heart failure and its treatment in women - dhzb: home failure and its treatment in women role of...

© Urban & Vogel 2005Herz © Urban & Vogel 2005Herz

Heart Failure and its Treatment in WomenRole of Hypertension, Diabetes, and Estrogen

Vera Regitz-Zagrosek, Elke Lehmkuhl1

Herzinsuffizienz und ihre Behandlung bei Frauen. Rolle von Hochdruck, Diabetes und Östrogen

ZusammenfassungFrauen und Männer unterscheiden sich deutlich in den Risikofaktoren und dem Verlauf einer Herzin-suffizienz.

Im Gegensatz zu Männern sind bei Frauen ar-terieller Hypertonus und Diabetes mellitus die führenden Risikofaktoren für die Entwicklung einer Herzinsuffizienz. Hypertonus ist bei Frauen auch die Hauptursache für linksventrikuläre Hy-pertrophie und Schlaganfall. Linksventrikuläre Hypertrophie tritt bei Frauen später auf, erhöht jedoch die Mortalität in stärkerem Maße als bei Männern. Der klinische Verlauf einer Herzinsuffi-zienz ist bei Frauen im Allgemeinen jedoch be-nigner und häufiger durch eine gut erhaltene sys-tolische Ventrikelfunktion gekennzeichnet.

Im weiblichen und männlichen menschlichen Herzen finden sich Östrogenrezeptoren. Aufgr-und von Tiermodellen geht man heute davon aus, dass diese die Entstehung der myokardialen Hy-pertrophie und die Progression von Herzinsuffi-

zienz modulieren. Einige der zugrundeliegenden Stoffwechselschritte sind mittlerweile bekannt und umfassen u.a. die Phosphorylierung intrazel-lulärer Kinasen und die Produktion von Stickstoff-monoxid (NO). Interessanterweise kommt es bei Hypertrophie und Herzinsuffizienz beim alten Menschen zu einer Zunahme der Östrogenrezep-toren im Myokard.

Der klinische Verlauf einer Herzinsuffizienz ist bei Frauen durch das häufigere Auftreten einer diastolischen Funktionsstörung charakterisiert. Eine Ursache dafür ist möglicherweise, dass myo-kardiales Remodeling – Fibrose und Apoptose – im Alter und als Konsequenz mechanischer Belas-tung bei Frauen und Männern unterschiedlich verlaufen.

Die Einhaltung von Leitlinien zur Diagnose und Therapie der Herzinsuffizienz wird bei Frauen weniger konsequent verfolgt als bei Männern. Frauen sind insgesamt in klinischen Studien zur Herzinsuffizienz unterrepräsentiert, und in fast

AbstractLarge differences exist between women and men in the syndrome of heart failure (HF).

In contrast to men, hypertension and diabe-tes represent the major risk factors for develop-ment of HF in women and hypertension is also the major cause of left ventricular hypertrophy and stroke. Left ventricular hypertrophy in women increases the risk for mortality to a higher degree than it does in men. The clinical course of HF is generally more benign and more frequently char-acterized by HF with preserved systolic function.

Estrogen receptors are present in the human heart. Based on data from rodent models, they are believed to modulate hypertrophy and the pro-gression of HF. Some of the signaling pathways have been described and involve phosphorylation of intracellular kinases and production of nitric oxide. Interestingly, estrogen receptors are upreg-ulated in human hypertrophy and HF.

The clinical course of HF in women is charac-terized by the more frequent occurrence of dia-stolic HF. Myocardial remodeling with age and, as a consequence, of mechanical load is different in both genders.

Adherence to guidelines in the diagnosis and treatment of HF is less strict in women than in men, leading to undertreatment with inhibitors of the renin-angiotensin system. Women are gen-erally underrepresented in clinical trials in HF and gender-specific analyses have been neglected in most older large survival trials. In some of the large survival studies angiotensin-converting en-zyme inhibitors or β-receptor blockers did not reach significant endpoints in women. However, meta-analyses show overall positive effects for these groups of substances. Angiotensin receptor blockers were effective in large studies including high percentages of women.

Key Words: Women · Gender differ-ences · Heart failure ·Estrogen · Medical therapy

Schlüsselwörter: Frauen · Geschlechtsspe-zifische Unterschiede · Herzinsuffizienz · Östrogen · Medikamen-töse Therapie

1 Cardiovascular Disease in Women CCR, Charité, University Medicine Berlin, and Deutsches Herz-zentrum Berlin, Germany.

Herz 2005;30:356–67

DOI 10.1007/s00059-005-2718-1

356 Herz 30 · 2005 · Nr. 5 © Urban & Vogel

Regitz-Zagrosek V, Lehmkuhl E. Heart Failure and its Treatment in Women

357Herz 30 · 2005 · Nr. 5 © Urban & Vogel

allen älteren großen Überlebensstudien wurden ke-ine geschlechtsspezifischen Auswertungen durch-geführt. In einigen Studien mit Angiotensin-Con-verting-Enzym-Hemmern erreichten Analysen hin-sichtlich der Endpunkte keine statistische Signifikanz bei Frauen. Allerdings weisen Metaanalysen auf eine insgesamt positive Wirkung dieser Substan-zgruppen bei Frauen hin. Für die β-Blocker wurde die

Wirksamkeit bei Frauen in Metaanalysen belegt. Angiotensinrezeptorblocker erwiesen sich in großen Studien mit hohem Frauenanteil als effektive Thera-pie in der Behandlung der Herzinsuffizienz. Digital-iswirkungen sind in hohem Maß blutspiegelabhän-gig – es ist möglich, dass dies die Übersterblichkeit der Frauen unter Digitalistherapie erklärt.

Gender-Specific Aspects in the Etiology of Heart FailureHypertension as a Risk Factor for Heart Failure in Women

In the general population, hypertension affects about 15% of women and 20% of men. However, since the prevalence of hypertension increases strikingly with menopause, more women than men become hypertensive with age. 45% of wom-en and 41% of men between 65 and 74 years are reported to be hypertensive [1, 2]. Since the prev-alence of hypertension in the patients > 75 years is even higher and women live longer than men, > 60% of the hypertensives in the population are women [1, 3]. Systolic and diastolic blood pres-sures rise with age in both sexes, but the increase in systolic blood pressure is steeper in women, whereas diastolic blood pressure is lower in wom-en throughout life [4, 5]. This leads to an increased pulse pressure in women, a key point, since pulse pressure has been shown to be an important and independent predictor of cardiovascular out-come. Menopause is the time of the steepest in-crease in blood pressure in women [5].

Hormone disturbances, i.e., irregular cycle length, late menarche, or early menopause, increase the risk for both hypertension and diabetes in wom-en [6]. These gynecologic disease states in younger women are linked to cardiovascular disease in later life. For example, polycystic ovary syndrome (PCOS) has been shown to increase the risk of car-diovascular disease [7, 8]. This syndrome is charac-terized by sexual hormone disturbances, insulin re-sistance, overweight, and hirsutism/virilism. It often occurs within families, can be genetically based, and has been demonstrated in the brothers of the af-fected women [9]. In addition to PCOS, preeclamp-sia as well as gestational diabetes significantly pre-dict the risk of hypertension in later life [10].

Hypertension represents the major risk factor for development of left ventricular hypertrophy, stroke and heart failure (HF) in women. Left ven-tricular hypertrophy, an independent risk factor for cardiovascular disease, is driven by hypertension and is magnified in obese women with hyperten-sion. The incidence of left ventricular hypertrophy

in obese women reaches 58% [11]. Left ventricular hypertrophy in women carries a greater risk for mortality than it does in men [12]. The incidence of stroke is also higher in hypertensive women than in hypertensive men [13]. Furthermore, systolic blood pressure elevation better predicts stroke mortality in women < 70 years than it does in similar-aged men [14]. Hypertension is the major driving force for HF in women, whereas in men the primary eti-ology is myocardial infarction (Figure 1) [13]. In the Framingham Heart Study, the hazard for develop-ing HF in hypertensives was increased twofold in men and 3.2-fold in women after adjustment for age. Hypertension remained the predominant risk factor after adjustment for angina, myocardial in-

Figure 1. Causes of heart failure (HF) in women and men, based on the Framingham Heart Study: hypertension as major reason for HF in women (women [black] vs. men [white]) [13]. PAR: population-attributable risk; HTN: hypertension; MI: myocardial in-farction; AP: angina pectoris; VHD: valvular heart disease; LVH: left ventricular hyper-trophy; DM: diabetes mellitus.Abbildung 1. Ursachen der Herzinsuffizienz bei Frauen und Männern, basierend auf Ergebnissen aus der Framingham Heart Study: Hypertonie als Hauptursache der Herz-insuffizienz bei Frauen (Frauen [schwarz] vs. Männer [weiß]) [13]; PAR: „population at-tributable risk“; HTN: Hypertonie; MI: Myokardinfarkt; AP: Angina pectoris; VHD: Herz-klappenerkrankungen; LVH: linksventrikuläre Hypertrophie; DM: Diabetes mellitus.

0

10

20

30

40

50

60

HTN MI AP VHD LVH DM

PA

R (%

)

Hazard ratio

W 3.35 6.01 1.68 2.13 2.85 3.73

M 2.07

6.34 1.43 2.47 2.19 1.82



farction, diabetes, left ventricular hypertrophy and valvular heart disease. Hypertension was the cause of HF in 59% of women and 39% of men [13]. In the SOLVD HF trial treatment arm (i.e., ejection fraction [EF] < 35% plus overt symptoms) 55% of women versus 39% of men exhibited hypertension [15]. The most recent Framingham data showed that the lifetime risk for developing HF at age 40 was 28% for hypertensive men and 29% for hyper-tensive women. Framingham data also showed that if only patients without antecedent myocardial in-farction were analyzed, the lifetime risk for devel-oping HF at age 40 was 11% for men and 15% for women. These data underscore the greater rele-vance of hypertension for the development of HF in women. While the importance of blood pressure control is evident for both men and women, control of hypertension is poor and a significant underuse of modern treatment strategies is found with wom-

en beeing treated more frequently with diuretics than men (Figure 2) [16]. Yet treatment of hyper-tension in women is critically important, since it has been shown to prevent about 40% of strokes and 20% of myocardial infarctions in postmenopausal women (Figure 3) [17].

Obesity and Diabetes as Risk Factors for Heart Failure in Women

Obesity and diabetes both belong to the major de-veloping health risks in our society. They affect all parts of the society, children as well as adults, but represent a more severe risk in women than in men. Age, body mass index, and genetic factors play a comparable role in both genders, whereas physical inactivity is more important in women [18].

Overweight is a major risk factor for diabetes in both genders. It is important to note that the pattern of fat distribution appears more critical than weight by itself, since peripheral obesity has been reported to be protective against atheroscle-rosis whereas central adiposity represents a major risk factor [19]. The combination of obesity and hormonal disturbances in postmenopausal wom-en is particularly dangerous. Irregular cycle length, late menarche and early menopause in-crease the risk for diabetes, as they do for hyper-tension. Women with hormone disturbances, with long or highly irregular menstrual cycles and PCOS have an exceedingly high prevalence of diabetes which increases further with obesity [7, 8]. Furthermore, gestational diabetes is a strong predictor for the development of both hyperten-sion and diabetes later in life.

The prevalence of known diabetes is about 8% in Germany in the population from 18–79 years. However, the prevalence of unrecognized diabetes and impaired oral glucose tolerance and elevated fasting glucose blood levels together reaches 27% [20]. Fasting glucose has a higher im-pact on cardiovascular risk in women compared to men [21]. The prevalence of diabetes increases with age, however, the increase is steeper in wom-en [22, 23]. Lifestyle modifications such as appro-priate diet and physical activity like walking lead to reduction of diabetes type 2 risk in women [24, 25]. However, lifestyle modifications are signifi-cantly underused [26] in the general population.

Diabetic women have a three- to sixfold and diabetic men a two- to fourfold increased risk of myocardial infarction [27]. The prevalence and severity of cardiovascular disease as well as worse prognosis are higher in diabetics versus nondia-betics, with the risk enhanced in diabetic women versus diabetic men.

0

5

10

15

20

25

30

35

40

Treated Diuretics β-blockers Calcium blockers ACEI

% o

f hyp

erte

nsiv

es

Figure 2. Awareness and effectiveness of treatment of hypertension. Hypertension affects about 30–40% of the Southern German population (women [black] vs. men [white]). Diuretics are more frequently used in women. Numbers include use of drugs in monotherapy and combination therapy (adapted from [16]).Abbildung 2. Diagnose und Effektivität der Behandlung der Hypertonie. Hypertonie betrifft ca. 30–40% der Bevölkerung Süddeutschlands (Frauen [schwarz] vs. Männer [weiß]). Diuretika wurden häufiger bei Frauen eingesetzt. Zahlen beinhalten die An-wendung von Medikamenten als Monotherapie oder Kombinationstherapie (adapti-ert nach [16]).

Stroke

Myocardial infarction

Fatal myocardial infarction

Total mortality

-25 %−25%

-38 %−38%

-17 %−17%

-11 %-11%

Metaanalysis of 26,000 women

Figure 3. Decrease in mor-tality by treatment of hy-pertension in postmeno-pausal women. Risk reduc-tions for stroke, myocardial infarction, fatal myocardial infarction and total mor-tality are indicated (adapt-ed from [17]).Abbildung 3. Abnahme der Mortalität durch Behand-lung der Hypertonie bei postmenopausalen Frauen. Risikoreduktion für Schlag-anfall, Herzinfarkt, tödli-chen Herzinfarkt und Ge-samtmortalität sind dar-gestellt (adaptiert nach [17]).



The Nurses’ Health Study provided data on the increase in cardiovascular risk by diabetes during 20 years follow-up in 116,177 women aged 30–55 years. Analysis was based on 16,036 per-son-years in diabetic women versus 873,219 per-son-years in women without diabetes [27]. Dia-betic women were older and more obese and, af-ter age adjustment, had greater than threefold increases in the prevalence of hypertension and hypercholesterolemia. Diabetes increased the age-adjusted risk for coronary heart disease 6.7-fold, for stroke 4.1-fold and total cardiovascu-lar mortality 6.3-fold. Duration of diabetes > 20 years increased the risk of cardiovascular disease 13-fold [27]. Furthermore, the Framingham Heart Study, the Chicago Heart Study, and the Minne-sota Heart Survey all obtained evidence that dia-betic patients had a greater risk for the develop-ment of HF after myocardial infarction and con-firmed the higher incidence of early and late mortality in women compared to men [28–30].

The Role of Estrogen and Estrogen Receptors in Myocardial Hypertrophy and Heart Failure

A role of estrogen and estrogen receptors (ERs) in the development of hypertrophy and HF was suggested by the observation that hormone re-placement therapy reduces myocardial hypertro-phy in women [31]. Women have a lower tenden-cy to develop myocardial hypertrophy following comparable mechanical load than men [32]. Women were better protected against apoptotic death signals and showed a later onset of cardiac decompensation than men with HF [33].

In an impressive number of transgenic animal models, a more severe hypertrophic phenotype is developed in male than in female animals and the transition to HF occurs earlier in the male animals [34, 35]. The models are frequently characterized by anomalies in calcium handling or development of fibrosis. Generally, death from HF occurs earli-er in the male than in the female animals.

In a number of these models, the more severe cardiovascular phenotype in male transgenic ani-mals or in ovarectomized females can be rescued by the administration of estrogen. This suggests that estrogen prevents or at least slows down the development of hypertrophy and HF in these models. Indeed, estrogen has been shown to re-duce infarct size and apoptosis [36]. Estrogen was responsible for attenuating pressure overload hy-pertrophy in vivo [37] and to antagonize cardio-myocyte hypertrophy in vitro by ER-dependent mechanisms [38].

So far, both ERs have been described in the human and rodent heart [39, 40]. In rat cardio-myocytes, immunofluorescence confirmed the intracellular co-localization of both ERα and ER� subtypes [41]. In adult rat hearts, ERα was found to be the predominant type of ER whereas ER� expression was high in neonatal animals and was downregulated later in life [42].

In the human cardiovascular system the pres-ence of ERα has recently been confirmed (Figure 4) [43]. ERα can be activated by its ligand, estro-gen, and in a ligand-independent manner and it can act via genomic and nongenomic pathways [38, 44]. Cardioprotective effects have been illus-trated in characterized ERα knockout (ERKO) mice, which underwent an ischemia-reperfusion procedure. ERKO mice produced less nitric ox-ide, accumulated more Ca2+ in the heart and showed higher impairment of mitochondrial re-spiratory function after ischemia treatment than their control littermates, referring ERα to multi-ple cardioprotective mechanisms [45].

So far, the regulation of human myocardial ER content in response to hypertrophy has not yet been investigated. We recently described for the first time a significant upregulation of ERα mRNA and protein and ER� mRNA in human heart hypertrophy [43]. The relative increase in ER� was greater in the female than in the male hearts which was due to slightly lower basal levels and to slightly higher ER� expression in the hy-pertrophied hearts.

Signaling of 17�-estradiol in the human myo-cardium is still a matter of debate. E2 treatment modulates expression of natriuretic peptides in the atria and in the left ventricle of intact rats [37, 42] and signaling via the mitogen-activated pro-tein kinase (MAPK) pathways in cardiomyocytes [37, 41, 46]. It has been shown that in rat cardio-myocytes 17�-estradiol treatment increased ex-pression of eNOS, iNOS [41] and connexin 43 [39]. Furthermore, estrogenic stimulation was associated with an activation of protein kinase B/Akt in the human myocardium and in mouse cardiomyocytes, which will lead to a phosphoryla-tion of forkhead-transcription factors [47]. These mechanisms are generally believed to be anti-apoptotic and cardioprotective [48]. In most of the studies, relative contributions of ERα and ER� to these effects have not been investigated. However, increases in eNOS and iNOS gene ex-pression in myocytes were mediated by ER� [49]. This underscores the role of the ER� subtype in the modulation of myocardial gene expression.

The isoform CnA� of the phosphatase calci-neurin is particularly relevant for the development



of cardiac hypertrophy, since isolated knockout of this gene prevents the development of a hypertro-phic response [50]. We observed a strong inverse correlation between the ER� and CnA� mRNA content in patients with aortic stenosis which may link the increase in ER� to the suppression of this hypertrophic mediator [43]. This is in agreement with cardioprotective effects of ER� upregulation.

A relation between ER expression and mark-ers of hypertrophy such as natriuretic peptides has been reported in the literature [42]. In con-trast to the rat, the ventricular brain natriuretic peptide (BNP) or atrial natriuretic peptide (ANP) gene expression does not correlate with ERα or ER� in human myocardium [43].

There is an ongoing debate, whether sex dif-ferences in cardiac functions in elderly patients may also be linked to ERs. ERs can be activated by peptide growth factors in the absence of ste-

roid hormones [51–53]. In agreement with these data, transcriptional activity of ERs can be found independently of plasma estrogen levels [54]. Therefore, ER-dependent effects may be also rel-evant in postmenopausal women and in men.

Presentation and Clinical Course of Heart Failure in Women

HF affects about 1–3% of the population of the western societies in an age- and gender-dependent manner. There are contradictory reports regarding prognosis in HF in women versus men. Although NHANES I reported a 10-year mortality of 70% in men versus 50% in women [55], the SOLVD trial demonstrated higher morbidity and mortality in women [56]. The most recent analysis of the Fram-ingham data showed that 5-year mortality declined from 57% and 70% in women and men in 1950–1969

Figures 4A to 4D. Detec-tion of estrogen receptor (ER) α in 5-µm paraffin sections of the left ventri-cle of a control human heart by immunofluores-cent staining and confocal laser-scanning microsco-py. A and B show the same section stained for ERα (FITC-green; A) and Caveo-lin3 (Cy3-red; B). C and D show the merged images of A (FITC-green) and B (Cy3-red) and DAPI (blue in D) in the control heart (S. Mahmoodzadeh, S. Eder, unpublished) [43].Abbildungen 4A bis 4D. Nachweis von Östrogen-rezeptor in 5-µm-Paraffin-schnitten von linksventri-kulärem Myokard eines menschlichen Herzens (Kontrolle) mit immuno-fluoreszierender Färbung und konfokaler Laserscan-nermikroskopie. A und B zeigen dieselbe Region, die zum Nachweis von Östrogenrezeptor α (FITC-Grün; A) und Caveolin3 (Cy3-Rot; B) gefärbt wur-de. C und D zeigen die Überlagerungen der Dar-stellungen von A (FITC-Grün) und B (Cy3-Rot) und DAPI (blau in D) im Kon-trollherzen (S. Mahmood-zadeh, S. Eder, unver-öffentlicht) [43].

A B

C D

DAPICaveolin3ER-alpha



to 45% and 59% in 1990–1999. Overall, there was an improvement in the survival rate after the onset of HF of 12% per decade in women and men [57].

In previous studies, diagnosis and treatment of HF focused on systolic dysfunction. More recently, the importance of diastolic HF (i.e., signs and symp-toms of HF in the presence of preserved left ven-tricular function, most frequently defined as EF > 45%) has been highlighted [58]. Diastolic HF has a higher prevalence in women, in the elderly, in hy-pertensives and in obesity (Figure 5). Since diastolic HF is also associated with impaired survival, options for diagnosis and treatment must be considered [59]. BNP is not a distinguishing factor between diastolic and systolic HF [58]. While higher BNP levels may be associated with poorer prognosis, BNP appears to be less reliable as a diagnostic tool in women than in men. Normal BNP levels are reported to be high-er in women than in men, yet, paradoxically, BNP levels rise to a higher degree in men with HF com-pared to women, even in cases of comparable func-tional impairment [60, 61].

The basis of the higher incidence and preva-lence of diastolic HF in elderly women is not yet clear. In an analysis of 19,710 HF patients aged ≥ 65, preserved left ventricular systolic function was present in 35% (n = 6,700), 79% of whom were women [62]. Age-related changes in myo-cardial structure and function have been suggest-ed as contributing factors. Decreased �-adrener-gic receptor density and �-adrenergic receptor inotropic response in the aging female heart, in-creased angiotensinogen levels, increased angio-tensin-converting enzyme (ACE) activity and AT1 expression, and increased myocardial colla-gen content may also play a role. Diabetes and hypertension are the two most important risk fac-tors for the development of diastolic HF in wom-en as they are in systolic HF [58].

Therapeutic decisions in diastolic HF cannot yet be based on large clinical studies. However, therapy is important, since mortality in these pa-tients is increased fourfold in comparison with con-trol subjects free of HF [59]. In experimental stud-ies, both angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) therapy have been shown to enhance relaxation. ARB treatment has been shown to improve exer-cise performance in patients with diastolic dysfunc-tion and a hypertensive response to exercise [63]. A decrease in systemic arterial pressure in such pa-tients is associated with an improvement in dia-stolic function. Inhibition of the renin-angiotensin system (RAS) may also interfere with collagen synthesis and is thought to be as important in dia-stolic HF as in systolic HF [58].

Treatment of Heart Failure in WomenNew guidelines from the American Heart Associa-tion (AHA) take a novel approach to the classifica-tion of HF that emphasizes both the evolution and the progression of the disease. The novel AHA clas-sification identifies four stages of HF (Figure 6) [64]. Stage A represents the patient who is at high risk for HF but has no structural disorder of the heart. Stage B refers to the patient with a structural disorder of the heart but normal systolic function (EF > 40%) who has never developed symptoms of HF. Stage C denotes the patient with past or current symptoms of HF and/or decreased left ventricular ejection fraction (LVEF), and stage D designates the patient with end-stage disease. This classification recogniz-es that therapeutic interventions performed prior to the appearance of left ventricular dysfunction can reduce the morbidity and mortality of HF. It com-plements, but does not replace, the New York Heart Association (NYHA) functional classification.

These new recommendations highlight the importance of the very early therapy of HF, i.e., treatment at the stages of high risk for HF but preceding structural changes to the heart. This emphasis includes the treatment of hypertension and, in selected patients, inhibition of the RAS in stage A, RAS inhibition and �-blockers in stage B, diuretics, RAS inhibition, �-blockers and digi-talis in stage C, and special measures in stage D. The suggestions are based on evidence from large clinical studies showing that treatment according to these guidelines prolongs life.

Several recent HF studies reveal gender bias in the diagnosis or treatment of HF [65–67]. A re-cent Scandinavian analysis found that treatment as well as the diagnosis of HF differed in women and men. Diagnosis was based on an objective test (echocardiography) in only 20% of women [65]. A

0

20

40

60

80

100%

LVEF

> 0.600.50−0.590.41−0.490.31−0.40< 0.30

10

3

8

9

10

3

5

19

3

3

Men(n = 40)

Woman(n = 33)

Figure 5. Prevalence of systolic and diastolic heart failure in a cohort of 73 Framingham Heart Study subjects, 33 women and 40 men, studied by echo-cardiography (adapted from [59]).Abbildung 5. Prävalenz von systolischer und dia-stolischer Herzinsuffizienz bei 73 Teilnehmern der Framingham Heart Study, 33 Frauen und 40 Männer, die echokardiographisch untersucht wurden (adap-tiert nach [59]).



sex disparity was found in the use of ACEIs, lead-ing to less precriptions in women [66, 67]. The sex disparity was confirmed in a Scandinavian study. There, also ACEI doses were lower in women (44% vs. 56%) [65]. By contrast, women were more frequently prescribed digitalis (41% vs. 37%) and diuretics (89% vs. 80%) [65]. A second recent European investigation supported a severe under-utilization of diagnostic tests in women as well as underutilization of therapy in accordance with guidelines in women [68]. A recent American study found that cardiologists more frequently prescribed combination therapy in male versus fe-male patients (adjusted odds ratio [OR] 2.07), whereas digoxin was used more frequently by non-cardiologists in female patients [69]. The less fre-quent use of echocardiography to diagnose HF as well as less aggressive use of antihypertensives in women diagnosed with HF may help explain why women display more symptoms of HF and greater functional impairment than men with comparable levels of left ventricular dysfunction.

DigitalisDigitalis is one of the oldest drugs to be used for HF therapy. In 1997, the Digitalis Investigation Group (DIG) reported the results of a randomized trial evaluating the efficiency of digoxin therapy for patients with HF [70]. Digoxin did not reduce the overall mortality or three of the five secondary outcomes (death due to cardiovascular causes, death due to the worsening of HF, and the com-bined endpoint of death or hospitalization due to worsening of HF in an ancillary trial). However,

digoxin did decrease the risk of hospitalization for worsening HF and the overall risk of hospitaliza-tion during 3 years of follow-up. After the publica-tion of these results, guidelines from the AHA, American College of Cardiology, and European Society of Cardiology strongly endorsed the use of digoxin for patients with HF. However, the DIG trial did not prespecify or report sex-specific sub-group analyses. Therefore, a post hoc subgroup analysis was conducted in 2002 to assess whether there were sex-based differences in the effect of digoxin among the 6,800 patients, 5,281 men and 1,519 women, in the trial. An absolute 5.8% differ-ence was found between men and women in the effect of digoxin on the rate of death from any cause (with a p = 0.034 for the interaction). In the multivariate analysis, digoxin was associated with a significantly higher risk of death among women compared to placebo but had no significantly in-creased risk among men. It was concluded that the effect of digoxin differs between women and men and that digoxin therapy was associated with an increased risk for death from any cause among women, but not men, with HF and depressed LVEF [71]. Dose-related effects as well as an inter-action with hormone replacement therapy were discussed as potential explanations for this unan-ticipated result. In the absence of definitive evi-dence it may be wise to reexamine the use of di-goxin in women with HF and to withhold the drug, if it is not strongly indicated. In any case, these data reinforce the potential for gender-related effects and thus underscore the need to perform either gender-specific clinical trials or to include suffi-cient numbers of women in trials.

DiureticsDiuretics are more frequently used in women de-spite the fact that they may cause more adverse events in women [72]. For example, hyponatre-mia and hypokalemia occur more frequently in women than in men taking diuretics [1, 72]. This may suggest the possibility of more arrhythmia problems in women, since they have longer QT intervals than men and more QT-associated rhythm disturbances. However, no such data have been reported in large studies so far.

The use of diuretics in hypertension has re-ceived renewed attention due to the recent ALL-HAT study [73]. Unfortunately, initial reports of this trial did not include gender-specific analysis of outcome other than reduction in hypertension. ALLHAT did, however, confirm less aggressive treatment patterns in women compared to men, since fewer women reached blood pressure goals

Stage A Stage B Stage C Stage D

High risk for

developing HF

Structural disorders

Past or current symptoms of HF

End -stage disease

Antihypertensivetherapy,lifestylemodification

Like under A, plus ACEIs andβ-blockers afterAMI

Like under B,+ diuretics+ ACEI+ β-blocker+ digitalis

Like under C,+ LVAD+ HTX+ hospice care

Figure 6. Novel heart failure classification and guidelines for medical and specialized treatment by the AHA [64]. AMI: acute myocardial infarction; HTX: heart transplanta-tion; LVAD: left ventricular assist device.Abbildung 6. Neue Klassifikation der Herzinsuffizienz und Leitlinien für medika-mentöse und spezielle Therapie der AHA [64].



and there was more monotherapy and less upti-tration in women compared with men [74].

β-Blockers�-blockers are a well-established therapy that im-prove survival in HF. However, their mechanisms of action are not completely clear. They may in-clude reduction of ischemic events in coronary heart disease. However, benefit has also been re-ported in HF of nonischemic etiologies. In dilated cardiomyopathy, ventricular enlargement and re-modeling are reduced by �-blockers and plasma norepinephrine levels decrease with �-blockers. Adrenergic stimulation contributes to ventricular remodeling by activation of hypertrophic path-ways. Experimental data suggest that estrogen leads to a reduction of the activity of a central hy-pertrophic pathway, the p38MAPK pathway, by stimulation of its inhibitor MAPK phosphatase 1 (MKP1) [75]. In addition, female cardiomyocytes exhibit a lower density of �-adrenoreceptors than male cells, and have less responsiveness to isopro-terenol leading to a reduced calcium influx after �-adrenergic stimulation [76]. Menstrual cycle af-fects �-adrenoreceptor responsiveness [77]. Gen-der differences exist in pharmacokinetics and pharmacodynamics of �-blockers, resulting in greater drug exposure in women [78, 79].

As in many HF clinical trials, women repre-sented minorities in clinical trials testing b-block-ers. It is of note that two major trials, the Metopro-lol CR/XL study and the COPERNICUS trial, failed to find a benefit on mortality reduction in women [80, 81]. In the Metoprolol CR/XL study, women were the only subgroup for whom a mor-tality benefit was not demonstrated (risk reduc-tion 0.92 in women vs. 0.61 in men). However, the primary combined endpoint (all-cause mortality + all-cause hospitalizations) was reduced by 29% in women (p < 0.044). A detailed gender-specific analysis was published for the CIBIS II study (Ta-ble 1) [82, 83]. In this study, the 575 women were older than the 2,132 men, had some indications of more severe disease and were less frequently treated with ACEIs and aspirin and had more fre-quently undefined causes of HF. Nevertheless, they profited significantly from the treatment with bisoprolol. Women who were treated with biso-prolol had even a higher unadjusted effect on all-cause mortality than did men. Pooling of mor-tality results from MERIT-HF, CIBIS II, and CO-PERNICUS showed similar survival benefits in women and men [84]. Thus, the conflicting results in the large �-blocker studies are probably due to the underrepresentation of women in the trials.

Angiotensin-Converting Enzyme Inhibitors (ACEIs)

ACEIs represent the standard and first-line thera-py for HF based on more than ten large outcome trials [85]. However, in several multicenter studies, data are insufficient to prove a mortality reduc -tion in women. In CONSENSUS I, SAVE and SOVLD, only small percentages of women were included (Table 2) [86–89]. A meta-analysis includ-ing 7,105 HF patients receiving ACEIs described a significant reduction in total mortality (OR 0.77; 95% confidence interval [CI] 0.67–0.88) and in the combined endpoint of mortality or hospitalization for HF (OR 0.65; 95% CI 0.57–0.74). This me-ta-analysis claimed that the effects were compara-ble in women and men, but detailed data by gender were not included [85]. It may well be that signifi-cant reductions for mortality and for the combined second endpoint of all-cause mortality and hospi-talizations for HF were observed mainly in men. Since there was no evidence of statistical heteroge-neity reported, the apparent lack of response could reflect the small number of women treated, as it was the case in the �-blocker studies [84]. In the SOLVD arm made up of asymptomatic HF patients, ACEIs significantly reduced the number of HF-related hos-pitalizations, but did not significantly reduce num-ber of cardiovascular deaths [90]. Again, no analysis was performed by gender. However, later trials, such as AIRE and HOPE, showed a significant ben-efit of ACEIs in women [91, 92].

ACEIs are also effective in preventing HF [92]. Ramipril reduced the HF onset rate in high-risk patients without manifest HF from 11.5% to 9.0%, (RR [relative risk] 0.77, 0.68–0.87). ACEIs have been shown to improve insulin sensitivity, prevent cardiovascular events and re-duce the number of new cases of type 2 diabetes [92–94]. However, once again, gender-specific analyses are not provided, with the percentage of women being low (20–30%). Effects on HF and diabetes may be due to inhibition of the RAS, since similar effects have been reported for ARBs (see below). It is of note, however, that the recent Second Australian National Blood Pressure Study

Table 1. Outcome in women in large β-blocker trials. NS: not significant; RR: relative risk.Tabelle 1. Prognose bei Frauen in den großen β-Blocker-Studien. NS: nicht signifikant; RR: relatives Risiko.

Patients Women RR mortality RR mortality (n) (%) men women

CIBIS II [83] 2,647 19.4 0.71 0.52, p < 0.001MERIT-HF [80] 3,991 22.5 0.61 0.92, NSCOPERNICUS [81] 1,094 23.4 0.65 0.65, NS



demonstrated a significant reduction in cardio-vascular events in men but not in women, despite similar reductions in blood pressure in both gen-ders [95]. When considering treatment options, it is also of note that ACEI side effects such as cough are reported to be more frequent in wom-en. For example, monitoring of three different ACEIs used in general practice in Great Britain demonstrated a higher incidence of cough in women (Table 3) [96].

Angiotensin Receptor Blockers (ARBs)In HF, ARB therapy resulted in a significant re-duction of HF hospitalizations with a particularly favorable effect on the combined endpoints of mortality and morbidity, on left ventricular re-modeling and on neurohormonal activation [97–99]. In Val-HeFT, they significantly reduced mortality in ACEI-naive patients (Figure 6) and led to a significant improvement in quality of life in the whole cohort [97].

The very recently published CHARM pro-gramme confirmed beneficial effects of ARBs in HF. In CHARM, a significant reduction of mortal-ity was found in the overall study including 7,601 patients (CHARM-Overall), where an ARB was either added to optimized therapy (CHARM-Add-ed) or an ARB was used as an alternative in ACEI-intolerant patients (CHARM-Alternative),

or an ARB was used in patients with preserved LVEF (CHARM-Preserved) [100–103].

There is a broad database for ARBs in women. In the LIFE study, large percentages of women were included and they profited comparably to men [104]. In the CHARM programme, the beneficial effects were comparable in women and men [100]. Interestingly, the percentage of women was 21% in the CHARM-Added, 32% in the CHARM-Alter-native and 40% in the CHARM-Preserved trial, which may indicate that women with severe HF and ACEI treatment are more difficult to find than women with HF and ACEI intolerance or women with HF and preserved LVEF [101–103].

Inhibition of the RAS may be of particular relevance in postmenopausal women where AT1-mediated effects are likely to be augmented as the downregulation of the RAS by estrogens diminishes. Not only AT1, but more generally, global RAS activity is downregulated in premeno-pausal women by estrogen and this natural down-regulation disappears with menopause [105, 106]. In addition, circulating biomarkers of inflamma-tion or fibrinolysis are increased in postmeno-pausal women, including C-reactive protein, in-terleukin-6 and plasminogen activator inhibitor-1 (PAI-1) [107, 108]. Thus, ARBs may provide spe-cific advantages in postmenopausal women with hypertension and HF due to reported effects of ARB on AT1 blockade, PAI-1 secretion , and re-duction in oxidative stress and the low frequency of side effects [109, 110].

References1. Hayes SN, Taler SJ. Hypertension in women: current un-

derstanding of gender differences. Mayo Clin Proc 1998;73:157–65.

2. Gasse C, Hense HW, Stieber J, et al. Assessing hyperten-sion management in the community: trends of preva-lence, detection, treatment, and control of hyperten-sion in the MONICA Project, Augsburg 1984–1995. J Hum Hypertens 2001;15:27–36.

3. Staessen J, Bulpitt CJ, Fagard R, et al. The influence of menopause on blood pressure. J Hum Hypertens 1989;3:427–33.

4. Franklin SS, Gustin W IV, Wong ND, et al. Hemodynamic patterns of age-related changes in blood pressure: the Framingham Heart Study. Circulation 1997;96:308–15.

5. Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hy-pertension in the US adult population: results from the Third National Health and Nutrition Examination Survey, 1988–1991. Hypertension 1995;25:305–13.

6. Bairey Merz CN, Johnson BD, Sharaf BL, et al. Hypoes-trogenemia of hypothalamic origin and coronary ar-tery disease in premenopausal women: a report from the NHLBI-sponsored WISE study. J Am Coll Cardiol 2003;41:413–9.

7. Solomon CG, Hu FB, Dunaif A, et al. Menstrual cycle ir-regularity and risk for future cardiovascular disease. J Clin Endocrinol Metab 2002;87:2013–7.

Table 2. Risk reduction with angiotensin-converting enzyme inhibitor therapy in women and men.Tabelle 2. Risikoreduktion unter Therapie mit ACE-Hemmern bei Männern und Frauen.

Patients Women Risk reduction, Risk reduction, (n) (%) primary primary endpoints, endpoints women

CONSENSUS [86] 253 30 Mortality: 51% 6%SOLVD [89] 2,569 20 Mortality: 16% Not specifiedSAVE [88] 2,231 18 Cardiovascular Not specified in the endpoints: 21% original study, 4%

Table 3. Risk for cough with angiotensin-converting enzyme inhibitor therapy in fe-males compared to males [96]. CI: confidence interval; RR: relative risk.Tabelle 3. Risiko für die Nebenwirkung Husten bei der ACE-Hemmer-Therapie bei Frauen und Männern [96]. CI: Konfidenzintervall; RR: relatives Risiko.

Drug Patient months Age-adjusted RR 95% CI p-value of exposure

Enalapril 21,983 1.4 0.8–2.5 0.17Lisinopril 18,749 1.6 1.2–2.2 < 0.01Perindopril 12,751 1.6 1.2–2.1 < 0.01

AcknowledgmentsThe authors acknowledge the valuable contributions of Margaret Forney Pres-cott for her critical com-ments and stimulating discussions.We greatly thank S. Mah-moodzadeh and S. Eder for contributing the pic-ture of myocardial estro-gen receptors.Supported by the DFG (grants to V.R.-Z.) and the BMBF (competence network heart failure).



8. Solomon CG, Hu FB, Dunaif A, et al. Long or highly ir-regular menstrual cycles as a marker for risk of type 2 diabetes mellitus. JAMA 2001;286:2421–6.

9. Dunaif A, Thomas A. Current concepts in the polycystic ovary syndrome. Annu Rev Med 2001;52:401–19.

10. Albareda M, Caballero A, Badell G, et al. Diabetes and abnormal glucose tolerance in women with previous gestational diabetes. Diabetes Care 2003;26:1199–205.

11. De Simone G, Devereux RB, Roman MJ, et al. Relation of obesity and gender to left ventricular hypertrophy in normotensive and hypertensive adults. Hypertension 1994;23:600–6.

12. Liao Y, Cooper RS, Mensah GA, et al. Left ventricular hy-pertrophy has a greater impact on survival in women than in men. Circulation 1995;92:805–10.

13. Levy D, Larson MG, Vasan RS, et al. The progression from hypertension to congestive heart failure. JAMA 1996;275:1557–62.

14. Casiglia E, Mazza A, Tikhonoff V, et al. Arterial hyper-tension and mortality in the elderly. Am J Hypertens 2002;15:958–66.

15. Johnstone D, Limacher M, Rousseau M, et al. Clinical characteristics of patients in studies of left ventricular dysfunction (SOLVD). Am J Cardiol 1992;70:894–900.

16. Gasse C, Stieber J, Doring A, et al. Population trends in antihypertensive drug use: results from the MONICA Augsburg Project 1984 to 1995. J Clin Epidemiol 1999;52:695–703.

17. Gueyffier F, Boutitie F, Boissel JP, et al. Effect of antihy-pertensive drug treatment on cardiovascular outcomes in women and men. A meta-analysis of individual patient data from randomized, controlled trials. The INDANA Investigators. Ann Intern Med 1997;126:761–7.

18. Meisinger C, Thorand B, Schneider A, et al. Sex differ-ences in risk factors for incident type 2 diabetes melli-tus: the MONICA Augsburg cohort study. Arch Intern Med 2002;162:82–9.

19. Tanko LB, Bagger YZ, Alexandersen P, et al. Peripheral adiposity exhibits an independent dominant antiath-erogenic effect in elderly women. Circulation 2003;107:1626–31.

20. Rathmann W, Haastert B, Icks A, et al. High prevalence of undiagnosed diabetes mellitus in Southern Germa-ny: target populations for efficient screening. The KO-RA survey 2000. Diabetologia 2003;46:182–9.

21. McPherson K, Steel CM, Dixon JM. ABC of breast dis-eases. Breast cancer – epidemiology, risk factors, and genetics. BMJ 2000;321:624–8.

22. Lundberg V, Stegmayr B, Asplund K, et al. Diabetes as a risk factor for myocardial infarction: population and gender perspectives. J Intern Med 1997;241:485–92.

23. Tuomilehto J, Korhonen HJ, Kartovaara L, et al. Preva-lence of diabetes mellitus and impaired glucose toler-ance in the middle-aged population of three areas in Finland. Int J Epidemiol 1991;20:1010–7.

24. Hu FB, Stampfer MJ, Solomon C, et al. Physical activity and risk for cardiovascular events in diabetic women. Ann Intern Med 2001;134:96–105.

25. Hu FB, Sigal RJ, Rich-Edwards JW, et al. Walking com-pared with vigorous physical activity and risk of type 2 diabetes in women: a prospective study. JAMA 1999;282:1433–9.

26. Stampfer MJ, Hu FB, Manson JE, et al. Primary preven-tion of coronary heart disease in women through diet and lifestyle. N Engl J Med 2000;343:16–22.

27. Manson JE, Colditz GA, Stampfer MJ, et al. A prospec-tive study of maturity-onset diabetes mellitus and risk

of coronary heart disease and stroke in women. Arch Intern Med 1991;151:1141–7.

28. Greenland P, Knoll MD, Stamler J, et al. Major risk fac-tors as antecedents of fatal and nonfatal coronary heart disease events. JAMA 2003;290:891–7.

29. Pan WH, Cedres LB, Liu K, et al. Relationship of clinical diabetes and asymptomatic hyperglycemia to risk of coronary heart disease mortality in men and women. Am J Epidemiol 1986;123:504–16.

30. Sprafka JM, Burke GL, Folsom AR, et al. Trends in preva-lence of diabetes mellitus in patients with myocardial infarction and effect of diabetes on survival. The Min-nesota Heart Survey. Diabetes Care 1991;14:537–43.

31. Modena MG, Molinari R, Muia N Jr, et al. Double-blind randomized placebo-controlled study of transdermal estrogen replacement therapy on hypertensive post-menopausal women. Am J Hypertens 1999;12:1000–8.

32. Carroll JD, Carroll EP, Feldman T, et al. Sex-associated differences in left ventricular function in aortic steno-sis of the elderly. Circulation 1992;86:1099–107.

33. Guerra S, Leri A, Wang X, et al. Myocyte death in the failing human heart is gender dependent. Circ Res 1999;85:856–66.

34. Du XJ. Gender modulates cardiac phenotype develop-ment in genetically modified mice. Cardiovasc Res 2004;63:510–9.

35. Xin HB, Senbonmatsu T, Cheng DS, et al. Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy. Nature 2002;416:334–8.

36. Patten RD, Pourati I, Aronovitz MJ, et al. 17beta-estradi-ol reduces cardiomyocyte apoptosis in vivo and in vitro via activation of phospho-inositide-3 kinase/Akt sig-naling. Circ Res 2004;95:692-9.

37. Van Eickels M, Grohe C, Cleutjens JP, et al. 17beta-estra-diol attenuates the development of pressure-overload hypertrophy. Circulation 2001;104:1419–23.

38. Babiker FA, De Windt LJ, van Eickels M, et al. 17beta-estra-diol antagonizes cardiomyocyte hypertrophy by auto-crine/paracrine stimulation of a guanylyl cyclase A recep-tor-cyclic guanosine monophosphate-dependent protein kinase pathway. Circulation 2004;109:269–76.

39. Grohe C, Kahlert S, Lobbert K, et al. Cardiac myocytes and fibroblasts contain functional estrogen receptors. FEBS Lett 1997;416:107–12.

40. Taylor AH, Al-Azzawi F. Immunolocalisation of oestro-gen receptor beta in human tissues. J Mol Endocrinol 2000;24:145–55.

41. Nuedling S, Kahlert S, Loebbert K, et al. 17beta-estradiol stimulates expression of endothelial and inducible NO synthase in rat myocardium in-vitro and in-vivo. Car-diovasc Res 1999;43:666–74.

42. Jankowski M, Rachelska G, Donghao W, et al. Estrogen receptors activate atrial natriuretic peptide in the rat heart. PNAS 2001;98:11765–70.

43. Nordmeyer J, Eder S, Mahmoodzadeh S, et al. Upregula-tion of myocardial estrogen receptors in human aortic stenosis. Circulation 2004;110:3270–5.

44. Chen Z, Yuhanna IS, Galcheva-Gargova Z, et al. Estro-gen receptor alpha mediates the nongenomic activa-tion of endothelial nitric oxide synthase by estrogen. J Clin Invest 1999;103:401–6.

45. Zhai P, Eurell TE, Cotthaus R, et al. Effect of estrogen on global myocardial ischemia-reperfusion injury in fe-male rats. Am J Physiol Heart Circ Physiol 2000;279:H2766–75.

46. De Jager T, Pelzer T, Muller-Botz S, et al. Mechanisms of estrogen receptor action in the myocardium. Rapid



gene activation via the ERK1/2 pathway and serum re-sponse elements. J Biol Chem 2001;276:27873–80.

47. Camper-Kirby D, Welch S, Walker A, et al. Myocardial Akt activation and gender: increased nuclear activity in females versus males. Circ Res 2001;88:1020–7.

48. Matsui T, Li L, del Monte F, et al. Adenoviral gene trans-fer of activated phosphatidylinositol 3'-kinase and Akt inhibits apoptosis of hypoxic cardiomyocytes in vitro. Circulation 1999;100:2373–9.

49. Nuedling S, Karas RH, Mendelsohn ME, et al. Activation of estrogen receptor beta is a prerequisite for estro-gen-dependent upregulation of nitric oxide synthases in neonatal rat cardiac myocytes. FEBS Lett 2001;502:103–8.

50. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus pro-gestin and the risk of coronary heart disease. N Engl J Med 2003;349:523–34.

51. Smith CL, Conneely OM, O’Malley BW. Modulation of the ligand-independent activation of the human es-trogen receptor by hormone and antihormone. Proc Natl Acad Sci U S A 1993;90:6120–4.

52. Curtis SW, Washburn T, Sewall C, et al. Physiological coupling of growth factor and steroid receptor signal-ing pathways: estrogen receptor knockout mice lack estrogen-like response to epidermal growth factor. Proc Natl Acad Sci U S A 1996;93:12626–30.

53. Gruber CJ, Tschugguel W, Schneeberger C, et al. Produc-tion and actions of estrogens. N Engl J Med 2002;346:340–52.

54. Ciana P, Raviscioni M, Mussi P, et al. In vivo imaging of transcriptionally active estrogen receptors. Nat Med 2003;9:82–6.

55. Schocken DD, Arrieta MI, Leaverton PE, et al. Prevalence and mortality rate of congestive heart failure in the United States. J Am Coll Cardiol 1992;20:301–6.

56. Bourassa MG, Gurne O, Bangdiwala SI, et al. Natural his-tory and patterns of current practice in heart failure. The Studies of Left Ventricular Dysfunction (SOLVD) In-vestigators. J Am Coll Cardiol 1993;22:Suppl A:14A–9A.

57. Levy D, Kenchaiah S, Larson MG, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med 2002;347:1397–402.

58. Chatterjee K. Primary diastolic heart failure. Am J Geri-atr Cardiol 2002;11:178–87, quiz 188–9.

59. Vasan RS, Larson MG, Benjamin EJ, et al. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mor-tality in a population-based cohort. J Am Coll Cardiol 1999;33:1948–55.

60. Luchner A, Brockel U, Muscholl M, et al. Gender-specific differences of cardiac remodeling in subjects with left ventricular dysfunction: a population-based study. Cardiovasc Res 2002;53:720–7.

61. Emdin M, Passino C, Del Ry S, et al. Influence of gender on circulating cardiac natriuretic hormones in patients with heart failure. Clin Chem Lab Med 2003;41:686–92.

62. Masoudi FA, Havranek EP, Smith G, et al. Gender, age, and heart failure with preserved left ventricular sys-tolic function. J Am Coll Cardiol 2003;41:217–23.

63. Warner JG Jr, Metzger DC, Kitzman DW, et al. Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol 1999;33:1567–72.

64. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Asso-ciation Task Force on Practice Guidelines (Committee to

Revise the 1995 Guidelines for the Evaluation and Man-agement of Heart Failure): developed in collaboration with the International Society for Heart and Lung Trans-plantation; endorsed by the Heart Failure Society of America. Circulation 2001;104:2996–3007.

65. Agvall B, Dahlstrom U. Patients in primary health care diagnosed and treated as heart failure, with special reference to gender differences. Scand J Prim Health Care 2001;19:14–9.

66. Clinical Quality Improvement Network Investigators. Mortality risk and patterns of practice in 4606 acute care patients with congestive heart failure. The rela-tive importance of age, sex, and medical therapy. Arch Intern Med 1996;156:1669–73.

67. Chin MH, Goldman L. Factors contributing to the hos-pitalization of patients with congestive heart failure. Am J Public Health 1997;87:643–8.

68. Mejhert M, Holmgren J, Wandell P, et al. Diagnostic tests, treatment and follow-up in heart failure patients – is there a gender bias in the coherence to guidelines? Eur J Heart Fail 1999;1:407–10.

69. Harjai KJ, Nunez E, Stewart Humphrey J, et al. Does gender bias exist in the medical management of heart failure? Int J Cardiol 2000;75:65–9.

70. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart fail-ure. N Engl J Med 1997;336:525–33.

71. Rathore SS, Wang Y, Krumholz HM. Sex-based differ-ences in the effect of digoxin for the treatment of heart failure. N Engl J Med 2002;347:1403–11.

72. Gasse C, Hense HW, Stieber J, et al. Factors associated with differences in antihypertensive drug treatment: results from the MONICA Augsburg Population Sur-veys 1989/90 and 1994/95. Soz Präventivmed 2002;47:128–42.

73. The ALLHAT Study Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-con-verting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981–97.

74. Cushman WC, Ford CE, Cutler JA, et al. Success and pre-dictors of blood pressure control in diverse North Amer-ican settings: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens (Greenwich) 2002;4:393–405.

75. Dash R, Schmidt AG, Pathak A, et al. Differential regula-tion of p38 mitogen-activated protein kinase mediates gender-dependent catecholamine-induced hypertro-phy. Cardiovasc Res 2003;57:704–14.

76. Vizgirda VM, Wahler GM, Sondgeroth KL, et al. Mecha-nisms of sex differences in rat cardiac myocyte re-sponse to beta-adrenergic stimulation. Am J Physiol Heart Circ Physiol 2002;282:H256–63.

77. Mills PJ, Ziegler MG, Nelesen RA, et al. The effects of the menstrual cycle, race, and gender on adrenergic recep-tors and agonists. Clin Pharmacol Ther 1996;60:99–104.

78. Luzier AB, Killian A, Wilton JH, et al. Gender-related ef-fects on metoprolol pharmacokinetics and pharmaco-dynamics in healthy volunteers. Clin Pharmacol Ther 1999;66:594–601.

79. Riemer RK, Wu YY, Bottari SP, et al. Estrogen reduces beta-adrenoceptor-mediated cAMP production and the concentration of the guanyl nucleotide-regulatory protein, Gs, in rabbit myometrium. Mol Pharmacol 1988;33:389–95.

80. The MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised



Intervention Trial in Congestive Heart Failure (MER-IT-HF). Lancet 1999;353:2001–7.

81. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996;334:1349–55.

82. Simon T, Mary-Krause M, Funck-Brentano C, et al. Sex differences in the prognosis of congestive heart fail-ure: results from the Cardiac Insufficiency Bisoprolol Study (CIBIS II). Circulation 2001;103:375–80.

83. CIBIS-II Investigators. The Cardiac Insufficiency Biso-prolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9–13.

84. Ghali JK, Pina IL, Gottlieb SS, et al. Metoprolol CR/XL in female patients with heart failure: analysis of the ex-perience in Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF). Circula-tion 2002;105:1585–91.

85. Garg R, Yusuf S. Overview of randomized trials of angio-tensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA 1995;273:1450–6.

86. CONSENSUS. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CON-SENSUS). The CONSENSUS Trial Study Group. N Engl J Med 1987;316:1429–35.

87. Halm MA, Penque S. Heart failure in women. Prog Car-diovasc Nurs 2000;15:121–33.

88. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of capto-pril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the Survival And Ventricular Enlargement trial. The SAVE Investigators. N Engl J Med 1992;327:669–77.

89. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection frac-tions and congestive heart failure. N Engl J Med 1991;325:293–302.

90. The SOLVD Investigators. Effect of enalapril on mortal-ity and the development of heart failure in asymptom-atic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685–91.

91. The Acute Infarction Ramipril Efficacy (AIRE) Study In-vestigators. Effect of ramipril on mortality and morbid-ity of survivors of acute myocardial infarction with clini-cal evidence of heart failure. Lancet 1993;342:821–8.

92. Arnold JM, Yusuf S, Young J, et al. Prevention of heart failure in patients in the Heart Outcomes Prevention Evaluation (HOPE) study. Circulation 2003;107:1284–90.

93. Yusuf S, Gerstein H, Hoogwerf B, et al. Ramipril and the development of diabetes. JAMA 2001;286:1882–5.

94. Yusuf S, Sleight P, Pogue J, et al. Effects of an angioten-sin-converting-enzyme inhibitor, ramipril, on cardio-vascular events in high-risk patients. The Heart Out-comes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145–53.

95. Wing LM, Reid CM, Ryan P, et al. A comparison of out-comes with angiotensin-converting-enzyme inhibi-tors and diuretics for hypertension in the elderly. N Engl J Med 2003;348:583–92.

96. Mackay FJ, Pearce GL, Mann RD. Cough and angiotensin II receptor antagonists: cause or confounding? Br J Clin Pharmacol 1999;47:111–4.

97. Cohn JN, Tognoni G. A randomized trial of the angio-tensin-receptor blocker valsartan in chronic heart fail-ure. N Engl J Med 2001;345:1667–75.

98. Wong M, Staszewsky L, Latini R, et al. Valsartan bene-fits left ventricular structure and function in heart fail-ure: Val-HeFT echocardiographic study. J Am Coll Car-diol 2002;40:970–5.

99. Latini R, Masson S, Anand I, et al. Effects of valsartan on circulating brain natriuretic peptide and norepineph-rine in symptomatic chronic heart failure: the Valsar-tan Heart Failure Trial (Val-HeFT). Circulation 2002;106:2454–8.

100. Pfeffer M, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003;362:759–66.

101. McMurray JJV, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-en-zyme inhibitors: the CHARM-Added trial. Lancet 2003;362:767–71.

102. Granger C, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular sys-tolic function intolerant to angiotensin-convert-ing-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003;362:772–6.

103. Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved trial. Lancet 2003;362:777–81.

104. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascu-lar morbidity and mortality in the Losartan Interven-tion For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995–1003.

105. Danser AH, Derkx FH, Schalekamp MA, et al. Determi-nants of interindividual variation of renin and prorenin concentrations: evidence for a sexual dimorphism of (pro)renin levels in humans. J Hypertens 1998;16:853–62.

106. Fischer M, Baessler A, Schunkert H. Renin angiotensin system and gender differences in the cardiovascular system. Cardiovasc Res 2002;53:672–7.

107. Bermudez EA, Rifai N, Buring J, et al. Interrelationships among circulating interleukin-6, C-reactive protein, and traditional cardiovascular risk factors in women. Arterioscler Thromb Vasc Biol 2002;22:1668–73.

108. Pradhan AD, Manson JE, Rossouw JE, et al. Inflamma-tory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women’s Health Initiative observational study. JAMA 2002;288:980–7.

109. Sironi L, Calvio AM, Arnaboldi L, et al. Effect of valsartan on angiotensin II-induced plasminogen activator in-hibitor-1 biosynthesis in arterial smooth muscle cells. Hypertension 2001;37:961–6.

110. Wassmann S, Laufs U, Stamenkovic D, et al. Raloxifene improves endothelial dysfunction in hypertension by reduced oxidative stress and enhanced nitric oxide production. Circulation 2002;105:2083–91.

Address for CorrespondenceProfessor Vera Regitz-Zagrosek, MDDHZBAugustenburger Platz 113353 BerlinGermanyPhone (49/30) 4593-2410, -2230, Fax -2409e-mail: [email protected]

heart failure and its treatment in women - dhzb: home failure and its treatment in women role of...

Documents