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J Am Coll Cardiol, 1999; 34:1427-1434
© 1999 by the American College of Cardiology Foundation
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CLINICAL STUDIES

Evidence against a role of physiological concentrations of estrogen in post-myocardial infarction remodeling

Stephanie Hügel, MD*, Martin Reincke, MD*, Hinrik Strömer, MD*, Johannes Winning, MD*, Michael Horn, PhD*, Charlotte Dienesch*, Patricia Mora*, Harald H. H. W. Schmidt, MD{dagger}, Bruno Allolio, MD* and Stefan Neubauer, MD*

* Medizinische Universitätsklinik, Würzburg, Germany
{dagger} Institut für Pharmakologie und Toxikologie, Universität Würzburg, Würzburg, Germany

Manuscript received December 31, 1998; revised manuscript received May 20, 1999, accepted June 28, 1999.

Reprint requests and correspondence: Dr. Stephanie Hügel, Medizinische Universitätsklinik, Josef-Schneider-Str. 2, 97080 Würzburg, Germany
huegel{at}mail.uni-wuerzburg.de


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES

The purpose of this study was to examine whether endogenous estrogen deficiency induced by ovariectomy affects chronic left ventricular dysfunction post–myocardial infarction (MI).

BACKGROUND

Epidemiologic findings suggest that mortality of postmenopausal women is increased after MI, but the underlying mechanisms are unknown.

METHODS

Rats were either not ovariectomized (non-OVX), ovariectomized (OVX) or ovariectomized and treated with subcutaneous 17-beta-estradiol (E2) pellets (OVX + E2). Two weeks later, animals were sham-operated (Sham) or left coronary artery ligated (MI). Eight weeks later, in vivo echocardiographic and hemodynamic measurements were performed. Thereafter, hearts were isolated and perfused isovolumically.

RESULTS

Mean infarct size was similar among the three MI groups. Ovariectomy decreased serum E2 levels (11 ± 4 vs. 49 ± 11 pg/ml in non-OVX, p < 0.01) and increased body weight. These changes were reversed by E2 replacement. The degree of cardiac hypertrophy was similar for all groups post-MI. Left ventricular diameters were increased post-MI (8.9 ± 0.4 in non-OVX + MI vs. 6.7 ± 0.2 mm in non-OVX + Sham hearts, p < 0.0001), but OVX or OVX + E2 replacement did not alter left ventricular diameters in post-MI and Sham hearts. Left ventricular fractional shortening was severely impaired post-MI (19 ± 2% vs. 50 ± 3 in non-OVX + Sham hearts, p < 0.0001) with no influence of hormonal status. Left ventricular end-diastolic pressure, measured in vivo, was increased in all MI groups without significant differences between groups. Pressure-volume curves, obtained in perfused hearts, demonstrated a right and downward shift with reduced maximum left ventricular developed pressure post-MI (75 ± 6 vs. 108 ± 3 mm Hg in non-OVX + Sham hearts, p < 0.001) and were also unaffected by either OVX or E2 replacement.

CONCLUSIONS

Chronic endogenous estrogen deficiency does not have major effects on the development of cardiac hypertrophy, dysfunction and dilation post-MI.

Abbreviations and Acronyms
  CHD = coronary heart disease
  E2 = 17-beta-estradiol
  EDP = end-diastolic pressure
  eNOS = endothelial nitric oxide synthase
  HR = heart rate
  LV = left ventricle
  LVDP = left ventricular developed pressure
  MI = myocardial infarction
  OVX = ovariectomy

The incidence of cardiovascular disease in premenopausal women is lower compared with age-matched men but increases rapidly after menopause up to a level close to that in men (1). Premenopausal women appear to be protected from the development of coronary artery disease, and after menopause, estrogen replacement therapy reduces the incidence of coronary artery disease and the progression of coronary artery lesions (2–6). In postmenopausal women, prognosis post–myocardial infarction (MI) is inferior to that in males (7–12). Furthermore, epidemiologic data (13) suggest that death from MI is less frequent in women receiving estrogen replacement therapy compared with women not taking estrogens. The observational studies published to date (3,4,14,15) have shown that estrogen is associated with a 70% to 80% lower risk of death in women with established coronary artery disease.

This cardioprotective effect is generally believed to be related to the interaction of estrogens in the process of atherosclerosis (16). Additional protective mechanisms of estrogens may involve effects on vascular function and structure of the vessel wall involving numerous cellular and molecular mechanisms. Estrogens can modulate vascular function by increasing nitric oxide production via stimulation of endothelial nitric oxide synthase (eNOS) (17) and via a decrease of endothelin-1 levels (18,19). Furthermore, 17-beta-estradiol (E2) is an inhibitor of vascular smooth muscle cell proliferation and migration (20), phenomena that play a major role in atherosclerotic vascular disease. Besides scavenging free radicals (21), estrogen interferes with the renin-angiotensin system by decreasing aortic wall angiotensin-converting enzyme activity (22) and by downregulating angiotensin II receptor subtype 1 expression in vascular smooth muscle cells (23).

Recent studies (24,25) have demonstrated the presence of estrogen alpha and beta receptors in cardiac myocytes and fibroblasts. These estrogen receptors are functional and have been shown to regulate the expression of specific cardiac genes such as the progesterone receptor and the gap junction protein connexin 43 gene (25). These findings suggest that gender-based and pre- versus postmenopausal differences in cardiac pathophysiology may in part be due to direct effects of estrogens on cardiac cells such as myocytes and fibroblasts, which are involved in the remodeling process post-MI. Therefore, we hypothesized that postmenopausal estrogen deficiency has a detrimental effect on the remodeling process post-MI. In the present study, for the first time, we examine the effect of estrogen deficiency on post-MI remodeling in rats.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Animals, ovariectomy and estrogen substitution.   All procedures conformed to the Position of the American Heart Association on Research Animal Use, adopted by the American Heart Association November 11, 1984. Female Wistar rats weighing 160 to 180 g (Charles River Deutschland GmbH, Sulzfeld, Germany) were kept in a 12-h light-dark cycle at constant temperature and humidity. Animals were given water and commercial rat chow ad libitum.

Ovariectomies (OVX) or non-ovariectomies (non-OVX) were performed through dorsal incisions under ether anesthesia in 12-week-old rats. Rats were randomly assigned to one of three subgroups: OVX, non-OVX and OVX + E2. Immediately after OVX, half of the animals received subcutaneous implants of 90-day release pellets containing 1 mg of E2 (OVX + E2) (Innovative Research of America, Sarasota, Florida). The non-OVX group and the other OVX rats received matching placebo pellets. The sustained release pellets were designed to maintain E2 serum concentrations slightly above the physiologic range. Placebo pellets contained all the components of the E2 pellets except for the hormone itself.

Experimental MI.   Two weeks after OVX or non-OVX, MI or sham operations were performed in each group. Thus, together, six experimental groups were studied: 1) non-OVX sham operated (non-OVX + Sham); 2) non-OVX infarcted (non-OVX + MI); 3) OVX sham operated (OVX + Sham); 4) OVX infarcted (OVX + MI); 5) OVX, estrogen-treated sham operated (OVX + E2 + Sham); and 6) OVX, E2-treated infarcted rats (OVX + E2 + MI). Left coronary artery ligation was induced by a previously described technique (26,27). A left thoracotomy was performed under ether anesthesia and positive pressure ventilation. The heart was rapidly exteriorized by applying gentle pressure on both sides of the thorax. The left coronary artery was ligated between the pulmonary outflow tract and the left atrium. The heart was then replaced into the thorax, lungs were inflated by increasing positive end-expiratory pressure and the wound was closed immediately. Sham operation was performed using an identical procedure, except that the suture was passed under the coronary artery without ligation. Mortality rate of infarcted rats within the first 24 h after the operation was 40% to 50%.

Echocardiographic studies.   Seven to eight weeks after MI, all rats underwent transthoracic echo-Doppler examination. Previous reports have demonstrated the accuracy and the reproducibility of transthoracic echocardiography in rats for measuring left ventricle (LV) size and function (28–30). Briefly, rats were anesthetized with ketamine HCl (50 mg/kg; Parke-Davis, Berlin, Germany) and xylazine (10 mg/kg; BayerVital, Leverkusen, Germany), both given intraperitoneally. The chest was shaved, and rats were placed prone on a specially designed apparatus. Echocardiograms were performed from underneath with a commercially available echocardiographic system (Toshiba SSH-140A) equipped with a 7.0-MHz phased-array transducer (Toshiba Medical Systems GmbH, Munich, Germany). A two-dimensional short-axis view of the LV was obtained at the level of the papillary muscles. Two-dimensional targeted M-mode tracings were recorded through the anterior and posterior LV walls (Fig. 1). End-diastolic and end-systolic LV internal diameters were measured by the leading-edge method according to the American Society of Echocardiology (31). Measurements were taken as the average of three consecutive cardiac cycles.



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  		Figure 1 Representative M-mode tracings of the short-axis LV in a non-OVX + Sham (a), a non-OVX + MI (b), an OVX + MI (c) and an OVX + E2 + MI rat (d) eight weeks after left coronary artery ligation. There is increased LV cavity dimension, akinesis and thinning of anterior wall in all rats with MI.

 
Two-dimensionally guided pulsed-wave Doppler spectra of mitral inflow were recorded from an apical four-chamber view, with the sample volume placed near the tips of the mitral leaflets and adjusted to the position where velocity was maximal and the flow pattern was laminar (Fig. 2). In rats with MI (13 out of 35 rats), no A waves could be seen above the filter cutoff on the mitral inflow Doppler spectra. In these cases, peak A-wave velocity was considered to be 5 cm/s (the lowest limit of the high-pass wall filter cutoff on the Doppler spectral tracing). All rats remained in sinus rhythm. Thus, A waves cannot be absent but may be undetectable below the filter cutoff. Maximum early and late diastolic flow velocities were derived from mitral inflow velocities, and LV outflow tract velocimetry was recorded from five-chamber views. Cardiac output was calculated as:

Left ventricular outflow tract diameter was measured at the base of the aortic leaflets in a parasternal long-axis view. All Doppler spectra were recorded on paper at 130 mm/s and analyzed off-line as described previously (29).



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  		Figure 2 Left ventricular developed pressure-volume curves for all experimental groups; *p < 0.017 sham versus corresponding MI. A right and downward shift of the curve was observed for all MI groups. (Open circles) Non-OVX + Sham, (filled circles) non-OVX + MI, (open triangles) OVX + Sham, (filled triangles) OVX + MI, (open squares) OVX + E2 + Sham, (filled squares) OVX + E2 + MI.

 
In vivo hemodynamic measurements.   Eight weeks after left coronary artery ligation or sham operation, rats were anesthetized with ether. A polyethylene cannula was inserted into the trachea for artificial ventilation. The right carotid artery was isolated by cut-down, and a 1-mm micromanometer-tipped catheter (Millar Instruments, Houston, Texas) was passed retrogradely into the LV, then withdrawn to the aortic arch under continuous monitoring of developed pressures via a three-way stopcock (to allow flushing), with zero adjusted to mid-chest level to determine baseline on the recorder. Left ventricular systolic and end-diastolic pressures, mean arterial pressure and heart rate (HR) were measured under light ether anesthesia and spontaneous respiration.

Isolated rat heart preparation.   Immediately after in vivo hemodynamic measurements were completed, a transverse laparotomy and left and right anterolateral thoracotomy were performed, and the heart was rapidly excised and immersed in ice-cold buffer. The aorta was dissected free, and mounted onto a cannula attached to a perfusion apparatus, as previously described (32). Retrograde perfusion of the heart was begun in the Langendorff mode at a constant temperature of 37°C and a constant coronary perfusion pressure of 100 mm Hg. For perfusion, glucose-containing Krebs-Henseleit buffer was used as previously described (33). Coronary flow was continuously measured by an ultrasonic flow probe (Transonic Systems Inc., Ithaca, New York) built into the perfusate inflow tubing. As previously shown (34), the perfusion system allowed maintenance of hearts in a steady state for at least 90 min, with changes of less than 5% for all mechanical and metabolic parameters.

A water-filled latex balloon was inserted into the LV through an incision in the left atrial appendage, via the mitral valve, and secured by a ligature. The balloon was connected to a Statham P23Db pressure transducer (Gould Instruments, Glen Burnie, Maryland) via a small-bore polyethylene tubing for continuous measurement of left ventricular pressure and heart rate on a four-channel recorder (Graphtec Corp., Tokyo, Japan). All hearts were given 10 to 15 min for stabilization, where left ventricular end-diastolic pressure was set to 10 mm Hg by adjusting the balloon volume in the LV. A left ventricular pressure-volume curve was performed by stepwise inflation of the balloon by 0.03 ml until maximum left ventricular developed pressure (LVDP) was obtained or until end-diastolic pressure (EDP) exceeded 50 mm Hg. Recordings of all parameters were made at each step when a new steady state was reached, which occurred within 2 min.

Serum estrogen levels.   At the time of the excision of the heart, blood was taken for hormone measurements. Serum E2 levels were analyzed using a solid-phase 125I-radioimmunoassay technique (DPC Bierman, Bad Nauheim, Germany) according to the manufacturer’s instructions. Assay sensitivity was 1.4 pg/ml for E2.

Determination of infarct size.   The LV was shock-frozen in methylbutane (Sigma GmbH, Deisenhofen, Germany) precooled in liquid nitrogen. Hearts were then stored at –80°C. Sections of 14 µm were cut serially from apex to base by a commercially available cryostat (Kryostat Mycrotom Jung CM 3000; Leica, Nussloch, Germany) at a temperature of –26°C. Sections were stained for collagen using Picrosirius Red (Sirius red: Chroma-Gesellschaft Schmidt GmbH and Co., Köngen/N., Germany; picroacid: E. Merck, Darmstadt, Germany). The scar extension, clearly visible as red areas on each section, determines the infarct area. Slices were digitized, and lengths of scar and noninfarcted muscle for both endocardial and epicardial surfaces were determined by cursor measurements for every section. The ratio of the lengths of scar and surface circumferences defined the infarct size for endo- and epicardial surfaces, respectively. Final infarct size was determined as the average of endo- and epicardial surfaces and is given as percentage of total heart size. To ensure comparability of the infarcted groups, all hearts with an infarct size <30% (n = 12) and >50% (n = 3) were excluded from the analysis.

Statistical analysis.   All data are presented as mean ± standard error of the mean. With six experimental groups, 15 statistical comparisons are conceivable. Testing for this high number of comparisons with multifactorial analysis of variance would "overcorrect" significance levels. Therefore, we limited the statistical analysis to "biologically meaningful" comparisons, where each sham group is compared with the respective MI group and to the altered hormonal status. For example, the non-OVX + Sham group is compared with non-OVX + MI, OVX + Sham and OVX + E2 + Sham. Comparison of variables between two groups was made by using the unpaired Student t test. Bonferroni’s correction for multiple comparisons was applied to yield a significance level of 0.05:3 = 0.017. Calculations were performed by a commercially available program, Stat View SE + Graphics (Brainpower Inc., Calabasas, California).


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Animal characteristics and hormone determination.   Infarct size, body weight, tibial length, ex vivo heart weight and estradiol serum levels are shown in Table 1. Mean infarct size was 39 ± 1% on average and was not different among groups. Body weight was significantly higher in OVX rats and significantly smaller in rats receiving chronic E2 pellets compared with non-OVX animals. Also, tibial length was significantly larger in OVX rats and smaller in rats with E2 substitution compared with non-OVX animals. Heart weight and heart weight/body weight increased in all MI groups compared with sham-operated groups. Estrogen levels were significantly lower in the ovariectomized groups and somewhat but not significantly higher in rats receiving chronic E2 treatment compared with non-OVX animals.


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  		Table 1 Characteristics of Study Groups and Hormone Levels

 
Echocardiographic studies.   M-mode tracings of the left ventricular short axis from a non-OVX sham-operated, a non-OVX with MI, an OVX with MI and an OVX + E2 rat with MI are shown in Figure 1. Echocardiographic assessment of left heart geometry and function for the six groups are shown in Table 2. Compared with sham-operated hearts, MI hearts showed structural changes such as increased LV diastolic and systolic diameters. Structural changes after MI were unaltered when animals were OVX or OVX + E2 treated. All MI groups showed enlarged left atrium diameters indicating backward failure; this was also unaffected by OVX or OVX + E2.


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  		Table 2 M-Mode and Doppler Echocardiographic Data

 
Functional abnormalities accompanied structural remodeling of the LV post-MI (Table 2). The combination of impaired regional function and LV cavity enlargement resulted in a substantial decrease in fractional shortening (50 ± 3% in sham vs. 19 ± 2% in MI hearts; p < 0.0001). These echocardiographic changes post-MI are as previously reported (28). Modulation of hormonal status by OVX or OVX + E2 had no effect on echocardiographic indices of cardiac function in infarcted hearts.

Doppler-derived indices of systolic and diastolic function are shown in Table 2. Myocardial infarction caused alterations of LV diastolic filling indicated by a "restrictive pattern," that is, a decreased mitral A/E ratio (0.20 ± 0.09 and 0.61 ± 0.11 for non-OVX + MI vs. non-OVX + Sham). These parameters were unchanged by OVX or OVX + E2. In spite of functional and structural alterations, under the unstressed conditions studied here, all groups maintained normal cardiac output (in absolute as well as in relative terms).

In vivo hemodynamics.   In vivo hemodynamic parameters of the six groups are shown in Table 3. Hemodynamic changes of MI groups were characteristic of post-MI remodeling in the rat model (26,35): EDP increased, whereas HR, systolic LV pressure and mean arterial pressure were unchanged. The hormonal status did not affect in vivo hemodynamics.


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  		Table 3 In Vivo Hemodynamics

 
In vitro cardiac performance and pressure-volume relations.   Figure 3 shows LVDP-volume relations for the six experimental groups. The curve for the non-OVX + MI group was shifted right and downwards, indicating structural dilation and left ventricular dysfunction. Pressure-volume curves were not significantly affected by OVX or OVX + E2 treatment.


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Definition of the model.   The present study defines cardiac dimensions and function under estrogen deficiency caused by bilateral ovariectomy and under E2 repletion, mimicking a postmenopausal hormonal status as well as the effects of estrogen replacement therapy and using a clinically highly relevant model of heart failure occurring chronically post-MI. For non-OVX sham and MI groups, in vivo and in vitro findings were as previously reported (33,36,37). In MI hearts, structural dilation is indicated by increased left ventricular and left atrial diameters measured in vivo and rightward shift of pressure-volume curves ex vitro. Decreased systolic function is demonstrated by decreased fractional shortening (in vivo) and downward shift of the pressure-volume curves (ex vivo). In addition, diastolic dysfunction is attested to by increased left ventricular EDP and an abnormal left ventricular filling pattern (A/E wave). The model used here is well suited to study the chronic effects of both protective (37–39) and deleterious (40) interventions. Thus, with the number of experimental animals used here, this model would allow detection of major effects of estrogen status on the remodeling process, if such effects were present.

Effects of OVX and of estrogen replacement.   The major finding of the present study was that estrogen deficiency occurring after OVX does not have a major adverse effect on the remodeling process post-MI. In OVX rats, estradiol serum levels were still detectable but were significantly (approximately fourfold) reduced compared with non-OVX rats. This hormonal status is similar to that found in postmenopausal women, because nonovarian sources contribute to circulating estradiol levels to a small extent. The biological efficacy of OVX in this study is, next to decreased estradiol serum levels, demonstrated by increased body weight and increased tibial length, both abolished by E2 replacement. These effects of estrogen deficiency are well characterized (41–45) and correspond to the weight gain at the time of menopause (46).

In infarcted non-OVX animals, hearts developed substantial hypertrophy, as indicated by increased heart weight occurring in spite of the loss of approximately 40% of left ventricular tissue from infarction. Ovariectomy did not modulate the extent of hypertrophy, as attested to by similar heart weight and heart weight/tibial length ratios. The same was true for estrogen replacement after OVX. In this model, neither ovariectomy nor estrogen replacement had any effect on geometry or function in either sham-operated or infarcted hearts. Post-MI, the increase of left ventricular diastolic and systolic dimensions and decrease of fractional shortening were all similar for the three MI groups. Diastolic function was impaired to the same extent in all MI groups with increased left atrial dimensions, decreased mitral A/E ratios and increased left ventricular end-diastolic pressures in vivo. In vitro pressure-volume relations, showing a marked right and downward shift in the infarcted groups, were also unaffected by the hormonal status. Although a trend to higher developed pressures was observed post-MI in the estrogen replacement group, this finding did not reach statistical significance. In this study, we used a slightly supraphysiologic estrogen replacement dosage. It remains possible, however, that a protective effect of estrogens can be detected when higher, pharmacologic doses are used. Data in this respect are currently lacking, and this hypothesis merits testing.

Epidemiological findings in postmenopausal women led us to examine whether endogenous estrogen deficiency affects the remodeling process post-MI. The Framingham Study (1) addressed gender differences in cardiovascular morbidity and mortality over age. Premenopausal women seem to be protected from cardiovascular disease, whereas the risk of MI rises dramatically after menopause, resulting in a lifetime risk that is similar to that of men. Conversely, clinical studies (7–12) have shown that women have a higher mortality after MI compared with men. Estrogens may affect the extent of cardiovascular disease not only by their systemic actions, that is, altered lipid profile and lowering of blood pressure, but also by direct effects on the vascular wall, especially on vascular smooth muscle cells. In an experimental study, estrogen has been shown to inhibit the response to vascular injury in the mouse carotid artery, even without alterations in the systemic lipid profile (47). However, not only the vascular tissue but also the heart is a target organ for estrogen action. Cardiac myocytes and fibroblasts express functionally intact estrogen receptors (25). These are the major cells contributing to left ventricular hypertrophy. Clinical trials have shown that, indeed, women have a lower prevalence of left ventricular hypertrophy than men (48,49). The Framingham Heart Study showed that left ventricular mass is significantly greater in men than in women, even after indexing for body surface area. Farhat et al. (50) demonstrated in a rat model of pulmonary hypertension that OVX potentiates the extent of right ventricular hypertrophy, and, in sinoaortic denervated rats, Cabral et al. (51) demonstrated the inhibition of left ventricular hypertrophy development by estrogen. By contrast to these results, however, our findings clearly suggest that physiological concentrations of E2 do not have major effects on the remodeling process post-MI. The reason for these discrepancies are, at present, unclear but may be related to model-specific causes of hypertrophy (right vs. left heart, pressure vs. volume overload, etc.).

The discrepancy between clinical observations and the results of the present study may be explained by the design of epidemiologic studies. A recent clinical trial by Malacrida et al. (52) confirmed an increased mortality in women after a cardiovascular event compared with men. However, in this study, women were, on average, older than men. Adjustment for age and other differences of baseline clinical features reduced the difference to a nonsignificant relative risk of 1.1. Sonke et al. (53) showed higher case fatality for women after hospital admission compared with men, but, after adjustment for confounding variables, this increase was reduced to a relative risk of 1.18. They concluded that the higher case fatality after an acute cardiac event in women admitted to the hospital may largely be explained by differences in living status, history and medical treatment and is balanced by a lower case fatality before admission. It is, therefore, possible that the cardioprotective effects of estrogen are related to endothelial function, acute cardiac arrhythmias and reduction of infarct size. These effects were not examined in the present study, because hearts were selected to yield similar mean infarct sizes among the MI groups. This is a requirement if the chronic effects of interventions on post-MI remodeling are to be tested (35). The assumption that possible beneficial effects of estrogen are related to the acute/subacute stage of MI is supported by the observation that increased mortality in postmenopausal women is largely restricted (54,55) to in-hospital mortality. However, the new randomized trial Heart and Estrogen-progestin Replacement Study (HERS) (56) showed no reduction in the overall rate of coronary heart disease (CHD) events in postmenopausal women with established CHD during an average follow-up of 4.1 years, treating patients with oral conjugated equine estrogen plus medroxyprogesterone acetate. The risk of CHD events was increased in the early phase of hormone replacement therapy but decreased after several years of therapy. The results of this study cannot directly be extrapolated to our findings; however, the design of HERS was chosen to demonstrate a secondary prevention of CHD with hormone replacement therapy. By contrast, the purpose of our study was to show alterations in post-MI remodeling.

Study limitations.   We induced estrogen deficiency by bilateral ovariectomy. Therefore, estradiol serum levels were low but still detectable, similar to the menopausal situation. We do not know whether additional blockade of estrogen receptors by estrogen receptor antagonists (e.g., ICI182,780) may cause a detrimental effect on cardiac remodeling. However, this situation would be clinically less relevant. Moreover, we did not examine whether administration of pharmacological doses of estrogen may positively influence chronic cardiac structural and functional alterations. These studies remain to be done.


   Footnotes
 
This work was supported by a grant from the Bundesministerium für Bildung und Forschung (Interdisziplinäres Zentrum für Klinische Forschung der Universität Würzburg, FRG, Teilprojekt E2).


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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