artikel 1-s2.0-S0025712504000343-main

7/30/2019 artikel 1-s2.0-S0025712504000343-main

1/25

Heart failure in women

Lars H. Lund, MD, Donna Mancini, MD*

Columbia University College of Physicians and Surgeons, New York, NY, USA

Women exhibit distinct differences compared with men in regard to

epidemiology, risk factors, causes, mechanisms for disease development,

response to treatment, and outcomes in heart failure (HF). However,

because diagnostic criteria have been variable in large epidemiologic surveys

and because women have constituted a minority of enrollees in major HF

trials, many questions remain. Gender differences have been well elucidated

in the area of coronary artery disease (CAD) but less so in HF, even though

differences in HF are probably more distinct. The purpose of this review is

to describe known differences in HF between men and women.

Epidemiology

Improved management of hypertension (HTN), diabetes (DM), hyper-

cholesterolemia, and other risk factors for HF or CAD, as well as advances

in the treatment of acute coronary syndromes (eg, thrombolytics and

primary angioplasty) have had complex influences on the epidemiology of

HF. Improved management has allowed people to live longer with risk

factors and after acute coronary events, which has allowed time to developHF and, consequently, increased the incidence and prevalence of HF.

Conversely, improved management of risk factors has also prevented HF in

many people in whom it would otherwise have developed, with the opposite

effect on HF incidence and prevalence data. The aging of the population and

improved medical management of HF have also contributed to the

increasing prevalence. Finally, greater physician awareness and availability

of noninvasive imaging, leading to more frequent and accurate diagnoses,

may also have contributed to increasing incidence and prevalence.

* Corresponding author. Division of Cardiology, Department of Medicine, Columbia

University College of Physicians and Surgeons, 622 West 168th Street, New York, NY 10032.

E-mail address: [email protected] (D. Mancini).

0025-7125/04/$ - see front matter 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.mcna.2004.03.003

Med Clin N Am 88 (2004) 13211345
mailto:[email protected]:[email protected]

7/30/2019 artikel 1-s2.0-S0025712504000343-main

2/25

Most available data come from government agencies or from large

population cohorts (Table 1) [110], such as the Framingham Study (9405

participants, 47% male subjects who have been followed since 1949)

[1,2,4,6,8]. These studies provide statistical power but should be interpreted

cautiously because clinical criteria [1,2,46,8] or medical records [3,7] are

used for diagnosis. Some studies use self-reported HF data [3,7]. Self-

reported HF is less common than HF established by clinical indices,

especially among women (Fig. 1A) [5,11]. Furthermore, the type of HF (eg,

systolic versus diastolic) is often not differentiated.The most recently available figures [10] indicate that HF in the United

States affects 4.9 million people (2.5 million women and 2.4 million men),

which is close to 2% of the total population, with an annual incidence of

550,000 cases. Although the absolute number of patients with HF is higher

among women than men, women live longer and develop HF later in life.

Thus, the age-adjusted percentage of prevalence is lower in women (1.5%

white women versus 2.3% in men and 3.1% black women versus 3.5% in

men) [10], with an age-adjusted annual incidence of 564 per 100,000 in men

and 327 per 100,000 in women [8].In absolute figures, prevalence and incidence of HF have increased over

the last 40 years, with the more dramatic increase in prevalence (Fig. 2A)

[2,6,10]. Age-adjusted incidence has actually decreased by 31% in women

and 7% in men between the 1950s and the 1990s (see Fig. 2B) [8].

Stratified by age, both the prevalence and incidence of HF increase

dramatically after age 65 (Fig. 1) [5,6,9,10]. In the Framingham Study, mean

age at diagnosis increased from 57 in the 1950s to 76 in the 1980s [11]. In the

past, HF was more prevalent in women than men at the extremes of age (see

Fig. 1A, B) [5,6]. This difference in prevalence may be partly explained bygender differences in the cause of the disease. Pregnancy and connective tissue

diseases in younger women account for the higher prevalence in the young age

group (Table 2) [12]. Higher prevalence of CAD among men 45 to 80 years of

age [10] raises prevalence in this group. More HTN (leading to progressive

damage) and longer life span among women generally increase female

representation in the oldest age group; however, more recent data suggest that

Table 1

Major epidemiologic surveys

Source [Ref. no.] Years HF criteriaFramingham [1,2,4,6,8] 19491999 Framingham Study criteria

National Center for

Health Statistics [3]

19701978 Coding on death certificates

and hospital discharges

National Health

Interview Survey [9]

Annual survey;

data from 1999

Self-reported

National Health and

Nutrition Examination

Survey I and III [5,7,10]

I: 19711975

I follow-up:

19821986

III: 19881994

Self-reported, clinical

criteria, and medical records

1322 L.H. Lund, D. Mancini / Med Clin N Am 88 (2004) 13211345

7/30/2019 artikel 1-s2.0-S0025712504000343-main

3/25

rates are similar between the genders at the extremes of age and dramatically

higher among men than women in the middle age group (Fig. 1C, D) [9,10].

Morbidity and mortality

HF accounts for 1 million hospital discharge diagnoses annually (60%

women) and total mortality of over 260,000 [10]. HF is the leading cause of

hospitalization, accounting for at least 20% of all hospitalizations in the

patients over the age of 65 [13]. Among patients with reduced ejection

fraction (EF), women have more hospitalizations than men [14] and are

hospitalized longer [15], probably because they are older and more

frequently live alone [16]. Mortality rates are variable, reflecting differentcriteria for diagnosis and varying severity of HF. In longitudinal cohorts,

1-year survival in HF ranges from 55% to 90%, and 5-year survival ranges

from 20% to 55% [1,5,8,11,1719].

Generally, women have better survival, at least when results are adjusted

for age. In the Framingham Study, median survival after diagnosis was

3.2 years for women and 1.7 years for men, and 1-year survival was 57% for

men and 64% for women [11]. In Scotland, crude median survival and

survival rates were similar between the genders; however, the overall adjusted

hazards ratio for death was 0.87 for women compared with men (95%confidence interval (CI), 0.850.89) [18]. In the National Health and

Nutrition Examination Survey (NHANES) I, 10-year mortality was only

24% in women versus 54% in men [5]. In placebo-controlled trials, women

had a better prognosis than men in the Digitalis Investigation Group (DIG)

study [20], Survival and Ventricular Enlargement trial (SAVE) [21],

Metoprolol Extended-Release Randomized Intervention Trial in Heart

Failure (MERIT-HF) [22], and Cardiac Insufficiency Bisoprolol Study

(CIBIS) II [23] but a worse prognosis in the Cooperative New Scandinavian

Enalapril Survival Study (CONSENSUS) II [24], the Trandolapril CardiacEvaluation (TRACE) [25], Studies of Left Ventricular dysfunction (SOLVD)

[14], and the US carvedilol study (Table 3) [26]. In both men and women, the

prognosis is better in nonischemic disease causes (see Table 2) [12].

Despite improvements in therapy, the prognosis in population cohorts

only recently appears to be improving [13]. In the Framingham Study, there

was no change in age-adjusted survival over a period of 40 years [11]. This

probably reflects the fact that HF has become more severe. In Scotland,

crude median survival increased from 1.23 years to 1.64 years between 1986

and 1995. Adjusted for age and other factors, the improvements were moredramatic: 30-day mortality fell by 26% in men and 17% in women, and

longer term mortality fell by 18% in men and 15% in women [18]. In more

recent Framingham Study analysis, 1-year age-adjusted mortality fell from

30% to 28% in men and from 28% to 24% in women over 40 years (Fig. 3),

figures that correspond to a 12% relative improvement in survival per

decade [8].

1323L.H. Lund, D. Mancini / Med Clin N Am 88 (2004) 13211345

7/30/2019 artikel 1-s2.0-S0025712504000343-main

4/25

Fig. 1. Prevalence of HF by gender and age group in different time periods. (A) NHANES-I

(19711975) data show self-reported rates lower than clinical rates, especially those reported

among young women. (Data from Shocken DD, Pinsky JL, Kannel WB, Levy D. The

epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol 1993;22(Suppl A):6A13A.) (B) In the Framingham Study (19491988) a higher prevalence is shown among

women than men in older age groups. (Data from Ho KKL, Anderson KM, Kannel WB,

Grossman W, Levy D. Survival after the onset of congestive heart failure in Framingham Heart

Study Subjects. Circulation 1993;88:10715.)


7/30/2019 artikel 1-s2.0-S0025712504000343-main

5/25

Cause of death

The most common causes of death in HF are progressive HF and sudden

cardiac death (SCD), accounting for approximately 50% and 40% of deaths

Fig. 1 (continued) (C) Prevalence of HF by age and sex. More recent data in NHANES-III

(19881994) suggest a higher prevalence among men than among women, overall, and in all age

groups. (Data from American Heart Association. Heart disease and stroke statistics2003

update. Available at http://www.americanheart.org/presenter.jhtml?identifier=1928 and http://

www.americanheart.org/presenter.jhtml?identifier=2007. Accessed 2003.) (D) Self-reported data

in NHIS (1999) show that the prevalence of HF is higher in men at all ages. (From Ni H.

Prevalence of self-reported heart failure among US adults: Results from the 1999 National

Health Interview Survey. Am Heart J 2003;146(1):1218; with permission.)

http://www.americanheart.org/presenter.jhtml?identifier=1928http://www.americanheart.org/presenter.jhtml?identifier=2007http://www.americanheart.org/presenter.jhtml?identifier=2007http://www.americanheart.org/presenter.jhtml?identifier=2007http://www.americanheart.org/presenter.jhtml?identifier=2007http://www.americanheart.org/presenter.jhtml?identifier=1928

7/30/2019 artikel 1-s2.0-S0025712504000343-main

6/25

in HF, respectively [19,21,2729]. In HF, SCD occurs at a rate of six to ninetimes that of the general population [4,10]. In the total population, age-

adjusted SCD is 2- to 3-fold more common in men [30], and in the HF

population it is also more common in men [4]. Because SCD is much more

common in men than in women without documented heart disease, the

magnitude of the increase in relative risk (RR) for SCD in individuals with

HF compared with those without HF is higher for women than for men. In

Fig. 2. Absolute annual incidence and prevalence of HF in the United States in men and

women, reported over 4 decades. (A) Consolidation of data from large epidemiologic surveys.

(Data from Refs. [2,6,10].) Both absolute incidence and prevalence have increased over time.

Prevalence has increased more dramatically, consistent with an aging population and increased

longevity with HF. (B) Age-adjusted incidence has decreased over the last 40 years. (Data from

Levy D, Kenchaiah S, Larson MG, Benjamin EJ, Kupka MJ, Ho. KKL, et al. Long-term

trends in the incidence of and survival with heart failure. N Engl J Med 2002;347:1397402.)


7/30/2019 artikel 1-s2.0-S0025712504000343-main

7/25

Rotterdam, the adjusted RR of SCD in HF was 6.6 in women and 3.7 in

men with HF [19], and in the Framingham Study the adjusted RR was 9.1

and 6.2, respectively [4].

Etiology

HF is multifactorial, and many risk factors have direct and indirect

(through an intermediary) influence on its development. CAD, HTN,

idiopathic dilated cardiomyopathy, and valvular heart disease are the mostcommon causes in both genders; however, the relative roles of these diseases

are different in men and women (Figs. 4 and 5). A combination of CAD and

HTN is present in many patients. The best data examining risk factors and

attempting to establish causality are found in the NHANES-I Epidemio-

logic Follow-up Study [7]. Causality is best estimated by population

attributable risk (PAR) which is defined as ([RR1] P)/([RR1]

P+1) 100% [7], where P = proportion of population with risk factor at

baseline or cumulative proportion exposed during follow-up, and RR = re-

lative risk in persons with versus persons without given risk factor (derivedfrom Cox proportional hazards models). PAR estimates the proportion of

cases that could be eliminated if the risk factor were eliminated from the

total population [7]. For example, HTN is more common than CAD in the

general population (see Fig. 4A) and approximately equal to CAD in the HF

population (see Fig. 4B, C). Because HTN is more common in the general

population, its PAR is lower (see Fig. 5A, B). In multivariate analysis of

Table 2

Underlying causes in HF initially considered idiopathic

Cause Women n (%) Men n (%) TotalAdjusted HRfor mortality

All Causesa 492 (100) 738 (100) 1230

Idiopathic 234 (47.6) 382 (51.8) 616 (50.1) 1.00

Myocarditis 46 (9.3) 65 (8.9) 111 (9.0) 1.05

Ischemic 21 (4.3) 70 (9.5) 91 (7.4) 1.52*

Infiltrative 19 (3.9) 40 (5.4) 59 (4.8) 4.40*

Peripartum 51 (10.4) 0 (0) 51 (4.1) 0.31*

HTN 21 (4.3) 28 (3.9) 49 (4.0) 0.74

HIV 8 (1.6) 37 (5.1) 45 (3.7) 5.86*

Connective tissue disease 27 (5.5) 12 (1.6) 39 (3.2) 1.75*

Substance abuse 7 (1.4) 30 (4.1) 37 (3.0) 1.41

Doxorubicin 13 (2.6) 2 (0.3) 15 (1.2) 3.46*

Other 48 (9.8) 69 (9.4) 117 (9.5) 1.30

Abbreviation: HR, hazard ratio.

Data from Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL,

et al. Underlying causes and long-term survival in patients with initially unexplained

cardiomyopathy. N Engl J Med 2003;342(15):107784.a May not equal 100% because of rounding.

* P\ 0.05.

http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-

7/30/2019 artikel 1-s2.0-S0025712504000343-main

8/25

NHANES-I data, CAD, HTN, cigarette use, obesity, DM, and valvular

heart disease were all significant and independent risk factors for HF in both

genders, and male gender also was a significant risk factor. Inactivity was

a risk factor only in women [7]. HF increases dramatically with age, and age

itself is an important risk factor. Most risk factors are more common at

older ages and have a higher risk of causing HF in older ages, but HF ismore common in older ages even without a particular condition; therefore

the RR factor for each condition decreases with age [6]. Although from

different populations, this is illustrated by a RR factor for HF from DM of

8 and 4 in women and men, respectively, in ages less than 65 years old [6]

compared with an overall RR of HF from DM of less than 2 [7], even

though DM is more common in older ages.

Table 3

Mortality in clinical trials by men/women subgroups

All-cause mortality (%)

Trial n

Women

(%)

Follow-up

(mo) Subgroup Rx Placebo

RR, HR, OR, or

RRR (95% CI)

DIG [20] 6800 22 37 M 35.2 36.9 P = NS

W* 33.1 28.9 P\ 0.05

CONSENSUS II [24] 6090 26 6 M 9.0 8.8 P = NS

W 13.5 11.2 P = NS

SAVE [21] 2231 18 42 M 20.6 25.7 P\ 0.05; RRR,

22 (636)

Wa 19.9 20.1 P = NS; RRR,

2 (5737)

TRACE [25] 1749 28 2450 M 32.4 41.2 P\ 0.05; RR,

0.74 (0.620.89)

W 40.6 44.8 P = NS; RR,

0.90 (0.691.18)

ACE inhibitor

meta-analysis [84]

7105 NA 242 M 16.5 22.7 OR, 0.76

(0.650.88)

W 13.4 20.1 OR, 0.79

(0.591.06)

US Carvedilol [26] 1094 23 612 M 3.2 7.2 P\ 0.05; HR,0.41 (0.220.80)

W 3.1 9.6 P\ 0.05; HR,

0.23 (0.070.69)

MERIT-HF [22] 3991 22 12 M 7.4 11.8 P\ 0.05; HR, 0.61

Wa 6.9 7.4 P = NS; HR, 0.92

CIBIS II [22] 1647 31 16 M 12.9 18.2 P\ 0.05; HR, 0.71

W 7.0 13.6 P\ 0.05; HR, 0.52

Abbreviations: CI, confidence interval; HR, hazard ratio; NA, not available; OR, odds ratio;

RR, relative risk; RRR, relative risk reduction; Rx, treatment.a P for interaction between gender and treatment, NS (not significant).

* P for interaction between gender and treatment\0.05.

http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-

7/30/2019 artikel 1-s2.0-S0025712504000343-main

9/25

Ischemic heart disease

The incidence [10] and prevalence (see Fig. 4A) [7] of CAD and the

contribution of CAD to mortality in the population [31] are lower in women

than in men, but the decrease in cardiovascular mortality over the last

20 years is less significant in women [31]. Over the past 40 years, theprevalence of CAD among patients with HF has increased in both genders,

suggesting an increasing causative role of ischemic heart disease [32]. In HF

patients, CAD is less frequent in women than in men, ranging from 8% to

74% and 17% to 84%, respectively (see Fig. 4B) [6,9,33].

Previous incidents of myocardial infarction (MI) are less common among

women than men with HF [33]; however, women, and especially black

women, who sustain an MI, have a worse long-term prognosis. After MI,

22% of men and 46% of women will develop HF, and 25% of men and 38%

of women will die within 1 year [10]. Women are less likely to undergorevascularization than are men [34], but if they do, they have higher

incidence of subsequent HF [35] and mortality [36]. Women are less likely to

receive thrombolytics or aspirin, even when this likelihood is adjusted for

indications, but both are equally likely to receive b-blockers acutely, and are

slightly more likely to receive angiotensin-converting enzyme (ACE)

inhibitors [34]. Past inadequacies in the management of CAD in women

Fig. 3. Age-adjusted survival in men and women from 1970 to 1999. Survival data

(percentages) are shown for 30 days and 1 and 5 years. (Data from Levy D, Kenchaiah S,

Larson MG, Benjamin EJ, Kupka MJ, Ho KKL, et al. Long-term trends in the incidence of and

survival with heart failure. N Engl J Med 2002;347:1397402.)


7/30/2019 artikel 1-s2.0-S0025712504000343-main

10/25

Fig. 4. (A) Overall (crude) prevalence data from NHANES-I in the total population (ie, with

and without HF) of listed conditions. (Data from He J, Ogden L, Bazzano LA, Vupputuri S,

Loria C, Whelton PK. Risk factors for congestive heart failure in US Men and Women. ArchIntern Med 2001;161:9961002.) (B) Prevalence of risk factors in the HF population in the

NHIS, Framingham, and SOLVD studies (additional studies are cited in the text). (Data from

Refs. [6,9,33].) (C) Comparison of relative risk of heart failure for subjects with and without

predisposing conditions. (Data from He J, Ogden L, Bazzano LA, Vupputuri S, Loria C,

Whelton PK. Risk factors for congestive heart failure in US men and women. Arch Intern Med

2001;161:9961002.)


7/30/2019 artikel 1-s2.0-S0025712504000343-main

11/25

may have contributed to the high prevalence and incidence of HF among

older women today.

Hypertension

HTN affects 50 million Americans between the ages of 20 and 74 [10] and

is more common in men (26%30%) than women (21%27%) (see Fig. 4A)

[7,10]. In contrast, HTN is more common in HF (see Fig. 4B) and is a more

important risk factor for HF (see Figs. 4C, and 5A, B) in women than men.Systolic HTN predicts HF in women, whereas pulse pressure is more

predictive in men [4]. In the Framingham Study, the risk, adjusted for age

and other risk factors, of HF in HTN compared with those without HTN

was doubled in men and tripled in women [6,37]. The prevalence of HTN

with HF was 78% and 70% in women and men, respectively [6]; the PAR of

HF for HTN was 39% in men and 59% in women [37]. In NHANES-I, the

prevalence of HTN in the general population was 27% in women and 30%

in men, and the PAR of HF for HTN was 12% for women and 9% for men

[7]. In SOLVD, 55% of women and 39% of men had concomitant HTN[33], but HTN was considered to be primarily involved in only 7% [14].

These disparate numbers make sense if the respective populations are

examined. In the Framingham Study, diagnosis was clinical and broad and

included large numbers. In NHANES-I, only self-reported diagnoses were

included, yielding lower rates of HTN and, thus, a lower PAR of HTN. The

SOLVD study included only patients with depressed EF. Normal EF

Fig. 4 (continued)


7/30/2019 artikel 1-s2.0-S0025712504000343-main

12/25

accounts for half of all HF [17,38], and HTN is the main cause of HF with

normal EF (HFNEF), whereas CAD is the main cause of HF with depressed

EF.

Heart failure: normal ejection fraction

HFNEF, frequently termed diastolic HF, is mainly a disease of elderly

women, most of whom have HTN [39]. HFNEF is becoming increasinglyrecognized as a cause of HF [17,38,40]. When echocardiograms were

obtained on 73 Framingham Study subjects with HF, 51% had normal

EF. Sixty-five percent of those with normal EF were women, whereas

only 25% of those with reduced EF were women [17]. The prevalence of

HFNEF increases with age [40]. Prognosis in HFNEF is poor, although it is

better than in systolic dysfunction. The Framingham Study and the

Fig. 5. Approximate population-attributable risk for men (A) and women (B). The population-

attributable risk is the closest estimation of direct and primary causation (see text). The

cumulative population-attributable risk of all risk factors slightly exceeds 100%. Values in these

pie charts are approximate but proportional. (Data from He J, Ogden L, Bazzano LA,

Vupputuri S, Loria C, Whelton PK. Risk factors for congestive heart failure in US men and

women. Arch Intern Med 2001;161:9961002.)


7/30/2019 artikel 1-s2.0-S0025712504000343-main

13/25

Cardiovascular Health Study revealed annual mortality of 15% to 19% in

systolic HF, 8% to 9% in HFNEF, and 1% to 4% in matched controls

without HF [17,41]. HFNEF accounts for more deaths than systolicdysfunction in the elderly because it is more common in this age group [41].

The differential effects of sex hormones on the myocardial hypertrophic

response may account for the greater incidence of HFNEF in women [42,43].

In normal subjects, left ventricular (LV) mass and chamber size are lower in

women compared with men, even when normalized for body surface area

[44]. HTN is more predictive of HF in women than men (see Figs. 4C, and

5A, B) [6,7,37]. LV mass increases with age in women but decreases in men

[44]. Women have a more dramatic hypertrophic response to increased

myocardial work load and injury [45]. In response to renovascularhypertension in an animal model, myocardial mass was increased in female

rats by 46% compared with 14% in male rats [43]. Both male and female rats

exhibit hypertrophy in response to aortic banding, but only males develop

impaired contractility [46]. In a transgenic tumor necrosis factor-a mouse

model, both genders progress to HF, but female mice exhibit wall thickening

without dilation and preserved fractional shortening, whereas male mice

exhibit marked dilation and loss of fractional shortening [47].

Effects of sex hormones on cardiac function

Androgen and estrogen receptors have been detected in blood vessels and

atrial and ventricular tissue in both genders [42,48,46]. Distinct cardiovas-

cular effects result from these sex hormones (Table 4) [42,4951]. Estrogen

protects against HTN partly by decreasing renin activity, whereas

testosterone promotes HTN partly by increasing renin activity [49]. Estrogen

inhibits vascular remodeling, vasoconstriction, and smooth muscle cell

growth [49], and replacement therapy promotes vasodilation in postmeno-

pausal women [48]. The rate of collagen deposition in the myocardiumis decreased by estrogen whereas deposition is increased by the presence

of androgens. Estrogen also inhibits cardiac fibroblast and myocyte

Table 4

Differential effects of sex hormones

Site Androgens Estrogens

Cardiac

Contractility " $

LV mass" #

Fibrosis " #

Vascular Vasoconstriction Vasodilation

Skeletal muscle " #

Renal

Glomerulosclerosis " #

Renin " #

Data from Refs. [42,4951].


7/30/2019 artikel 1-s2.0-S0025712504000343-main

14/25

growth [42,49]. Gonadectomy decreases contractile performance among both

male and female rats, with a greater decline among males, and decreases heart

weight in males only [50]. Testosterone replacement increases cardiac andskeletal muscle mass and improves ventricular performance in rats in both

genders [51]. Oral contraceptive use protects against the development of

idiopathic dilated cardiomyopathy [52], and hormone replacement improves

survival in women with systolic HF [53], although as we are learning from the

Womens Health Initiative and Heart and Estrogen/progestin Replacement

Study [55], hormone replacement therapy is not beneficial and may be

harmful when used for primary [54] or secondary [55] prevention of CAD.

Diabetes mellitus, obesity, inactivity, and the metabolic syndrome

DM affects 8 million men and nearly 9 million women in the United

States [10]. Among whites it is more common in men, whereas the opposite

is true among blacks [10]. DM is an independent predictor of LV mass and

wall thickness in women but not men [56] and is independently associated

with increased LV mass and wall thickness, reduced LV systolic function,

and increased arterial stiffness [57]. Small-vessel disease, interstitial fibrosis,

and autonomic dysfunction are believed to contribute to diabetic cardio-

myopathy [58]. Thus, DM predisposes to HF in both genders but moreso in women (see Figs. 4C, and 5A, B) [6,7], and especially in younger

women [6]. The risk of HF is independent of CAD, HTN, age, and lipid

status [6,7] and is higher with older age, insulin use [59], and poor glycemic

control [60]. In early Framingham Study analysis, DM was present in 26%

of women and 14% of men with HF and associated with a 5- and 2.4-fold

increased risk of HF in women and men [1]. In later Framingham Study

data, the incidence of HF was 8- and 4-fold higher, respectively, in diabetic

women and men [6]. These risks were even greater when CAD was

eliminated, suggesting that DM has a distinct role in HF, even in theabsence of its indirect role as a cause of ischemic heart disease [61]. DM also

increases mortality in established HF [62].

Age-adjusted prevalence of obesity (defined as body mass index over 30)

has increased from 16% to 34% of women and from 11% to 28% of men

between 1960 and 2000 [10]. Among Americans over age 20, 26 million men

and 35 million women are obese [10]. Obesity is independently associated with

HF in both genders, but it is more predictive in women [7,63]. Obesity may be

an underlying cause in women who have HFNEF [64]. In the Framingham

Study, each incremental point in body mass index was associated with a 5%and 7% increased risk of HF in men and women, respectively [63]. Despite the

strong associations, whether obesity is an independent risk factor for HF or

even CAD is still controversial. Obesity increased risk of HF independently of

its intermediaries (HTN, DM, CAD, and LV hypertrophy). Obesity and the

metabolic syndrome, however, are associated not only with each other and

with elevated blood pressure, dyslipidemia, and insulin resistance but also


7/30/2019 artikel 1-s2.0-S0025712504000343-main

15/25

with elevated C-reactive protein levels, activation of the central nervous

system, and increased thrombosis, all of which may be the true culprits when

obesity has been implicated in HF [65].Thirty-eight percent of American adults report no leisure time physical

activity [10]. Inactivity is more common in women of all ages than in men

(see Fig. 4A) and is associated with an increased risk of CAD and HTN [10].

Inactivity predisposes to HF primarily through intermediate risk factors,

although in NHANES-I, inactivity independently increased the risk of HF,

significantly in women (RR 1.31, P = 0.002) and nonsignificantly in men

(RR 1.14, P = 0.19) (see Figs. 4C, and 5B) [7].

Alcohol

Observational studies suggest that light to moderate alcohol use reduces

the risk of CAD [66]. In NHANES-I, regular alcohol consumption was

associated with a decreased risk of developing HF in women (RR = 0.70,

P = 0.03) but not in men [7]; however, it has long been recognized that

chronic consumption of large amounts of alcohol is a risk factor for

cardiomyopathy. In one study, the prevalence of alcoholic women with

dilated cardiomyopathy (DCM) was similar to that of men, but women

required a lower lifetime dose of alcohol to develop DCM [67].

Idiopathic dilated cardiomyopathy

Because idiopathic dilated cardiomyopathy is often a diagnosis of

exclusion, and diagnostic approaches vary between studies, the epidemiol-

ogy of idiopathic dilated cardiomyopathy is difficult to establish. In

Olmstead County, the annual incidence was 7.6 per 100,000 men and 2.5

per 100,000 women [68]. In other studies, men account for approximately

80% of DCM cases [69,70], but in the Framingham Study, unknown causes

accounted for only 7% of all HF in men and women [32]. Underlying

conditions are not always obvious. In a group of 1230 patients (40% female)

with initially unexplained cardiomyopathy, further evaluation revealed that

half had specific causes (see Table 2) [12]. Underlying causes varied greatly

by gender and correlated strongly with prognosis (see Table 2). In this study

[12], male gender was independently associated with mortality (adjusted

hazard ratio 1.26, 95% CI 1.001.60). Peripartum cardiomyopathy was

significantly associated with better survival, whereas ischemic, infiltrative,

and HIV were significantly associated with higher mortality [12].

Signs and symptoms, clinical presentation, and diagnosis

The diagnosis of HF is generally based on clinical data in population-

based cohorts and on LV function in clinical trials. The most frequently


7/30/2019 artikel 1-s2.0-S0025712504000343-main

16/25

used criteria are the Framingham Study criteria [1], which do not reliably

distinguish between systolic and diastolic dysfunction. Women with HF

have a poorer quality of life and more symptoms than men, especially indecreased exercise tolerance [33,70]. Women have more signs of HF (edema,

S3 gallop, jugular venous distension) than men [33]. Although they are

fewer, women who do have systolic dysfunction have more LV dilation then

men [70]. Women are less likely to be referred to the hospital, managed by

cardiologist, or have cardiac diagnostic testing [15]. The reason for these

discrepancies are not known but may relate to older age at presentation,

causes of HF, or bias similar to that observed in CAD.

Exercise capacity

Peak oxygen consumption (VO2) is an important predictor of survival

and is frequently used to guide selection for transplantation [71]. It is less

accurate in women, however, for whom the predicted peak VO2 percentage

may be a better prognostic marker [72]. In HF, as in normal subjects, peak

VO2 is lower in women than men [70]. This is attributed to the lower

hemoglobin and reduced skeletal muscle mass, which in turn are the result

of sex hormones. Healthy men but not women increase their EF in response

to exercise [73] but in HF neither do. Stroke volume increases to a similardegree in both genders, but in women a 30% increase in end-diastolic

volume occurs. Thus, men appear to rely on contractility and women on the

FrankStarling mechanism to increase cardiac output [42].

Therapy

Numerous therapies that decrease morbidity or mortality in HF are now

available. Women have generally been under-represented in HF trials, withparticipation rates ranging from 0% to 32% (see Table 3) [16]. Selection

bias, age, and the likelihood that women are more likely to decline

participation are possible reasons, but a proportionately lower incidence of

systolic dysfunction in women is a significant reason. In the Losartan

Intervention for Endpoint (LIFE) trial, in which criteria were HTN and

LVH but not depressed EF, 60% of the participants were women [74]. In

many trials, outcomes are not reported separately for women and men. In

some trials, the point estimate of the benefit is similar in both genders, but

the 95% CI crosses 1 in women. In other studies, no benefit is seen at all inwomen. Outcomes in trials quantifying gender subgroup analyses are listed

in Table 3.

Women receive proven therapies less often than their male counterparts.

Rates of ACE inhibitor use ranged from 34% to 51% in women and 45% to

71% in men, in studies explicitly comparing genders [75,76]. The low rate of

use in women was attributed to contraindications and older age [75],


7/30/2019 artikel 1-s2.0-S0025712504000343-main

17/25

although more frequent HF with normal EF and, consequently, less

established benefit in women is also likely to be responsible. Elderly patients

have been included in the major ACE inhibitor trials and benefit similarly toyounger people, yet they are less likely to receive this treatment [77]. The fact

that elderly patients are more likely to be women may be the basis for under-

prescribing HF agents to women. In contrast, women tend to be more

compliant with prescribed HF therapy than men [78].

Digoxin

In a gender-specific analysis of DIG, women but not men experienced

higher adjusted mortality with digoxin use than with placebo (hazard ratio

[HR] 1.23, 95% CI 1.021.47) [20]. Mortality in men correlated with serum

digoxin levels. Women in the DIG had higher short-term serum concen-

trations than men. Whether higher levels explain the increased mortality in

women has not yet been analyzed. Overall, mortality was lower among

women than men in both treatment and placebo groups (see Table 2).

Hospitalization rates were lower in women on digoxin versus placebo.

Hydralazine and nitrates

Experience with hydralazine and nitrates is based primarily on the

Veterans Heart Failure Trials [79], which included only men and revealed

more benefits when compared with placebo but less benefits than with ACE

inhibitor. Use of hydralazine and nitrates is recommended for patients who

are intolerant to ACE inhibitors and angiotensin receptor blockers.

Although there appears to be no reason to believe this regimen has different

effects in men and women, there is no clinical evidence that it is effective in

women.

Angiotensin-converting enzyme inhibitors

In systolic HF, ACE inhibitors reduce hospitalization and prolong

survival [21,27,28,80], and in high-risk patients they prevent the de-

velopment of HF [81]. It is probable but not definite that ACE inhibitors

benefit women. In the Cooperative North Scandinavian Enalapril Survival

Study (CONSENSUS-I; severe HF), men had a significant 51% RRreduction for mortality at 6 months, but for women it was only 6% and

insignificant [82]. In SOLVD (treatment and prevention), enalapril reduced

mortality and hospitalization in both women and men, but the decrease was

less in women [83]. In the SAVE and TRACE (HF post-MI) trials, there was

only a 2% and 10% RR reduction (P = nonsignificant in both) for

mortality in women, compared with 22% and 26% in men, respectively


7/30/2019 artikel 1-s2.0-S0025712504000343-main

18/25

[21,25]. In the Acute Infarction Ramipril Efficacy (AIRE) trial (signs of

post-MI HF), ramipril decreased mortality in both women and men and

actually more so in women [84]. In a meta-analysis of 7105 patients in 32trials, the odds ratio for total mortality was 0.76 (95% CI 0.650.88) for

men and 0.79 (0.591.06) for women [85]. In a later meta-analysis of 12,763

patients in five trials (SAVE, AIRE, TRACE, and two SOLVD trials), the

odds ratio for death was 0.79 (0.720.87) for men and 0.85 (0.711.02) for

women [86].

Thus, there is a less convincing benefit of ACE inhibitors for women than

for men; however, there are important caveats. Many women with HF do

not have systolic dysfunction, a requirement for most ACE inhibitor trials,

and in SOLVD, women had more coughing and withdrew more frequently[87]. One can speculate why the benefits of ACE inhibition appear to be

diminished in women. African Americans respond less to ACE inhibitors,

possibly because of less of a renin component in the pathophysiology of

HTN and HF [88]; similarly, women may respond less because estrogen

decreases and testosterone increases renin activity [49]. Furthermore,

women have not been analyzed prospectively and separately. Thus, if a trial

reveals overall benefit, it is not appropriate to conclude that women do not

benefit because this subgroup result may be the result of a smaller sample

size. In the larger meta-analysis and in SAVE, the P values for theinteraction (heterogeneity) of gender and treatment were nonsignificant

(Table 3) [86,89]. In SAVE, a proportional hazards model revealed the

benefits of captopril to be independent of many variables, including gender,

and after adjustment for gender, the benefits remained significant [89].

Angiotensin II receptor blockers

In general, angiotensin receptor blockers have similar benefits to ACE

inhibitors and are a good alternative when ACE inhibitors are not tolerated.In a head-to-head comparison of captopril and losartan for HF, the former

was associated with a nonsignificantly lower mortality in both men and

women [90]. In the Valsartan Heart Failure Trial (Val-HeFT) [91] (valsartan

in addition to existing therapy, often including an ACE inhibitor), women

were analyzed separately and had benefits similar to those in men but

without reaching statistical significance.

b-Blockers

The US carvedilol trial was terminated early after a dramatic decrease in

mortality in both men and women and more so in women, with HR of

mortality of 0.41 and 0.23 in men and women, respectively [26]. A meta-

analysis of CIBIS and CIBIS-II revealed a larger mortality benefit in women

than men with a RR compared with placebo of 0.61 in women and 0.71 in


7/30/2019 artikel 1-s2.0-S0025712504000343-main

19/25

men (P\ 0.05 for both) [92]. In contrast, the MERIT-HF failed to reach

significant benefit for women, although overall the mortality reduction was

large and highly significant (absolute risk reduction [ARR] 3.8%, RR 0.66[95% CI 0.530.81]) [29]. Finally, the Carvedilol Prospective Randomized

Cumulative Survival (COPERNICUS) [93] trial showed a dramatic benefit

in both men and women with severe HF (symptoms at rest or with minimal

exertion) for both total mortality and for the combination of mortality and

hospitalization, although the overall mortality for women failed to reach

statistical significance. In a pooled analysis of the MERIT-HF, COPERNI-

CUS, and CIBIS II, the RR for mortality was 0.69 in women and 0.66 in

men [22]. How proposed mechanisms ofb-blockers might differ between the

genders is poorly understood.

Aldosterone antagonists

Aldosterone antagonists decrease mortality, hospitalization, and symp-

toms in HF. In the Randomized Aldactone Evaluation Study (RALES) [94],

overall mortality at 2 years was 35% in the spironolactone group and 46%

in the placebo group (RR 0.70, 95% CI 0.600.82), with a similar and

significant reduction in both men and women. Gynecomastia and breast

pain were reported in 10% of men but not reported in women. The

Eplerenone Postacute Myocardial Infarction Heart Failure Efficacy and

Survival Study (EPHESUS) [95] reported decreased overall mortality (RR

0.85, 95% CI 0.750.96) with eplerenone compared with placebo for

patients with acute MI complicated by HF. In subgroup analysis this benefit

was actually larger in women and failed to reach statistical significance in

men, but the P value for gender/treatment interaction was insignificant.

Mechanisms of benefit probably include inhibition of the negative effects of

aldosterone on the heart and possibly elevation of serum potassium; little is

known about how these effects may differ between genders, but again, thedifferent responses to pressure overload and MI probably play a role.

Cardiac transplantation

Orthotopic heart transplantation is associated with significant improve-

ment in survival and quality of life for patients with severe refractory HF.

Of the 2500 transplants performed annually in the United States, almost

80% are performed in men [96]. Women appear to be referred at equal levelsof severity of disease, based on clinical and hemodynamic parameters.

However, there is a higher acceptance of candidates with ischemic causes,

regardless of gender [97], which increases the proportion of men who

undergo transplantation. Once referred, women are as likely as men to be

found acceptable candidates [97], but they are less likely to accept [98].

Following transplantation, women tend to have more rejection and are less


7/30/2019 artikel 1-s2.0-S0025712504000343-main

20/25

likely to tolerate a steroid-free regimen [99]. In some analyses, women have

been reported to have worse survival after orthotopic heart transplantation

[100], but a majority of studies report comparable survival [96], which is now85%90% at 1 year.

Summary

Distinct differences in sex hormones and their effects and differences in

response to injury, pressure overload, and aging account for many of the

differences between women and men with HF. The typical woman with HF

is more likely to have HTN, diastolic dysfunction, DM, obesity, and

inactivity and is less likely to have CAD or a previous MI or systolicdysfunction. Women are more symptomatic and are perhaps less likely to

benefit from established treatments; however, survival is better for women if

controlled for age. As the therapeutic options for HF increase, sex-based

differences in treatment may need to be considered. Future studies directed

exclusively at women may be warranted to confirm or establish benefits of

existing and future treatments.

Acknowledgments

We thank Graham Barr, MD, DrPH, for statistical assistance.

References

[1] McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive

heart failure: The Framingham Study. N Engl J Med 1971;285(26):14415.

[2] Smith WM. Epidemiology of congestive heart failure. Am J Cardiol 1985;55:3A8A.

[3] Gillum RF. Heart failure in the United States 19701985. Am Heart J 1987;113:10435.

[4] Kannel WB. Epidemiological aspects of heart failure. Cardiol Clin 1989;7(1):19.[5] Shocken DD, Arrieta MI, Leaverton PE. Prevalence and mortality rate of congestive

heart failure in the United States. J Am Coll Cardiol 1992;20(2):3016.

[6] Ho KKL, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: the

Framingham Study. J Am Coll Cardiol 1993;22(Suppl A):6A13A.

[7] He J, Ogden L, Bazzano LA, Vupputuri S, Loria C, Whelton PK. Risk factors for

congestive heart failure in US men and women. Arch Intern Med 2001;161:9961002.

[8] Levy D, Kenchaiah S, Larson MG, Benjamin EJ, Kupka MJ, Ho KKL, et al. Long-term

trends in the incidence of and survival with heart failure. N Engl J Med 2002;347:

1397402.

[9] Ni H. Prevalence of self-reported heart failure among US adults: Results from the 1999

National Health Interview Survey. Am Heart J 2003;146(1):1218.[10] American Heart Association. Heart disease and stroke statistics2003 update. Available

at: http://www.americanheart.org/presenter.jhtml?identifier=1928 and http://www.

americanheart.org/presenter.jhtml?identifier=2007. Accessed 2003.

[11] Ho KKL, Anderson KM, Kannel WB, Grossman W, Levy D. Survival after the onset of

congestive heart failure in Framingham Heart Study subjects. Circulation 1993;88:

10715.

http://www.americanheart.org/presenter.jhtml?identifier=1928http://www.americanheart.org/presenter.jhtml?identifier=2007http://www.americanheart.org/presenter.jhtml?identifier=2007http://www.americanheart.org/presenter.jhtml?identifier=2007http://www.americanheart.org/presenter.jhtml?identifier=2007http://www.americanheart.org/presenter.jhtml?identifier=1928

7/30/2019 artikel 1-s2.0-S0025712504000343-main

21/25

[12] Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, et al.

Underlying causes and long-term survival in patients with initially unexplained

cardiomyopathy. N Engl J Med 2003;342(15):107784.

[13] Jessup M, Brozena S. Heart failure. N Engl J Med 2003;348(20):200718.

[14] Bourassa MG, Gurne O, Bangdiwala SI, Ghali JK, Young JB, Rousseau M, et al.

Natural history and patterns of current practice in heart failure. J Am Coll Cardiol 1993;

22(Suppl A):14A9A.

[15] Philbin EF, DiSalvo TG. Influence of race and gender on care process, resource use, and

hospital-based outcomes in congestive heart failure. Am J Cardiol 1998;82:7681.

[16] Petrie MC, Dawson NF, Murdoch DR, Davie AP, McMurray JJV. Failure of womens

hearts. Circulation 1999;99:233441.

[17] Vasan RS, Larson MG, Benjamin EJ, Evans JC, Reiss CK, Levy D. Congestive heart

failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence

and mortality in a population-based cohort. J Am Coll Cardiol 1999;33:194855.

[18] MacIntyre K, Capewell S, Stewart S, Chalmers JWT, Boyd J, Finlayson A, et al.

Evidence of improving prognosis in heart failure; trends in case fatality in 66,547 patients

hospitalized between 1986 and 1995. Circulation 2000;102:112631.

[19] Mosterd A, Cost B, Hoes AW, de Bruijne MC, Deckers JW, Hofman A, et al. The

prognosis of heart failure in the general population. The Rotterdam Study. Eur Heart J

2001;22:131827.

[20] Rathore SS, Wang Y, Krumholtz HM. Sex-based differences in the effect of digoxin for

the treatment of heart failure. N Engl J Med 2002;347(18):140311.

[21] Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ, Cuddy TE, et al. Effect of

captopril on mortality and morbidity in patients with left ventricular dysfunction after

myocardial infarction. N Engl J Med 1992;327(10):66977.[22] Ghali JK, Pina IL, Gottlieb SS, Deedwania PC, Wikstrand JC. Metoprolol CR/XL in

female patients with heart failure: analysis of the experience in Metoprolol Extended-

Release Randomized Intervention Trial in Heart Failure (MERIT-HF). Circulation 2002;

105:158591.

[23] Simon T, Mary-Krause M, Funck-Brentano C, Jaillon P. Sex differences in the prognosis

of congestive heart failure: results from the Cardiac Insufficiency Bisoprolol Study (CIBIS

II). Circulation 2001;103:37580.

[24] Swedberg K, Held P, Kjekshus J, Rasmussen K, Ryden L, Wedel H. Effects of the early

administration of enalapril on mortality in patients with acute myocardial infarction:

results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS

II). N Engl J Med 1992;327(10):67884.[25] Kober L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K, et al. A clinical

trial of the angiotensin-converting enzyme inhibitor trandolapril in patients with left

ventricular dysfunction after myocardial infarction. N Engl J Med 1995;333(25):16706.

[26] Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, et al. The effect

of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J

Med 1996;334(21):134955.

[27] The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left

ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325(5):

293302.

[28] The SOLVD Investigators. Effect of enalapril on mortality and the development of heart

failure in asymptomatic patients with reduced left ventricular ejection fraction. N Engl JMed 1992;327(10):68591.

[29] MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure:

Metoprolol CR/XL Randomised Intervention Trial in congestive Heart Failure (MERIT-

HF). Lancet 1999;353:20017.

[30] Kannel WB, Wilson PW, DAgostino RB, Cobb J. Sudden coronary death in women. Am

Heart J 1998;136:20512.


7/30/2019 artikel 1-s2.0-S0025712504000343-main

22/25

[31] Cooper R, Cutler J, Desvigne-Nickens P, Fortmann SP, Friedman L, Havlik R, et al.

Trends and disparities in coronary heart disease, stroke, and other cardiovascular diseases

in the United States. Circulation 2000;102:313747.

[32] Lorell BH, Stevenson LW. Congestive Heart Failure. In: Wilansky S, Willerson JT,

editors. Heart disease in women. Philadelphia: Elsevier Science; 2002. p. 3119.

[33] Johnstone D, Limacher M, Rousseau M, Liang CS, Ekelund L, Herman M, et al. Clinical

characteristics of patients in Studies of Left Ventricular Dysfunction (SOLVD). Am J

Cardiol 1992;70:894900.

[34] Gan SC, Beaver SK, Houck PM, MacLehose RF, Lawson HW, Chan L. Treatment of

acute myocardial infarction and 30-day mortality among women and men. N Engl J Med

2000;343(1):815.

[35] Hoffman RM, Psaty BM, Kronmal RA. Modifiable risk factors for incident

heart failure in the Coronary Artery Surgery Study. Arch Intern Med 1994;154:

41723.

[36] OConnor GT, Morton JR, Diehl MJ, Olmstead EM, Coffin LH, Levy DG, et al.

Differences between men and women in hospital mortality associated with coronary

artery bypass graft surgery. Circulation 1993;88:210410.

[37] Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression of hypertension

to congestive heart failure. JAMA 1996;275(20):155762.

[38] Senni M, Redfield MM. Heart failure with preserved systolic function. J Am Coll Cardiol

2001;38:127782.

[39] Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, et al.

ACC/AHA guidelines for the evaluation and management of chronic heart failure in the

adult. Executive Summary. J Am Coll Cardiol 2001;38(7):210113.

[40] Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure.Part I. Diagnosis, prognosis, and measurements of diastolic function. Circulation 2002;

105:138793.

[41] Gottdiener JS, McClelland RL, Marshall R, Shemanski L, Furberg CD, Kitzman DW,

et al. Outcome of congestive heart failure in elderly persons: influence of left ventricular

systolic function: The Cardiovascular Health Study. Ann Intern Med 2002;137(8):

6319.

[42] Beniaminovitz A, Mancini DM. Congestive heart failure. In: coronary artery disease in

women: what all physicians need to know. Philadelphia: American College of Physicians-

American Society of Internal Medicine; 1999. p. 47695.

[43] Malhotra A, Buttrick P, Scheuere J. Effects of sex hormones on the development

physiologic and pathologic cardiac hypertrophy in male and female rats. Am J Physiol1990;259(3 Pt 2):H86671.

[44] Levy D, Savage DD, Garrison RJ, Anderson KM, Kannel WB, Castelli WP.

Echocardiographic criteria for left ventricular hypertrophy: The Framingham Heart

Study. Am J Cardiol 1987;59:95660.

[45] Topol EJ, Traill TA, Fortuin NJ. Hypertensive hypertrophic cardiomyopathy of the

elderly. N Engl J Med 1985;312(5):27783.

[46] Weinberg EO, Thienelt CD, Katz SE, Bartunek J, Tajima M, Rohrbach S, et al. Gender

differences in molecular remodeling in pressure overload hypertrophy. J Am Coll Cardiol

1999;34:26473.

[47] Kadokami T, McTiernan CF, Kubota T, Frye CS, Feldman AM. Sex-related survival

differences in murine cardiomyopathy are associated with differences in TNF-receptorexpression. J Clin Invest 2000;106:58997.

[48] Lieberman EH, Gerhard MD, Uehata A, Walsh BW, Selwyn AP, Ganz P, et al. Estrogen

improves endothelium-dependent, flow-mediated vasodilation in postmenopausal wom-

en. Ann Int Med 1994;121:93641.

[49] Dubey RK, Oparil S, Imthurn B, Jackson EK. Sex hormones and hypertension.

Cardiovasc Res 2002;53:688708.


7/30/2019 artikel 1-s2.0-S0025712504000343-main

23/25

[50] Schaible TF, Malhotra A, Ciambrone G, Scheuer J. The effects of gonadectomy on left

ventricular function and cardiac contractile proteins in male and female rats. Circ Res

1984;54:3849.

[51] Scheuer J, Malhotra A, Schaible TF, Capasso J. Effects of gonadectomy and hormonal

replacement on rat hearts. Circ Res 1987;61:129.

[52] Coughlin SS, Tefft MC. The epidemiology of idiopathic dilated cardiomyopathy in

women: the Washington DC Dilated Cardiomyopathy Study. Epidemiology 1994;5(4):

44955.

[53] Reis SE, Holubkov R, Young JB, White BG, Cohn JN, Feldman AM. Estrogen is

associated with improved survival in aging women with congestive heart failure: analysis

of the vesnarinone studies. J Am Coll Cardiol 2000;36:52933.

[54] Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, et al. Estrogen

plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349(6):

52334.

[55] Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized trial of

estrogen plus progestin for secondary prevention of coronary heart disease in

postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS)

Research Group. JAMA 1998;280(7):60513.

[56] Galderisi M, Anderson KM, Wilson PWF, Levy D. Echocardiographic evidence for the

existence of a distinct diabetic cardiomyopathy (The Framingham Heart Study). Am J

Cardiol 1991;68:859.

[57] Devereux RB, Roman MJ, Paranicas M, OGrady MJ, Lee ET, Welty TK, et al. Impact

of diabetes on cardiac structure and function. Circulation 2000;101:22716.

[58] Zarich SW, Nesto RW. Diabetic cardiomyopathy. Am Heart J 1989;118:100012.

[59] Nichols GA, Hillier TA, Erbey JR, Brown JB. Congestive heart failure in type 2 diabetes.Diabetes Care 2001;24(9):16149.

[60] Iribarren C, Karter AJ, Go AS, Ferrara A, Liu JY, Sidney S, et al. Glycemic control and

heart failure among adult patients with diabetes. Circulation 2001;103(22):266873.

[61] Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the

Framingham Study. Am J Cardiol 1974;34(1):2934.

[62] Shindler DM, Kostis JB, Yusuf S, Quinones MA, Pitt B, Stewart D, et al. Diabetes

mellitus, a predictor of morbidity and mortality in the Studies of Left Ventricular

Dysfunction (SOLVD) trials and registry. Am J Cardiol 1996;77:101720.

[63] Kenchaiah S, Evans JC, Levy D, Wilson PWF, Benjamin EJ, Larson MG, et al. Obesity

and the risk of heart failure. N Engl J Med 2002;347(5):30513.

[64] Remes J, Miettinen H, Reunanen A, Pyorala K. Validity of clinical diagnosis of heartfailure in primary health care. Eur Heart J 1991;12:31521.

[65] Massie BM. Obesity and heart failurerisk factor or mechanism? N Engl J Med 2002;

347(5):3589.

[66] Pearson TA. Alcohol and heart disease. Circulation 1996;94:30235.

[67] Fernandez-Sola J, Estruch R, Nicolas JM, Pare JC, Sacanella E, Antunez E, et al.

Comparison of alcoholic cardiomyopathy in women versus men. Am J Cardiol 1997;80:

4815.

[68] Codd MB, Sugrue DD, Gersh BJ, Melton LJ. Epidemiology of idiopathic dilated and

hypertrophic cardiomyopathy. Circulation 1989;80:56472.

[69] Bagger JP, Baandrup U, Rasmussen K, Moller M, Vesterlund T. Cardiomyopathy in

western Denmark. Br Heart J 1984;52(3):32731.[70] De Maria R, Gavazzi A, Recalcati F, Baroldi G, De Vita C, Camerini F. Comparison of

clinical findings in idiopathic dilated cardiomyopathy in women versus men. Am J Card

1993;72:5805.

[71] Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH Jr, Wilson JR. Value of peak

exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory

patients with heart failure. Circulation 1991;83:77886.


7/30/2019 artikel 1-s2.0-S0025712504000343-main

24/25

[72] Aaronson KD, Mancini DM. Is percentage of predicted maximal exercise oxygen

consumption a better predictor of survival than peak exercise oxygen consumption for

patients with severe heart failure? J Heart Lung Transplant 1995;14(5):9819.

[73] Sullivan MJ, Cobb FR, Higginbotham MB. Stroke volume increases by similar

mechanisms during upright exercise in normal men and women. Am J Cardiol 1991;67:

140512.

[74] Kjeldsen SE, Dahlof B, Devereux RB, Julius S, Aurup P, Edelman J, et al. Effects of

losartan on cardiovascular morbidity and mortality in patients with isolated systolic

hypertension and left ventricular hypertrophy. JAMA 2002;288:14918.

[75] Hillis GS, Trent RJ, Winton P, MacLeod AM, Jennings KP. Angiotensin-converting

enzyme inhibitors in the management of cardiac failure: are we ignoring the evidence?

Q J Med 1996;89:14552.

[76] Chin MH, Goldman L. Factors contributing to the hospitalization of patients with

congestive heart failure. Am J Public Health 1997;87(4):648.

[77] Havranek EP, Abrams F, Stevens E, Parker K. Determinants of mortality in elderly

patients with heart failure. Arch Intern Med 1998;158:20248.

[78] Monane M, Bohn RL, Gurwitz JH, Glynn RJ, Avorn J. Noncompliance with congestive

heart failure therapy in the elderly. Arch Intern Med 1994;154(4):4337.

[79] Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, et al. A comparison of

enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive

heart failure. N Engl J Med 1991;325:30310.

[80] The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe

congestive heart failure. N Engl J Med 1987;316(23):142935.

[81] Arnold JMO, Yusuf S, Young J, Mathew J, Johnstone D, Avezum A, et al. Prevention of

heart failure in patients in the Heart Outcomes Evaluation (HOPE) study. Circulation2003;107:128490.

[82] Kimmelstiel C, Goldeberg RJ. Congestive heart failure in women: focus on heart failure

due to coronary artery disease and diabetes. Cardiology 1990;77(Suppl 2):S719.

[83] Wenger NK, Speroff L, Packard B. Cardiovascular health and disease in women. N Engl

J Med 1993;329(4):24753.

[84] The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on

mortality and morbidity of survivors of acute myocardial infarction with clinical evidence

of heart failure. Lancet 1993;342:8218.

[85] Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme

inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995;273:

14506.[86] Flather MD, Yusuf S, Kober L, Pfeffer M, Hall A, Murray G, et al. Long-term ACE-

inhibitor therapy in patients with heart failure of left-ventricular dysfunction: a systematic

overview of data from individual patients. Lancet 2000;355:157581.

[87] Kostis JB, Shelton B, Gosselin G, Goulet C, Hood WB Jr, Kohn RM, et al. Adverse

effects of enalapril in the Studies of Left Ventricular Dysfunction (SOLVD). Am Heart J

1996;131(2):3505.

[88] Exner DV, Dries DL, Domanski MJ, Cohn JN. Lesser response to angiotensin-

converting-enzyme inhibitor therapy in black as compared with white patients with left

ventricular dysfunction. N Engl J Med 2001;344(18):13517.

[89] Pfeffer MA, Braunwald E, Moye LA. ACE inhibitors after myocardial infarction [reply].

N Engl J Med 1993;328(13):968.[90] Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ, et al. Effect of

losartan compared with captopril on mortality in patients with symptomatic heart failure:

randomized trialthe Losartan Heart Failure Survival Study ELITE II. Lancett 2000;

355:15827.

[91] Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in

chronic heart failure. N Engl J Med 2001;345(23):166775.


7/30/2019 artikel 1-s2.0-S0025712504000343-main

25/25

[92] Leizorovicz A, Lechat P, Cucherat M, Bugnard F. Bisoprolol for the treatment of chronic

heart failure: A meta-analysis of individual data of two placebo-controlled studiesCI-

BIS and CIBIS II. Am Heart J 2002;143:3017.

[93] Packer M, Coats AJS, Fowler MB, Katus HA, Krumholtz H, Mohacsi P, et al. Effect of

carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344(22):16518.

[94] Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of

spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J

Med 1999;341(10):70917.

[95] Pitt B, Remme W, Zannad F, Neaton J, Martinez P, Roniker B, et al. Eplerenone,

a selective aldosterone blocker, in patients with left ventricular dysfunction after

myocardial infarction. N Engl J Med 2003;348(14):130921.

[96] Taylor DO, Edwards LB, Mohacsi PJ, Boucek MM, Trulock EP, Keck BM, et al. The

registry of the International Society for Heart and Lung Transplantation: Twentieth

official adult heart transplant report2003. J Heart Lung Transplant 2003;22:61624.

[97] Stevenson WG, Stevenson LW, Middlekauff HR, Fonarow GC, Hamilton MA, Woo

MA, et al. Improving survival for patients with advance heart failure: a study of 737

consecutive patients. J Am Coll Cardiol 1995;26:141723.

[98] Aaronson KD, Schwartz JS, Goin JE, Mancini DM. Sex differences in patient acceptance

of cardiac transplant candidacy. Circulation 1995;91:275261.

[99] Esmore D, Keogh A, Spratt P, Jones B, Chang V. Heart transplantation in females.

J Heart Lung Transplant 1991;10:33541.

[100] Wechsler ME, Giardina EGV, Sciacca RR, Rose EA, Barr ML. Increased early mortality

in women undergoing cardiac transplantation. Circulation 1995;91:102935.


artikel 1-s2.0-S0025712504000343-main

Documents

Transcript of artikel 1-s2.0-S0025712504000343-main