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(Circulation. 1997;96:2837-2841.)
© 1997 American Heart Association, Inc.

Articles

Short-term Anti-Ischemic Effect of 17ß-Estradiol in Postmenopausal Women With Coronary Artery Disease

Giuseppe M.C. Rosano, MD; Adriano Mendes Caixeta, MD; Sergio Chierchia, MD; Siguemituzo Arie, MD; Miguel Lopez-Hidalgo, MD; Wagner I. Pereira, MD; Filippo Leonardo, MD; Carolyn M. Webb, BSc; Fulvio Pileggi, MD; ; Peter Collins, MD

From the Istituto H San Raffaele, Roma/Milan, Italy (G.M.C.R., S.C., F.L.); the Instituto do Coração, Hospital das Clinicas, University of São Paulo, Brazil (A.M.C., S.A., M.L.-H., W.I.P., F.P.); and the Imperial College School of Medicine at the National Heart and Lung Institute, London, UK (C.M.W., P.C.).

Correspondence to Giuseppe M.C. Rosano, MD, Department of Cardiology, Ospedale San Raffaele, Via Elio Chianesi 33, 00144 Roma, Italy.

	Abstract

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Background Short-term administration of 17ß-estradiol improves effort-induced myocardial ischemia in female patients with coronary artery disease. 17ß-Estradiol also has direct and indirect coronary vascular smooth muscle relaxing properties. The aim of the present study was to evaluate the effect of short-term administration of 17ß-estradiol on pacing-induced myocardial ischemia by means of continuous monitoring of coronary sinus pH in 16 postmenopausal female patients with coronary artery disease.

Methods and Results Patients underwent incremental atrial pacing starting at a rate of 100 bpm and increments of 20 bpm every 2 minutes up to 160 bpm before and 20 minutes after either 17ß-estradiol (1 mg sublingual, 9 patients) or placebo (sublingual, 7 patients). The time to the onset of myocardial ischemia during pacing was significantly increased by 17ß-estradiol (mean±SD, 254±36 versus 298±23 seconds; P<.02) but not by placebo (262±45 versus 256±34 seconds; P=NS) The pH shift was significantly reduced by 17ß-estradiol but not by placebo at every step of the pacing protocol. The maximum pH shift at peak pacing was significantly reduced by the administration of 17ß-estradiol by 0.022 pH units (95% CI, 0.001, 0.043; P<.04) but not by sublingual placebo (-0.002 pH units; 95% CI, -0.0073, 0.0021; P=NS). The maximum pH shift at maximum comparable pacing was also reduced by 17ß-estradiol by 0.015 pH units (95% CI, 0.012, 0.017; P<.001) but not by placebo (-0.0022 pH units; 95% CI, -0.006, 0.0015; P=NS).

Conclusions 17ß-Estradiol reduces the degree of pacing-induced myocardial ischemia in postmenopausal patients with coronary artery disease. The reduction of pacing-induced coronary sinus pH shift is consistent with an anti-ischemic effect of the hormone and is not due to preconditioning, as evidenced by the absence of improvement after placebo.

Key Words: estrogen • hormones • coronary disease • ischemia • women

	Introduction

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The incidence of ischemic cardiovascular events in women before the age of natural menopause is small.¹ After the menopause, the incidence increases proportionally with time, and within 10 to 15 years it becomes similar to that of the male population of a comparable age.² This observation, together with the results of epidemiological studies that have shown an 50% reduction of coronary events in women receiving hormone therapy compared with nonusers, has led to the suggestion that estrogen deficiency may play a role in the development of coronary artery disease in women.³

Estrogens inhibit atherosclerosis and also play an integral role in the maintenance of arterial hemodynamics that prevent ischemia. Short-term administration of 17ß-estradiol has been shown to improve exercise-induced myocardial ischemia in postmenopausal female patients with coronary artery disease.⁴ 17ß-Estradiol given short-term to postmenopausal women increases blood flow in coronary arteries^5-7 and in peripheral blood vessels.^8,9 Many of these studies, however, achieved pharmacological plasma concentrations of estrogen. Endothelium-dependent dilation of the brachial artery has been demonstrated after long-term estrogen use in postmenopausal women.¹⁰ These short- and long-term effects may involve a number of mechanisms, including effects on endothelium-derived nitric oxide production and release^11,12 and/or direct vascular smooth muscle relaxation by modulation of ion channels.^13-15 Short-term effects of estrogen are unlikely to involve estrogen receptor-dependent mechanisms; however, the estrogen receptor may be involved in the vascular effects observed after long-term treatment.¹¹

Estrogen induces endothelium-independent, direct smooth muscle-relaxing effects in vitro in animal and human coronary arteries,^16,17 which may involve calcium antagonism.^13,16 A recent in vivo canine study demonstrated short-term estrogen-induced dilation of the coronary arteries.¹⁸ This effect, using supraphysiological doses of estrogen, was endothelium-independent, possibly involving ATP-sensitive potassium channels or/and calcium channels.

A decrease in pH in the coronary sinus blood is a metabolic marker of myocardial ischemia.^19,20 Continuous monitoring of coronary sinus pH during pacing by use of a catheter-tip ion-sensitive electrode is an accurate method for the detection of myocardial ischemia in patients with coronary artery disease.¹⁹

This study was performed to investigate the effect of 17ß-estradiol at physiological plasma concentrations on pacing-induced myocardial ischemia by monitoring coronary sinus pH.

	Methods

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Twenty postmenopausal women referred for cardiac catheterization because of symptoms suggesting ischemic heart disease were evaluated. Menopause was defined as the absence of a menstrual cycle for at least 12 months and was confirmed by serum levels of 17ß-estradiol <100 pmol/L and follicle-stimulating hormone levels >40 IU. The women were a mean of 8 years postmenopausal. Women who were entered into the study had 70% stenosis of one or more of the major coronary arteries. All patients had a significant stenosis of the left anterior descending coronary artery; 2 patients had one-vessel disease, 9 had two-vessel disease, and 5 had three-vessel disease. Patients with unstable angina, recent (<15 days) acute myocardial infarction, cardiac failure, primary valvar heart disease, or severe hypertension (systolic blood pressure >180 mm Hg or/and diastolic blood pressure >90 mm Hg) were excluded from the study. The study was approved by the Istituto do Coração (INCOR) Hospital Ethics Committee, and all patients gave written consent to the study.

The pH electrodes were constructed according to a previously published protocol.²¹ A fine Trimel-coated (Johnson Matthey) silver wire was threaded through medical-grade polyethylene tubing (0.9 mm external diameter, 125 cm long). The terminal 1 cm of insulation was removed from the silver wire, and a silver chloride coating was applied electrolytically. The silver chloride electrode was withdrawn into the polyethylene tubing, and an internal buffer solution (citrate-buffered saline) was introduced. A gap of 1 cm was left at the end of the tubing, into which a porous ceramic plug was inserted. A membrane of a pH-sensitive ligand (tridodecylamine; Fluka AG) was then applied by dip coating four or five times. Once dry, the end of the electrode was gently shaken to make contact between the internal electrolyte solution and the ceramic plug.

The electrode was insensitive to oxygen and ions other than hydrogen, with an output equal to the theoretical Nernst equation. All electrodes were calibrated and tested before each study. Only electrodes that demonstrated a linear reproducible response to pH in the range of 6 to 8 were used. Electrodes were sterilized before each study in aqueous glutaraldehyde. A 7F catheter was introduced under fluoroscopic control into the coronary sinus through the left subclavian vein. The tip was positioned just before the great cardiac vein (confirmed by contrast injection). The pH electrode was passed through the catheter, so that its tip protruded 1 cm from the end. A reference electrode was positioned at the proximal end of the coronary sinus catheter through a Y adapter. The electrode was then allowed to stabilize for 10 minutes before each study. Changes in pH were calculated from the change in millivolts with the Nernst equation.

Studies were performed directly after diagnostic cardiac catheterization. All patients were studied fasting and were in pharmacological washout. Nitrates, calcium channel blockers, and ß-blockers were withdrawn 24 hours, 72 hours, and 120 hours, respectively, before the study. Sublingual nitrates were allowed for the control of symptomatic episodes of myocardial ischemia up to 8 hours before the study. After a diagnostic cardiac catheterization showing coronary artery disease, a 7F guiding catheter was inserted into the coronary sinus via the antecubital vein (10 patients) or the femoral vein (6 patients), and its position was checked by fluoroscopy. A 5F pacing wire was inserted percutaneously from the right femoral vein (6 patients) or from the right cephalic vein (10 patients) and placed into the right atrium. After cannulation of the coronary sinus, the pH electrode was inserted into the guiding catheter, advanced under fluoroscopic control, and placed 1 cm within the coronary sinus. The guiding catheter was flushed with heparinized saline solution, and blood was drawn into the guiding catheter.

After 10 minutes was allowed for stabilization of the output of the pH electrode, pH monitoring was commenced. The coronary sinus pH was continuously monitored at baseline for 5 minutes, during incremental atrial pacing, and during the recovery period until the coronary sinus pH returned to baseline levels. Atrial pacing was started at 100 bpm, and the frequency of stimulation was increased by 20 beats every 3 minutes up to a heart rate of 160 bpm. Right ventricular pacing was performed in 7 patients and showed atrioventricular block at higher stimulation rates. Atrial pacing was stopped if any of the following developed: crescendo angina, ST-segment depression >3 mm, hypotension (systolic blood pressure <90 mm Hg), or complex arrhythmias (Lown class >3). The ECG was monitored continuously, and a 12-lead ECG was obtained at the end of each step of the pacing protocol and every 2 minutes during the recovery phase. The lead monitored during the study was the one that showed the greatest ST-segment depression during a previous exercise ECG.

Patients were thereafter randomized to receive either sublingual 17ß-estradiol (1 mg, Bristol Myers Squibb Co) or placebo. The study drug was administered at least 10 minutes after the first pacing protocol and after complete recovery of coronary sinus pH back to baseline. Twenty minutes after administration of sublingual 17ß-estradiol or placebo, the pacing protocol was repeated and the coronary sinus pH monitored.

Blood samples for the evaluation of serum 17ß-estradiol were obtained from the study patients before the administration of the study drug and at the end of the second pacing protocol.

In a different group of similar postmenopausal women (n=25; mean age, 62±4 years), the pharmacokinetics of 1 mg of sublingual 17ß-estradiol was assessed. Blood samples for estimation of 17ß-estradiol were taken at 10, 20, 40, and 60 minutes after administration.

Statistical Analysis
Evaluation of the pH tracings was made by experienced investigators unaware of the clinical data. The pH change was taken as the difference in mV/mm from baseline to peak change. The degree of change was converted to pH units by use of the Nernst equation. Paired and unpaired nonparametric tests (Wilcoxon) were used to test statistical significance among and between groups, respectively. Because the protocol involved different levels of pacing before and after measurements for each treatment, the data were analyzed by ANOVA for repeated measures. A value of P<.05 was considered significant. Values are expressed as mean±SD.

	Results

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Sixteen patients met the inclusion criteria and entered the study protocol. None of the women had received estrogen replacement therapy in the 8 months preceding the study. Nine patients were randomized to receive 17ß-estradiol and 7 to receive placebo. The clinical features of the two study groups are shown in Table 1. No difference in the incidence of risk factors for coronary artery disease or in the extent of coronary artery disease was noted. All but 2 patients experienced typical chest pain during pacing, and all showed significant (>1 mm) ST-segment depression during the pacing protocol. The blood pressures were not different between the two groups, and the blood pressures before and immediately after each pacing stage were the same (Table 2).

View this table: [in this window] [in a new window]   Table 1. Clinical Features of the Treatment Groups

View this table: [in this window] [in a new window]   Table 2. Mean Blood Pressure Recordings Before and After Estradiol and Placebo at Incremental Pacing Rates

The time of onset of myocardial ischemia during pacing (ST>1 mm) was significantly increased by 17ß-estradiol (254±36 versus 298±23 seconds; P<.02) but not by placebo (262±45 versus 256±34 seconds; P=NS). The degree of pH shift was significantly reduced by 17ß-estradiol but not by placebo at each step of the pacing protocol (Figure). The maximum pH shift at peak pacing was significantly reduced by the administration of 17ß-estradiol, by 0.022 pH units (95% CI 0.001, 0.043; P<.04), but not by sublingual placebo (-0.002 pH units; 95% CI -0.0073, 0.0021; P=NS). The maximum pH shift at maximum comparable pacing was also reduced by 17ß-estradiol, by 0.015 (95% CI, 0.012, 0.017; P<.001), but not by placebo (-0.0022; 95% CI, -0.006, 0.0015; P=NS). The plasma levels of 17ß-estradiol increased from 64±24 to 426±89 pmol/L in patients receiving 17ß-estradiol. The levels were unchanged in patients receiving placebo (72±29 versus 72±25 pmol/L).

Administration of 1 mg of 17ß-estradiol resulted in a significant increase in 17ß-estradiol plasma levels at 10, 20, 40, and 60 minutes. The levels were 234±56, 468±115, 1980±456, and 2124±568 pmol/L, respectively. These data confirm physiological levels of estrogen at 20 minutes after sublingual administration of 1 mg of 17ß-estradiol.

	Discussion

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The present study demonstrates that 17ß-estradiol at physiological plasma concentrations reduces the degree of myocardial ischemia in female postmenopausal patients with coronary artery disease. These results confirm the observation of Rosano et al⁴ showing that sublingual administration of 17ß-estradiol improves exercise-induced myocardial ischemia in a similar patient population. In the exercise study, however, the plasma levels of 17ß-estradiol were 2500 pmol/L, greater than the physiological range for the follicular phase of normal menstruating women and significantly greater than those obtained in this study. The plasma levels of 17ß-estradiol achieved in this study were similar to those usually achieved during estrogen replacement therapy with 17ß-estradiol. The fact that plasma concentrations of 17ß-estradiol in the present study were lower than those reported in the exercise study despite the use of the same dose of 17ß-estradiol is mainly a factor of the different timing of testing. In the exercise study, patients were studied after 40 minutes of sublingual 17ß-estradiol administration, whereas in the present study, patients were evaluated 20 minutes after the administration of sublingual 17ß-estradiol. We have also measured levels of 17ß-estradiol over a 60-minute period after 1 mg sublingual 17ß-estradiol.

Monitoring of coronary sinus pH is an accurate method for the detection of myocardial ischemia²¹ and is more accurate than the exercise ECG to evaluate myocardial ischemia. The technique provides direct and continuous monitoring of hydrogen ion concentration in the coronary sinus blood, which is dependent on the degree of aerobic metabolism by the myocardium. The technique of coronary sinus pH monitoring has been used to assess myocardial ischemia in a number of cardiac conditions, such as coronary heart disease,^19,20,22 hypertrophic obstructive cardiomyopathy,²³ and cardiac syndrome X.²²

Both direct effects of estrogen on the vascular smooth muscle myocyte and indirect effects via the endothelium could cause coronary vasodilation, which would result in a decrease in myocardial ischemia. Calcium channels, ATP-sensitive potassium channels, large-conductance calcium- and voltage-activated potassium channels, and chloride channels are all affected by estrogen.^{13,14,18,24,25} Estrogen inhibits agonists that activate both receptor- and potential-operated calcium channels in animal coronary arteries and cardiac myocytes.^13,16 A calcium antagonistic property of estrogen has been confirmed in coronary vascular myocytes by measurement of cytosolic calcium concentration, contraction, and calcium current.¹⁴ This calcium antagonistic property could be one of the mechanisms of estrogen-induced, endothelium-independent relaxation in animal and human coronary arteries. Physiological concentrations of estrogen relax human epicardial coronary arteries in vitro. Supraphysiological concentrations (>0.1 µmol/L) of estrogen cause dilation of conductance and resistance coronary arteries in dogs when administered short-term into the coronary circulation.¹⁸ This in vivo effect was shown to be endothelium-independent and partially mediated by effects on ATP-sensitive potassium and/or calcium channels. There is already emerging evidence of more than one type of estrogen receptor²⁶; such receptors may, at the plasma membrane level, be involved in vascular smooth muscle relaxation. Other potential mechanisms may include effects on prostaglandin synthesis²⁷ and inhibition of constrictor substances such as angiotensin II²⁸ and endothelin-1.²⁹

Indirect mecanisms via the endothelium-dependent nitric oxide pathway may also be involved in contributing to a reduction in myocardial ischemia. Estrogen can induce calcium-dependent nitric oxide synthase, increasing its activity and causing nitric oxide release,¹¹ which results in relaxation of vascular smooth muscle by nitric oxide-induced stimulation of guanylate cyclase. Estrogen receptor has been identified in endothelial cells from human aorta and coronary and umbilical arteries.^30,31 Estrogen increases nitric oxide synthase activity in heart, kidney, and skeletal muscle; this effect is dependent on sex and exposure time to estrogen.¹¹ It has been suggested that the number and/or availability of estrogen receptors in male tissues may initially be too low, requiring a period of estrogen priming in men compared with women. In vivo studies in sheep confirm that estrogen-induced increases in blood flow in the uterine artery can be antagonized by nitric oxide synthase inhibition.³² From studies of inhibitors of nitric oxide synthase, preliminary data are now emerging in humans, demonstrating an effect of estrogen via nitric oxide synthase in the peripheral vasculature of the forearm.^12,33

In our study, the time from drug administration to measurement of the pH changes may be an important variable. Sublingual estradiol begins to increase plasma levels 5 minutes from the time of administration. Our findings therefore reflect estrogen effects after 15 minutes of exposure to the coronary vascular bed. This is consistent with a direct effect of estrogen on the coronary artery, possibly by ion channel modulation. It is also consistent with the findings of other groups in which the acetylcholine changes, reflecting enhanced endothelial nitric oxide production, occurred within 20 minutes from intracoronary administration, suggesting that even what is thought to be a hormone receptor-dependent action could also occur within a short time. In contrast, studies show that decreased vascular resistance in peripheral arteries induced by estrogen appears to require a longer time, 40 minutes, to become manifest.⁹

The two pacing protocols potentially could have caused cardiac preconditioning, thus reducing the degree of myocardial ischemia during the second period of pacing. Patients allocated to placebo did not show any change in the degree of pacing-induced myocardial ischemia; therefore, no effect resulting in cardiac preconditioning is observed in this protocol. The two pacing protocols were separated by at least 30 minutes, and the duration of myocardial ischemia during the first pacing protocol was <10 minutes. Therefore, the ischemic time was limited, and the recovery period was long enough to avoid an effect via preconditioning.

The plasma levels of 17ß-estradiol achieved during optimal hormone replacement therapy may be slightly lower than those achieved in this study. It is therefore possible that the anti-ischemic effect seen in this study may be less evident during long-term therapy. However, it is also possible that the longer-term vascular effects of 17ß-estradiol may be potentiated by other mechanisms, such as further enhancement of nitric oxide production and/or prostacyclin, resulting in anti-ischemic effects similar to those seen in the present study. Whatever the mechanism(s), short-term administration of estrogen has anti-ischemic properties in the human myocardium on cardiac pacing.

In conclusion, the short-term systemic administration of 17ß-estradiol reduces the degree of pacing-induced myocardial ischemia in postmenopausal women with documented coronary artery disease.

View larger version (26K): [in this window] [in a new window]   Figure 1. Effect of estrogen on coronary sinus pH. Change in pH with pacing at baseline (open bars) and after subjlingual placebo (stippled bars) or 1 mg of sublingual 17ß-estradiol (solid bars). Values are mean±SD. *P<.05.

	Acknowledgments

 
Dr Rosano was supported by an Educational Grant from the Fundação E. Zerbini, São Paulo, Brazil.

Received May 6, 1997; revision received August 8, 1997; accepted August 12, 1997.

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