and other risk factors) for developing heart failure in hypertensive compared with normotensive subjects is about doubled in men and tripled in women.9 In terms of population attributable risk, the effect of hypertension is greater in women (59%) than men (39%).9 These findings are supported by more recent studies such as the SOLVD trials in which in the treatment trial women were more likely to have concomitant hypertension (55% of women versus 39% of men, P<0.001).10 The higher prevalence of hypertension in women when compared with men with heart failure is seen in both blacks (64.2% of women versus 60.2% of men; P<0.05) and whites (42.9% of women versus 35.7% of men; P<0.05).8B This difference between men and women may reflect a sex difference in the cardiac response to an increase in afterload.11

Coronary Artery Disease
The SOLVD trials10 reported that coronary heart disease and, in particular, past myocardial infarction are less frequently identified as an etiological factor in women than in men with heart failure (Table 1Down).


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  		Table 1. Coronary Heart Disease as a Cause of Chronic Heart Failure in SOLVD

Furthermore, although white women admitted with heart failure have less coronary artery disease than their male counterparts, black women appear to have more coronary artery disease than black men.8B

Although the incidence of myocardial infarction is lower in women than in men, women who do sustain a myocardial infarction are more likely to develop heart failure.12 13 14 Interestingly, women are also more likely to develop heart failure after CABG than men (relative risk in CASS, 2.71; 95% CI, 1.86 to 3.93).15

Diabetes Mellitus
Diabetes seems to be a stronger risk factor for heart failure in women than in men, especially in younger women. Several studies,16 17 including SOLVD,18 have reported that women with heart failure are more likely to have diabetes than men (SOLVD,19 49.3% women and 37.2% men, P<0.02). In the Framingham study, although both young women and young men with diabetes had a greater incidence of heart failure than those without, the effect was greater in women (an 8-fold versus a 4-fold increase).3

A distinct diabetic cardiomyopathy has been proposed, and in the Framingham study, increased wall thickness and left ventricular mass were found in women but not in men with diabetes mellitus.20

Obesity, Cholesterol, and Smoking
Obesity (relative weight) is independently associated with congestive heart failure in women and men.21 The Framingham study identified a greater predictive value of obesity in women.22 The ratio of total to HDL cholesterol has also been identified as an independent risk factor for heart failure.22 Total cholesterol is significantly related to the incidence of heart failure only in men <65 years of age. Smoking in the same study was also found to increase the risk of heart failure in young men and old women.22 Smoking is less common in female than male heart failure patients.14

Valvular Heart Disease
The SOLVD,23 Framingham,24 and hospital-based8B studies report a predominance of women with valvular heart disease. However, data from the 30-year follow-up of the Framingham study suggest a declining frequency of heart failure secondary to valvular disease in both sexes.24 Rheumatic heart disease declined from 22% to 15% in women and 15% to 3% in men over this time period.24

Idiopathic Dilated Cardiomyopathy
Women are reported to have a markedly lower prevalence of idiopathic dilated cardiomyopathy in many studies (male-to-female ratio, 1.9–4.3:1),8B 25 26 27 28 perhaps because the male population has a greater prevalence of covert alcohol abuse or asymptomatic coronary artery disease. Women who do develop idiopathic dilated cardiomyopathy, however, have greater ventricular dimensions and shorter exercise duration.29 It should be noted, however, that more women than men had an "unknown" cause of left ventricular systolic dysfunction in the SOLVD trials (16% versus 9% in men in the prevention arm and 26% versus 16% in the treatment arm, P<0.001).10

Alcoholic Cardiomyopathy
The evidence of a sex influence on susceptibility to alcohol-induced heart failure is inconclusive. Despite a mean lifetime alcohol dose of 60% of that of their male counterparts, women have been found to suffer from alcoholic cardiomyopathy at a similar rate.30 Another study has found a positive association between alcoholic cardiomyopathy and male sex.31 Further studies are required to examine this issue.

Peripartum Cardiomyopathy
Peripartum cardiomyopathy is a rare but important disorder that has been reviewed elsewhere.32

X-Linked Cardiomyopathy
Families with patterns of inheritance suggesting an X-linked cardiomyopathy have been described.33 34 35 36 37 Clinical expression is that of early onset and rapid progression in men and later onset and slower progression in women. Work to further classify the genetic abnormalities concerned is continuing.


*    Diagnosis
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 up arrowIntroduction
 up arrowEpidemiology
 up arrowEtiology
 *Diagnosis
down arrowPatient Management
 down arrowMorbidity
 down arrowMortality
 down arrowWomen in Clinical Trials...
 down arrowHeart Transplantation
 down arrowConclusions
 down arrowReferences
 
The few small studies that have looked at the diagnosis of heart failure have reported a striking sex difference. This relates to the prevalence of left ventricular systolic dysfunction in patients treated with diuretics for "heart failure" or presenting with symptoms and signs suggestive of new-onset heart failure. One Scottish study reported that 19 of 30 men (63%) being treated with diuretics alone had echocardiographic evidence of left ventricular dysfunction compared with 13 of 48 women (27%).38 Obesity and pulmonary diseases were frequently the underlying pathology. A second Scottish study found that only 12 of 66 women (18%) and 19 of 53 men (36%) being treated for heart failure by their general practitioners had echocardiographic evidence of left ventricular dysfunction.39 A Finnish study found that 21 of 37 men (57%) but only 7 of 51 women (14%) with suspected heart failure had definite heart failure as assessed by a clinical scoring system.40 In a recent study from London, Cowie et al41 reported that 41% of male but only 17% of female patients referred with suspected heart failure actually had this syndrome. Data from another English study of 505 patients receiving diuretics from their general practitioners also suggest that diagnosis of heart failure in women is less accurate than in men.42 Although more women than men were found to be prescribed a loop diuretic, fewer women satisfied the authors' criteria for a diagnosis of heart failure. The cause of symptoms and signs in the women without left ventricular systolic function was not clear in these reports. Whereas "diastolic dysfunction" is possible, 2 of the above studies found that obesity was more prevalent in women,38 40 and in 1 study, diastolic dysfunction as measured by the mitral valve Doppler E/A ratio was uncommon.43


*    Patient Management
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 up arrowIntroduction
 up arrowEpidemiology
 up arrowEtiology
 up arrowDiagnosis
 *Patient Management
down arrowMorbidity
 down arrowMortality
 down arrowWomen in Clinical Trials...
 down arrowHeart Transplantation
 down arrowConclusions
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Hospital Referral
Few studies have examined the possibility of a sex bias in referring patients with heart failure to hospitals. One study, however, has found that women with heart failure were less likely to be referred to hospital than men and were more likely to be treated by their general practitioners.42 Women with heart failure are less likely to be referred to a teaching hospital and, once admitted, are less likely to be managed by cardiologists than men.8B

Patient Investigation
There are few data in the literature on the use of investigations according to sex. In 1 report, however, women were less likely than men to undergo measurement of left ventricular function (36% of women versus 42% of men).44 A further large study of patients admitted with heart failure found that women were equally likely to have an echocardiogram but were less likely to undergo cardiac catheterization. Both black and white women were less likely than men to undergo ventriculography, Holter monitoring, and exercise stress testing.8B


*    Morbidity
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 up arrowIntroduction
 up arrowEpidemiology
 up arrowEtiology
 up arrowDiagnosis
 up arrowPatient Management
 *Morbidity
down arrowMortality
 down arrowWomen in Clinical Trials...
 down arrowHeart Transplantation
 down arrowConclusions
 down arrowReferences
 
The major source of information on sex and morbidity is studies on hospital admissions and discharges for heart failure.

Quality of Life
The limited data available on quality of life in heart failure include an analysis by the SOLVD investigators that found that women experience greater shortness of breath on exertion (58% versus 48% of men, P<0.001) and make up fewer of the NYHA class 1 subgroup (6% versus 12%, P<0.001) than men.10 This trend toward greater functional impairment was seen in both the treatment and prevention trials. In a series of 45 894 patients admitted with heart failure, women had lower baseline physical health status and experienced less improvement in the year after admission than men.44A In contrast to these two large studies, several small studies have failed to show differences in quality of life.44B 44D Women with idiopathic dilated cardiomyopathy have been found to have a shorter exercise duration.29 Although far from exhaustive, this evidence suggests that women with heart failure have a poorer quality of life.

Symptoms and Signs
Women appear to experience more symptoms and present more frequently with signs of heart failure. The SOLVD investigators found that women had more edema than men (15% of men versus 22% of women).10 More women than men had an audible third heart sound (17% versus 11%, P<0.001) and elevated jugular venous pressure (17% versus 5%, P<0.001).10 Women with idiopathic dilated cardiomyopathy report more symptoms and a shorter exercise duration and present more frequently with heart failure signs.29 Again, the data are limited but are consistent with the findings on quality of life reported earlier.

Hospitalizations for Heart Failure
In keeping with the population prevalence of heart failure, published reports of hospitalization from the United Kingdom,8 Sweden,31 New Zealand,45 the United States,6 7 16 46 and the Netherlands47 all show higher hospital admission and discharge rates for men than women in younger age groups with a diminishing difference in older age categories. Because the highest prevalence rate is found in older subjects and because there are more older women than men in most first-world populations, the absolute number of hospitalizations for women is greater than that for men.7 8

Women in the SOLVD Registry had a higher annual admission rate than men (22% versus 17%, P=0.05).48 Women also have consistently longer stays in the hospital than men.8 8B 45 47 The reason for this is not clear. Women with congestive heart failure are older,47 48 49 and age influences length of stay.45 47 Women may also have more comorbidity and be more likely to live alone. Readmission rates, however, were independent of sex in 2 studies8 50 and lower for women in another.51

Thromboembolism
Left ventricular ejection fraction is inversely associated with the risk of thromboembolism in women but not in men.52 Women with heart failure are also at greater risk of pulmonary embolism than men (P=0.01).52

It is not clear whether or not the sex difference in morbidity in the above studies reflects later referral, more advanced ventricular dysfunction, or a biological difference between the sexes (or some combination of these factors).


*    Mortality
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 up arrowIntroduction
 up arrowEpidemiology
 up arrowEtiology
 up arrowDiagnosis
 up arrowPatient Management
 up arrowMorbidity
 *Mortality
down arrowWomen in Clinical Trials...
 down arrowHeart Transplantation
 down arrowConclusions
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The 2 largest US epidemiological studies, Framingham49 and the first NHANES-1,2 both reported a better survival in women with heart failure. Median survival was 3.2 years for women versus 1.7 for men in the Framingham study. The 5-year survival rate was 38% for women compared with 25% for men. This survival benefit was apparent despite the greater average age of women (72 years) compared with men (68 years). Adjusting for age and origin of heart failure exaggerated this difference in prognosis. NHANES-1 also reported a better outlook for women than men over a 10- to 15-year period of follow-up, and this was seen across all age groups.2 Other population surveys6 53 and studies of patients admitted to hospital8B 50 also report a more favorable prognosis in women.

In contrast, the SOLVD investigators reported quite the opposite finding; they described a worse outlook for women who had a 1- year mortality rate of 22% compared with 17% for men (P=0.05).48 This survival differential was apparent for total mortality, cardiac mortality, death from progressive pump failure, and presumed arrhythmic death.

These contrasting findings are interesting and important. As alluded to earlier, fewer women with the symptoms and signs of heart failure have left ventricular systolic dysfunction, ie, the form of heart failure with the gravest prognosis.

Interestingly, even in the CONSENSUS-1 study, in which patients were not recruited on the basis of left ventricular function, women were much more likely to have echocardiographic fractional shortening above the median than men (48% of women versus 15% of men, P<0.05).54 Framingham49 and NHANES-12 did not assess left ventricular function, whereas all patients in SOLVD48 had reduced left ventricular ejection fractions. SOLVD, therefore, represents a more homogeneous group of patients with a particular type of heart failure. Etiology may also explain in part the differences between SOLVD and Framingham and NHANES-1. As with men, women with heart failure that is not caused by coronary heart disease fare better than those with coronary heart failure. SOVLD contained more women with coronary heart failure than Framingham or NHANES-1. Whatever the explanation, the worse prognosis of women in SOLVD is unsurprising given their greater symptom burden and poorer quality of life (see above). Women in the SOLVD trials also had more cardiomegaly (cardiothoracic ratio >0.5) than men: 51% versus 37% in men in the prevention arm (P<0.001) and 65% versus 53% in the treatment arm (P<0.001).10 Once again, it is unclear whether these sex differences reflect later referral, more advanced disease, or a biological difference between the sexes.


*    Women in Clinical Trials in Heart Failure
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 up arrowIntroduction
 up arrowEpidemiology
 up arrowEtiology
 up arrowDiagnosis
 up arrowPatient Management
 up arrowMorbidity
 up arrowMortality
 *Women in Clinical Trials...
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Women have been hugely underrepresented in heart failure trials and trials of left ventricular dysfunction. The proportion of randomized patients in the major trials ranges from 0% to 32%, yet there are probably more women than men with heart failure in the population (Table 2Down). This almost certainly does not represent differences in the willingness of women and men to participate in trials. In the SOLVD closeout questionnaire, women more frequently reported participating to attempt to liver longer, whereas men were more likely to want to contribute to medical science.55


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  		Table 2. Women in Large Heart Failure Trials

Trials of Digoxin, ß-Blockers, and Hydralazine Plus Isosorbide Dinitrate
Trials of digoxin in heart failure have not reported subgroup analyses by sex.66 67 68 Although reporting a total of only 14 deaths in women, the US Carvedilol Group found a statistically significant reduction in the number of deaths in women and men.65 The other large ß-blocker trials have not reported sex-specific mortality.66 67 68 The V-HeFT Trial, which showed a mortality benefit with the vasodilating combination of isosorbide dinitrate and hydralazine, recruited only men.56

Trials With ACE Inhibitors in Heart Failure
ACE inhibitors are widely used in the management of heart failure in both men and women. The large multicenter trials that have reported mortality and morbidity benefit, however, have contained only a small proportion of women. Subgroup analysis of the CONSENSUS-1 study showed a statistically significant reduction in mortality with enalapril in men but not in women.69 Whereas men achieved a 51% reduction in 6-month mortality (P<0.001), women achieved only a 6% reduction (P=NS). The SOLVD investigators found that men and women treated with enalapril experienced a reduction in mortality and hospitalizations, although this effect was less for women.1 These trials, however, contained small numbers of women and were not designed to examine mortality benefit in women and men separately. In a meta-analysis of the ACE inhibitor trials, the survival benefit with active therapy appeared to be similar in both sexes: 0.76 for men and 0.79 for women.70 Active therapy had a similar effect on the combined end point of total mortality and hospitalizations: 0.63 for men and 0.78 for women. However, the odds ratios (ACE inhibitor versus placebo) for women, unlike those for men, crossed 1.00 for the end point of total mortality and the combined end point of total mortality and hospitalization for heart failure.

Trials With ACE Inhibitors in Patients With Post–Myocardial Infarction Left Ventricular Systolic Dysfunction and Heart Failure
In the AIRE study, treatment with ramipril in patients with signs of heart failure after myocardial infarction led to a significant reduction in mortality in both sexes.71 The other 3 studies of ACE inhibitors in patients with left ventricular dysfunction after myocardial infarction did not report a significant mortality benefit for women. TRACE included 28% women, and the relative risks with trandolapril were 0.75 (95% CI, 0.62 to 0.89) for men and 0.90 (95% CI, 0.69 to 1.18) for women.72 In the SMILE trial, the relative risks with zofenopril were 0.59 (95% CI, 0.36 to 0.95) for men and 0.70 (95% CI, 0.40 to 1.21) for women.73 In SAVE, the results for women were again disappointing.74 There was only a 2% mortality risk reduction in women versus a 22% risk reduction in men. For the combined end point of cardiovascular death and morbidity, there was only a 4% risk reduction in women but a 28% risk reduction in men. After adjustment for other variables (such as age), however, the relative risks of an end point for women and men were 19% and 21% in the ACE inhibitor group.

Although these results with ACE inhibitors in heart failure and after myocardial infarction reflect, at least in part, the small numbers of women included in the trials, they do leave open the possibility that ACE inhibitors are less effective in women. This, in turn, could reflect a higher rate of treatment withdrawal in women (see the "Adverse Effects" section).

Angiotensin II Receptor Antagonists
The ELITE study recently compared the effects of the angiotensin II type 1 receptor antagonist losartan and the ACE inhibitor captopril, suggesting that the former treatment may be more effective.61 Again, the numbers of women were small (ratio of men to women: losartan, 234:118; captopril, 248:122). The distribution of deaths in women (9 of 118 and 8 of 122 deaths in the losartan and captopril groups, respectively) does not support the extrapolation of any trend in mortality benefit to women.

Sex Differences in the Adverse Effect Rate in ACE Inhibitor Trials
There was a higher rate of adverse effects reported by women than by men in the SOLVD trials. This sex difference was seen during both the medication challenge phase of SOLVD75 and long-term treatment.76 The sex difference in coughing is perhaps best recognized and may reflect the greater average milligram-per-kilogram dose of drug received by women in trials using a fixed absolute-dosing regimen. Women, however, are also more likely to experience other side effects, including a greater rise in creatinine, taste disturbance, skin rash, and gastrointestinal upset.

Other Sex Influences on Response to Pharmacological Treatment
Female sex is a risk factor for torsade de pointes with D-sotalol, an agent shown to increase mortality in patients with left ventricular systolic dysfunction.77

Underprescription of ACE Inhibitors in Women With Heart Failure and Left Ventricular Dysfunction
Women receive ACE inhibitors less often than men as treatment for heart failure,78 79 even in the absence of contraindications.80 The cause of ACE inhibitor underprescription for both sexes, and particularly the sex disparity, is unclear. Oversight and ignorance of prognostic benefit would seem likely candidates for suboptimal use in both sexes. Perhaps physicians recognize women to be at greater risk of adverse effects than men, although this should not necessarily preclude treatment.

Adherence to Prescribed Therapy
In 1 study, women were significantly more adherent to prescribed digoxin treatment than men.81


*    Heart Transplantation
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 up arrowIntroduction
 up arrowEpidemiology
 up arrowEtiology
 up arrowDiagnosis
 up arrowPatient Management
 up arrowMorbidity
 up arrowMortality
 up arrowWomen in Clinical Trials...
 *Heart Transplantation
down arrowConclusions
 down arrowReferences
 
Women constitute only 20% of patients undergoing transplantation.82 The reasons for this striking sex discrepancy are unclear. Premature coronary heart disease in men and a male preponderance of idiopathic dilated cardiomyopathy may lead to more men in a younger age group with heart failure of greater severity than women. It has also been reported that women are more likely to decline transplantation.83 Women have an increased frequency of allograft rejection and are less likely to tolerate a steroid-free regimen after transplantation.84 It is not clear whether women and men have comparable survival after transplantation.85 86

Is There a Pathophysiological Basis for the Sex Differences in Heart Failure?
Although many of the sex differences in heart failure highlighted in this review may be explained by differences in referral and treatment patterns, there is also evidence that some of these differences could have a pathophysiological basis. The myocardial response to injury may vary between sexes.

Sex differences in left ventricular responses to hypertension11 and aortic stenosis87 88 89 have been found. Premenopausal women with mild hypertension have smaller ventricular dimensions and enhanced ventricular performance compared with men.11 Olivetti et al90 found that aging female hearts do not suffer from the annual 1-g myocyte loss seen in male hearts. Data from SOLVD found male but not female sex to be a predictor of left ventricular dilatation (P<0.04).91

Women admitted with heart failure have less frequent serious ventricular arrhythmias than men.8B

Investigation of possible sex differences in the neuroendocrine response to heart failure is awaited. Variation in vascular responsiveness according to sex has not been described in heart failure.

Any pathophysiological basis of sex differences in heart failure is likely to reflect a complex interaction of hormonal, vascular, and ventricular factors.


*    Conclusions
up arrowTop
 up arrowIntroduction
 up arrowEpidemiology
 up arrowEtiology
 up arrowDiagnosis
 up arrowPatient Management
 up arrowMorbidity
 up arrowMortality
 up arrowWomen in Clinical Trials...
 up arrowHeart Transplantation
 *Conclusions
down arrowReferences
 
Heart failure in women differs in many aspects from that of men. Contrasts in origin, diagnostic yield, prognosis, and possibly response to treatment have been outlined. Some of these differences may have a pathophysiological basis. These sex differences may have widespread implications in the field of heart failure. Elucidation of a pathophysiological basis of sex differences, together with clinical trials designed to study the impact of treatments in women, could lead to some aspects of heart failure management being sex based. Until now, women have been profoundly underrepresented in clinical trials, and little investigation of sex influence on pathophysiology has been carried out. The large and consistent difference in the yield of left ventricular systolic dysfunction in women versus men with suspected heart failure is puzzling and requires explanation. What is wrong with these female patients? It is hoped that the coming decade will see increased interest in this important area and, ultimately, a benefit for female heart failure sufferers.


*    Acknowledgments
 
Dr Petrie is funded by a British Heart Foundation junior research fellowship (No. FS/97031:1997).


*    References
up arrowTop
 up arrowIntroduction
 up arrowEpidemiology
 up arrowEtiology
 up arrowDiagnosis
 up arrowPatient Management
 up arrowMorbidity
 up arrowMortality
 up arrowWomen in Clinical Trials...
 up arrowHeart Transplantation
 up arrowConclusions
 *References
 

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