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European Journal of Heart Failure 2002 4(6):719-726; doi:10.1016/S1388-9842(02)00170-8
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© 2002 European Society of Cardiology

Acute haemodynamic effects of oestrogen administration in male patients with chronic heart failure

Stamatis Adamopoulos, Dionyssios Leftheriotis*, Eftihia Sbarouni, George Karavolias and Dimitrios Th Kremastinos

Second Department of Cardiology, Onassis Cardiac Surgery Centre 356 Syngrou Avenue, 176 74 Athens, Greece

* Corresponding author. Tel.: +30-1-9493-372/000; fax: +30-1-9493-373. E-mail address: elbee{at}ath.forthnet.gr


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Background: Although there are many studies concerning the effects of long-term oestrogen administration on systemic haemodynamics in postmenopausal women, the effects of oestrogen in patients with chronic heart failure are not defined.

Aim: The goal of this study was to evaluate the acute haemodynamic effects of oestrogen in male patients with chronic heart failure.

Methods and results: We studied 15 men with advanced heart failure (NYHA II–IV, EF<35=). A Swan–Ganz thermodilution catheter was advanced in their pulmonary artery and central haemodynamics were assessed at baseline, after placebo administration, and following 0.625 and 1.25 mg of oestrogen infusion. Simultaneously, all patients underwent limb plethysmography. Analysis of variance with repeated measures was used to compare the sequential measurements. Following oestrogen administration, right atrial, pulmonary artery and pulmonary capillary wedge pressures, as well as systemic, pulmonary and forearm vascular resistance were decreased; cardiac output, cardiac index, stroke volume, stroke volume index, stroke work index and forearm blood flow were increased.

Conclusions: In male patients with chronic heart failure, acute oestrogen administration improves the indices of cardiac systolic performance and decreases pulmonary and systemic vascular resistance. These findings imply a beneficial effect of oestrogen in selected patients with chronic heart failure.

Key Words: Oestrogen • Heart failure • Acute effect • Haemodynamics

Received October 11, 2001; Revised July 22, 2002; Accepted July 23, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Although there are many observational studies regarding oestrogen replacement therapy and cardiovascular risk in postmenopausal women [1,2], the effects of oestrogen on systemic haemodynamics have not been, so far, fully elucidated, especially in patients with heart failure. There are studies providing indications that stroke volume and cardiac output increase, whereas systemic vascular resistance falls during ovulation induction [3], as well as during oral contraceptive administration in nonpregnant women [4,5]. Echocardiographic studies on postmenopausal women after transdermal oestrogen administration failed to prove any effect on myocardial contractility [6], while Doppler studies have shown that a single dose of oral oestrogen [7] and long-term oestrogen replacement therapy improves left ventricular diastolic function in postmenopausal women [8]. In a recent study, using thoracic electrical bioimpedence to evaluate the possible variations in cardiac haemodynamic parameters in healthy postmenopausal women treated with oestrogen replacement therapy, a decrease in systemic vascular resistance has been observed, accompanied by an improvement in end-diastolic index, acceleration index and cardiac index rate [9]. In addition, oestrogen replacement therapy seems to be associated with decreased overall and cardiac mortality among aging women with symptomatic congestive heart failure [10].

The effects of oestrogen administration have been studied in ovariectomised rats with heart failure and a decrease in total peripheral resistance and left ventricular end-diastolic pressure have been observed, without any increase in cardiac output [11]. In other studies, however, ovariectomised rats with heart failure, receiving oestrogen replacement therapy, had increased left ventricular shortening fraction, compared with those without treatment [12]. A recent study regarding the effects of oestrogen on venous function in rats with chronic heart failure, has shown a decrease in arterial and venous resistance, leading to an increase in cardiac output [13].

It seems, therefore, that the haemodynamic properties of oestrogen, concerning the failing myocardium, have been evaluated in animal studies, but the effects of oestrogen administration in humans with chronic heart failure have not, yet, been described. In our study, the acute haemodynamic effects of conventional doses of conjugated oestrogens, administered as an intravenous bolus, in male patients with advanced chronic heart failure were investigated, using a thermodilution pulmonary artery catheter and venous occlusion limb plethysmography.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Patients
We studied 15 consecutive male patients with heart failure of various aetiologies, undergoing cardiac evaluation for heart transplantation. All patients were in a stable haemodynamic state, their systolic blood pressure was higher than 80 mmHg and they were not receiving vasodilators or intravenous inotropic drugs during the study. None of them had severe renal or hepatic failure. The investigation conforms with the principles outlined in the Declaration of Helsinki and informed consent was obtained before patients entered the study. The clinical characteristics and medical treatment of our study population are shown in Table 1.


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  		Table 1 Clinical characteristics of the study population (n=15)

 
2.2. Study protocol
Cardiac catheterization was performed with local anaesthesia at the site of puncture. To keep basal haemodynamic conditions stable, no changes in chronic treatment were accepted before the procedure and patients received their medications the morning of the study. A 7Fr Swan–Ganz thermodilution catheter was inserted through the right jugular vein and advanced in the pulmonary artery, in a position providing a satisfactory pulmonary capillary wedge pressure trace with inflation of the balloon. After a 20-min period of stabilisation, baseline measurements were performed, including cuff systolic and diastolic blood pressure, right atrial, pulmonary artery and pulmonary capillary wedge pressure. Pressures were monitored and recorded simultaneously by a computer and their values were the mean of 15 cardiac cycles. Transpulmonary pressure gradient was calculated as the difference between the mean pulmonary artery pressure and the mean pulmonary capillary wedge pressure. Cardiac output and cardiac index were determined by thermodilution, using iced normal saline. The values used were the average of three sequential measurements. Systemic and pulmonary vascular resistance and vascular resistance indices, as well as stroke volume, stroke volume index and stroke work index were also calculated. Then, 1 ml of normal saline 0.09% was injected as a placebo via the Swan–Ganz catheter and all these measurements were repeated 10 min later. Subsequently, 0.625 mg of conjugated oestrogens were injected as a bolus via the same catheter and all measurements were repeated 10 min after drug administration. Finally, another injection of 1.25 mg of conjugated oestrogens followed and all measurements were repeated once more 10 min later. The type of conjugated oestrogens used was Premarin (Wyeth, Paris, France) and the doses that we administered were identical to those previously described [14–16].

Our patients underwent limb plethysmography, while their central haemodynamic parameters were assessed. Forearm blood flow was measured by venous occlusion plethysmography, using mercury in silastic gauges connected to a plethysmograph (Hokanson EC-4; DE Hokanson WA, USA). The venous cuff was connected to a rapid cuff inflator (Hokanson E-20 rapid cuff inflator) filled from a compressor (Hokanson AG-101 cuff inflator source), allowing inflation of the cuff to a preset pressure (50 mmHg) in less than 0.3 s. All patients were in the supine position, the limb bearing the apparatus was positioned above heart height before readings were taken and it was held immobile during the study. Limb blood flow was derived from the rate of increase in limb circumference during venous occlusion, using an electronic calibration signal and expressed in ml/100 ml/min. Forearm blood flow calculations were obtained at baseline state, 10 min after placebo administration and 10 min following each oestrogen injection (0.625 and 1.25 mg, respectively). Forearm vascular resistance was calculated from mean blood pressure/forearm blood flow (arbitrary units). Forearm vascular resistance changes and forearm blood flow alterations (%) were assessed after placebo and oestrogen administration and were compared with baseline values.

During the infusions, a double blind procedure was followed. Patients were not aware of the agent they were administered (normal saline or oestrogen). The physician performing the infusions and analysing all recordings and measurements was also unaware of the type of the infused substances.

2.3. Statistics
We used analysis of variance (ANOVA) with repeated measures to compare baseline parameters with those following placebo administration and those recorded after the two subsequent administrations of oestrogen. When a significant difference was found, post-hoc analysis using the least significant difference test was performed to further compare baseline values with those achieved after each dose of oestrogen, as well as the two doses between them. A P value <0.05 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
3.1. Pulmonary and systemic vascular resistance and pressures
None of the recorded haemodynamic parameters changed significantly after normal saline administration (Table 2). Heart rate and mean systemic blood pressure did not change significantly following oestrogen injection in either dose, while pulmonary artery pressure and pulmonary capillary wedge pressure were decreased (ANOVA, P<0.01 for each parameter), as shown in Table 2. Transpulmonary pressure gradient, however, remained unaltered. A decrease in right atrial pressure was observed after oestrogen administration (ANOVA, P<0.05). Systemic and pulmonary vascular resistance were both significantly decreased (ANOVA, P<0.05 for both parameters). Systemic vascular resistance index was also decreased following oestrogen infusion (ANOVA, P<0.01, Fig. 1). A trend towards a decrease in pulmonary vascular resistance index was observed with oestrogen, though statistically nonsignificant (ANOVA, P=0.06). Venous occlusion limb plethysmography showed a decrease in forearm vascular resistance (ANOVA, P<0.05, Fig. 2a), combined with an increase in forearm blood flow (ANOVA, P<0.05, Fig. 2b). Post-hoc comparison between values at baseline and those following 0.625 and 1.25 mg of conjugated oestrogen are shown in Table 2. When measurements after the first oestrogen infusion (0.625 mg) were compared to those following the second infusion (1.25 mg), no significant differences were observed.


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  		Table 2 Haemodynamic results prior to and following oestrogen administration

 


Figure 1
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  		Fig. 1 Changes in systemic vascular resistance index (SVRI) and pulmonary vascular resistance index (PVRI) following placebo and oestrogen administration. BL, baseline; PL, placebo; 0.625 mg; first dose of oestrogen; 1.25 mg, second dose of oestrogen. *post hoc P value <0.05.

 


Figure 2
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  		Fig. 2 (a) The response of forearm vascular resistance (FVR) to placebo and oestrogen administration. (b) The response of forearm blood flow (FBF) to placebo and oestrogen administration. BL, baseline; PL, placebo; 0.625 mg, first dose of oestrogen; 1.25 mg, second dose of oestrogen; *post hoc P value <0.05; **post hoc P value <0.01.

 
3.2. Cardiac performance
Cardiac output and cardiac index were increased following oestrogen administration (ANOVA, P<0.05 for both indices, Table 2). Stroke volume and stroke volume index were also increased with oestrogen (ANOVA, P<0.01 for each parameter). The changes in cardiac index and stroke volume index are depicted in Fig. 3. Finally, oestrogen infusion was associated with an increase in stroke work index of our patients (ANOVA, P<0.05). In Table 2 (post hoc comparisons), the differences between measurements following each dose of oestrogen and baseline values are shown. No significant differences were observed between values following the first oestrogen infusion (0.625 mg) and those following the second one (1.25 mg).


Figure 3
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  		Fig. 3 Changes in cardiac index (CI) and stroke volume index (SVI), following placebo and oestrogen administration. BL, baseline; PL, placebo; 0.625 mg, first dose of oestrogen; 1.25 mg, second dose of oestrogen; *post-hoc P value <0.05; **post-hoc P value <0.01.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
The haemodynamic properties of oestrogen have been investigated in animals with heart failure and an increase in cardiac output has been reported [11,12]. There are studies suggesting that this beneficial effect is mediated through an increase in heart rate, secondary to systemic vasodilation [17,18]. In another study, an improvement in stroke volume has been observed, secondary to an increase in blood volume [19].

In humans with heart failure, however, the haemodynamic response to oestrogen administration has not, so far, been studied. This is, to our knowledge, the first attempt to describe the central and peripheral haemodynamic changes following acute infusion of conventional doses of oestrogen in male patients with advanced chronic heart failure.

4.1. Systemic and pulmonary circulation
Long-term conventional doses of oestrogen replacement therapy in postmenopausal women without evidence of chronic heart failure do not seem to affect systemic blood pressure [20], but have been shown to decrease carotid artery impedance [21]. In addition, 1 month of oestrogen replacement therapy decreased forearm vascular resistance in normotensive postmenopausal women [22].

Acute administration of 17β-oestradiol, achieving physiologic serum levels typical of reproductive women at midcycle, did not induce vasodilation in peripheral circulation, while blood flow and vascular resistance were similar to values observed following ethanol diluent alone [23,24]. In another study, however, acute administration of supraphysiological dose of oestrogens had caused an increase in forearm blood flow 40 min later, combined with a decrease in forearm vascular resistance, while no alteration in blood pressure had been observed [25]. A recently published study has shown that acute administration of oestradiol in males causes an increase in their forearm blood flow, secondary to vasodilation, which is not due to alterations in vascular angiotensin-converting enzyme activity or to altered sensitivity to angiotensin II [26]. Sublingual administration of 1 or 2 mg of 17β-oestradiol in postmenopausal women, augments aortic and brachial blood flow, as a result of vasodilation [27].

In our study, we evaluated for the first time the effects of oestrogen administration, not only on systemic, but also on pulmonary circulation. Acute infusion of conjugated oestrogens seems to reduce pulmonary artery and pulmonary capillary wedge pressure in patients with chronic heart failure. Transpulmonary pressure gradient remained unchanged in our patients, obviously, because of an almost equal decrease in pulmonary artery and pulmonary capillary wedge pressure. Although no significant effect was observed on mean systemic blood pressure, the decrease in pulmonary artery and pulmonary capillary wedge pressure was associated with a statistically significant decrease in pulmonary vascular resistance and systemic vascular resistance. The beneficial effect of oestrogen administration on the peripheral systemic circulation was confirmed by the decrease observed in forearm vascular resistance and the increase in forearm blood flow, as depicted by venous occlusion limb plethysmography. No dose-related response was observed in the parameters evaluated in our study.

4.2. Inotropic effects
Experimental studies in female rats, have shown that 17β-oestradiol increased cardiac output in a dose-dependent manner, due to a reduction in peripheral resistance, but, in higher doses, myocardial contractility was depressed, as shown by isovolumic left ventricular systolic pressure and dp/dt max [28]. Furthermore, there are studies demonstrating a negative inotropic effect of 17β-oestradiol on guinea-pig isolated ventricular myocytes, by inhibiting inward calcium current and reducing the intracellular free calcium [29].

When the effects of oestrogen administration on human myocardial function were studied, controversial results were observed. Ten weeks of hormone replacement therapy, in conventional doses, improved Doppler aortic flow indices (peak flow velocity, flow velocity integral and mean acceleration) in postmenopausal women [30], although only the increase in mean acceleration was maintained up to 1 year [31,32]. These findings were thought to represent a transient vasodilatory, but also a positive inotropic effect. Five weeks of hormone replacement therapy have caused an increase in end-diastolic volume, stroke volume and cardiac output in perimenopausal women [33], while an increase in left ventricular mass and cardiac output has also been observed after short-term oestrogen oral administration [34]. Acute oestrogen administration at physiologic dose had no inotropic effect on myocardial contractility, studied by pulsed wave Doppler tissue imaging [6].

In our study, however, an increase in cardiac output and cardiac index was observed following oestrogen administration, combined with an increase in stroke volume, stroke volume index and stroke work index. These findings could be attributed to the decreased pressures in pulmonary circulation that, perhaps, resulted in increased left ventricular preload and, thus in improvement in stroke volume by Starling's mechanism. In addition, the decrease in systemic and pulmonary vascular resistance results in improvement of ventricular performance, secondary to afterload reduction. Nevertheless, improvement of cardiac output and cardiac index, could also imply a positive inotropic effect of oestrogen, acting directly on ventricular myocardium.

Oestrogen affects sympathetic nervous system by inhibiting epinephrine release [17,35] and the slower heart rate observed in postmenopausal women receiving oestrogen compared with those not receiving hormone therapy has been attributed to the oestrogen-mediated suppression of adrenergic activity [36,37]. In a recent study, acute intravenous administration of oestrogen, in conventional replacement doses, decreased significantly heart rate and, thus, cardiac output in postmenopausal women without structural heart disease [38]. In our study, no significant alteration was recorded in patients’ heart rate, following the injection of conjugated oestrogens; this was possibly due to the excessive sympathoexcitation associated with advanced chronic heart failure, which was not altered by conventional doses of oestrogen.

4.3. Clinical implications—mechanisms
The improvement in cardiac performance and the decrease in systemic and pulmonary vascular resistance, observed in our study, though of limited magnitude, were consistently observed in most of patients. Acute oestrogen administration in patients with chronic heart failure seems to improve their haemodynamic status. This could be attributed to the vasodilatory effect of oestrogens [39], that cause an increase in ventricular preload and decrease cardiac afterload.

Cyclic AMP release [40], vascular nitric oxide activity [41], inhibition of vascular calcium inward channel [42] and potassium channels’ modulation [39] have all been proposed as oestrogen-induced vasodilatory mechanisms. Increased prostacycline (PGI2) release [43], decreased plasma endothelin levels [44] and modulated angiotensin-converting-enzyme activity [45] are also involved in the beneficial effect of oestrogens on cardiovascular function. Nevertheless, a potential positive inotropic effect on myocardium should be considered. Perhaps, long-term oestrogen therapy may improve haemodynamic parameters to such an extent, that could be used as an adjunctive treatment for haemodynamically stable patients with congestive heart failure. Chronic oestrogen administration may beneficially affect cardiac performance, through additional mechanisms, such as the decrease of proinflammatory cytokines and inhibition of the apoptotic process [10,46,47].

4.4. Limitations of the study
Beta adrenergic blockade was not included in our patients’ treatment during the study. Although the studied population was rather homogeneous regarding their medication, we cannot exclude the possibility that patients’ response to oestrogens would be affected by the presence of beta-blockade.

Before oestrogen infusion, we have used normal saline as a placebo, while the conjugated oestrogen that we have administered to our patients was diluted in alcoholic solution. Since we have not evaluated the potential haemodynamic effects of oestrogen's solvent, we think that this point might consist a limitation of our study. However, in a study investigating the effects of oestrogen on coronary circulation no effect of ethanol diluent alone on the evaluated haemodynamic parameters was observed [48]. Additionally, rest and relaxation may induce vasorelaxation and an increase in cardiac output. Since we have not included a randomised controlled placebo group in our study, we consider this as a limitation, although the studied patients were at rest not only following but also before oestrogen's administration.

A homogeneous male population has been included in the study. Our observations regarding the haemodynamic effects of acute oestrogen infusion in the studied patients cannot be extrapolated to female patients with heart failure. The comparison between male and female individuals with chronic heart failure with regard to their response to oestrogen administration could be the subject of a future study.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
In male patients with chronic heart failure, acute intravenous administration of conjugated oestrogens improves the indexes of cardiac systolic function and decreases pulmonary and systemic (central and peripheral) vascular resistance. This may be of clinical importance in patients with advanced chronic heart failure and implies that oestrogen could possibly be used as an adjunctive treatment for haemodynamically stable patients.


   Acknowledgements
 
The secretarial assistance of Ms Eleni Binou is gratefully acknowledged.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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