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(Circulation. 2001;103:1497.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Tamoxifen Effects on Endothelial Function and Cardiovascular Risk Factors in Men With Advanced Atherosclerosis

Sarah C. Clarke, MB, MRCP; Peter M. Schofield, MD, FRCP; Andrew A. Grace, PhD, FRCP; James C. Metcalfe, PhD; Heide L. Kirschenlohr, PhD

From the Department of Cardiology, Papworth Hospital NHS Trust (S.C.C., P.M.S., A.A.G.), Papworth Everard, UK, and Department of Biochemistry, University of Cambridge (J.C.M., H.L.K.), Cambridge, UK.

Correspondence to James Metcalfe, Department of Biochemistry, University of Cambridge, Downing Site, Tennis Court Rd, Cambridge CB2 1QW, UK. E-mail jcm{at}mole.bio.cam.ac.uk

	Abstract

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Background—Tamoxifen and its analogues act as selective estrogen receptor modulators (SERMs) in women, with estrogen-like activities on some plasma cardiovascular risk factors (eg, lipoproteins). Effects of SERMs on men with coronary artery disease (CAD) have not been reported.

Methods and Results—Thirty-one men with angiographically proven CAD were recruited; 16 were treated with tamoxifen (40 mg/d) for 56 days, and 15 were untreated. All the CAD patients were medicated with aspirin and an HMG-CoA reductase inhibitor for 6 weeks before entering the study. Ten men with angina-like symptoms but normal coronary arteries by angiography (NCA group) were also treated with tamoxifen. Blood samples were collected at days -7, 0, 7, 14, 21, 28, and 56 of treatment. Endothelium-dependent flow-mediated dilatation (ED-FMD) of the brachial artery was measured by high-resolution ultrasound at 5 visits. Tamoxifen caused an increase in %ED-FMD maximal at 28 days in the CAD group (2.1±0.3% to 7.5±0.7%; P<0.0001) and the NCA group (3.8±0.4% to 7.9±1.0%; P<0.0001), with no significant change in the untreated group. Tamoxifen also caused decreases in several plasma cardiovascular risk factors, including total cholesterol, triglycerides, lipoprotein(a), and fibrinogen. Except for the triglyceride response, these effects were similar to those reported for postmenopausal women treated with tamoxifen.

Conclusions—Tamoxifen substantially increased ED-FMD in men with CAD who were taking conventional medication. Together with the effects on risk factors, the data strongly support clinical evaluation of SERMs for the treatment of men with CAD.

Key Words: atherosclerosis • endothelium • hormones • lipids • vasodilation

	Introduction

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Tamoxifen is used as an effective antiestrogen in treatment of breast cancer in women. Studies of tamoxifen for breast cancer have suggested that in addition to its antiestrogenic activity on breast tumors, tamoxifen has cardiovascular protective effects.^{1 2 3} A Scottish study showed a 60% reduction in fatal myocardial infarction¹ (MI) and a 50% to 70% reduction in non-fatal MI² in studies of more than 1000 women. The Stockholm Breast Cancer Group Study showed similar reductions in cardiac morbidity of 30% to 60% in more than 2000 women treated with tamoxifen.³ However, MI was a secondary end point in these studies, the confidence intervals were large, and the data refer to patients with a specific disease. Nevertheless, the apparently beneficial cardiovascular effects of tamoxifen in women with breast cancer are consistent with the estrogen-like activity of tamoxifen in some other tissues, including bone⁴ and endometrium.⁵ The profile of estrogen-like actions of tamoxifen and its analogues in some target tissues and of antagonist activity in others has led to the description of these drugs as selective estrogen receptor modulators (SERMs).⁶ The SERMs have a spectrum of potentially beneficial effects on cardiovascular risk factors in women, broadly similar to those of estrogen, which may contribute to the protection by tamoxifen against MI reported for breast cancer patients. One SERM, raloxifene, is in a phase 3 trial (RUTH, or Raloxifene Use for The Heart) of cardiovascular disease in women.⁷

Estrogen therapy for men at doses that might be sufficient to modulate cardiovascular risk factors has unacceptable side effects and is mainly used for treatment of male-to-female transsexuals.^{8 9} However, there are no reports of estrogen-like side effects of tamoxifen in men treated for breast¹⁰ and other cancers.^{11 12} We therefore hypothesized that tamoxifen might confer on men any beneficial effects of estrogen therapy on the cardiovascular system without the side effects. To test this hypothesis, we examined the effects of tamoxifen on endothelial function and on other cardiovascular risk factors in groups of men with angiographically proven coronary artery disease (CAD) or with angina-like symptoms but normal coronary arteries by angiography. Endothelial function has been shown to be substantially enhanced by long-term estrogen therapy in genetic males^{8 9} and has been considered as a potential surrogate marker of cardiovascular benefit from therapeutic agents.¹³ Impaired endothelial function is correlated with the presence of CAD,^{14 15 16 17} and the presence of atherosclerosis in superficial arteries such as the brachial artery is correlated with the presence of disease in other large arteries of the same patient, including coronary atherosclerosis.¹⁶ The change in endothelium-dependent flow-mediated dilatation (ED-FMD) of the brachial artery in response to reactive hyperemia was used to monitor endothelial function.^{17 18}

	Methods

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Patients
This study was approved by the Huntingdon Local Ethics Committee. Thirty-one male patients were recruited who had a reduction of 75% in the intraluminal diameter of all 3 coronary arteries, defined as the triple-vessel disease (TVD) patients. All 31 TVD patients were taking aspirin and a cholesterol-lowering statin, and 25 of 31 were taking antianginal medications (Table). The statin and aspirin medications had been taken continuously by the TVD patients for 6 weeks before the study. Another group of 10 male patients with a history of chest pain suggestive of angina pectoris but with normal coronary angiograms (NCA group) was recruited to compare with the TVD group for responses to tamoxifen. There was no evidence of cardiovascular disease on physical examination in the NCA group, but the exercise test (Bruce protocol) was positive, defined by 1 mm of horizontal or downward-sloping ST-segment depression at 80 ms after the J point, for each NCA patient. None of the NCA patients were taking a statin.

View this table: [in this window] [in a new window]   Table 1. Baseline Clinical Data

Other entry criteria were that symptoms of angina had been stable for 1 month and no patient had suffered an MI in the previous 3 months. Patients with uncontrolled hypertension or carcinomas were excluded. Patients meeting the above criteria and who gave informed consent (41 of 44) were recruited.

Tamoxifen Treatment and Blood Assays
Sixteen of the 31 TVD patients and the 10 NCA patients were treated with tamoxifen (40-mg single oral dose daily) from day 0 for 56 days. The remaining 15 TVD patients were an untreated control group. The TVD patients were allocated to a group at baseline visit (day -7) in secured, random-sequence blocks of 10 generated before the study. All clinical and laboratory staff were blinded to patient codes. All patients were instructed to continue taking their normal medication at the usual prescribed time throughout the study period (day -7 to day 56). No sublingual nitrates were taken within 24 hours before any scan session. All vascular reactivity studies were performed at the same time of day for each patient to ensure constant conditions with respect to medication.

Symptomatology was assessed at baseline and after the final visit for each patient by a Likert-style condition-specific symptom scale, an Activities of Daily Living Scale, and the generic health questionnaire SF36 and did not change significantly for any of the groups. No patient reported adverse effects at any visit. There were no increases in alanine aminotransferase to grade I response levels (ie, >26% increase above the upper limit of the normal range of 36 IU/L at any visit) that required treatment to be terminated.

Blood samples (20 mL) were collected at days -7, 0, 7, 14, 21, 28, and 56 from all patients, and platelet-poor plasma was prepared (DiatubeH; Diagnostica Stago). In addition to routine hematology and biochemistry, 17-ß-estradiol, testosterone, and follicle stimulating hormone (FSH) levels were assayed in the plasma samples with the Technicon Immuno 1 System (Bayer). Lipoprotein(a) [Lp(a)] and plasminogen activator inhibitor-1 (PAI-1) were assayed by ELISAs (Immuno GMBH and Technoclone).

Endothelial Function
ED-FMD and endothelium-independent flow-mediated dilatation (EI-FMD) of the brachial artery were assessed by high-resolution external ultrasound at days 0, 7, 14, 28, and 56 by a protocol very similar to that described previously.¹⁷ Resting brachial artery internal diameter was measured at end diastole over consecutive beats, and a mean internal diameter was determined over a 5-second period. A tourniquet placed distally around the forearm was inflated to 300 mm Hg for 4.5 minutes to induce reactive hyperemia. After rapid release, the internal brachial artery diameter was measured 55 to 65 seconds later. After 10 minutes’ rest to allow the brachial artery to return to baseline, another resting scan was performed. Sublingual nitroglycerin (400 µg) was administered, and brachial artery diameter was determined after 3 minutes.

Scans were analyzed by 2 independent observers unaware of patient identity, visit number, or treatment. Scans were excluded from data analyses only if (1) the brachial artery image was not reproduced compared with previous visit(s), (2) an undamped distensibility waveform with a typical arterial morphology that was stable over 5 waveforms (essential for the measurement of artery diameter) was not achieved, or (3) the sample cursor position was incorrect. Twenty (9.8%) of 205 planned scans were omitted from data analyses for these reasons, and 9 of 205 patient visits were missed; the total number of scans analyzed was 176 (86%) of 205. Intraobserver and interobserver variability were comparable with previously reported studies of endothelial function by the same technique.^{17 18} ED-FMD and EI-FMD are reported as percentage changes from the resting diameter of the artery. The peak response to hyperemia (defined as 100xFmax/Fbase, where Fmax was the maximum flow in a single cardiac cycle within the first 15 seconds after cuff deflation and Fbase was the flow during the resting scan) was measured and calculated as described previously.¹⁹

Statistical Analyses
All data are presented as mean±SEM. The baselines for brachial artery parameters are at day 0; all other parameters are compared with a baseline average of values at day -7 and day 0. Baseline comparisons between the patient groups in the Table were made by unpaired Student’s t test after testing for normal distribution. The data for FMD and blood analyses were analyzed both without repair for missing scans and visits and with repair by insertion of the interpolated value for missing data at days 7, 14, and 28 or by insertion of the corresponding day 28 value for missing day 56 data. Data repair made no significant difference (P<0.05) to any mean ED-FMD value or other data for any patient group at any visit. All graphical data are presented without repair. The effects of tamoxifen treatment on all parameters reported were compared on repaired data sets by repeated-measures ANOVA followed by post hoc Scheffé test (StatView 5.0.1; SAS Institute Inc). Statistical significance was inferred at P<0.05.

	Results

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Baseline Data
Baseline data for the 3 patient groups in the Table showed no differences between the treated and untreated TVD groups that reached significance. The average ages of the TVD groups were greater than that of the NCA group. All TVD patients but no NCA patients were taking statins; consequently, total cholesterol, LDL cholesterol, and LDL:HDL ratios were significantly lower in the TVD groups. Neutrophil and monocyte counts were significantly lower in the NCA group than in the TVD groups. FSH was also lower in the NCA group; at least part of this difference was attributable to the lower age of the NCA group. Baseline levels for the TVD and NCA groups for estradiol, testosterone, and FSH were within the ranges reported previously for adult men.

Endothelial Function
The mean ED-FMD value at baseline for the NCA group (3.8±0.4%) was significantly higher than for the treated (2.1±0.3%; P=0.004) and untreated (1.6±0.4%; P=0.002) TVD groups, consistent with data showing that ED-FMD decreases with increasing age²⁰ and is depressed in patients with proven CAD¹⁴ (Figure 1A). The EI-FMD at baseline for the NCA group (13.2±1.1%) was also significantly higher than for the treated and untreated TVD groups (9.6±1.0, P=0.04 and 6.6±1.0, P=0.0003, respectively; Figure 1B), which also differed significantly (P=0.04), but not owing to nitrates (P=0.60) or other medications.

View larger version (20K): [in this window] [in a new window]   Figure 1. Effect of tamoxifen treatment on blood vessel parameters. A, ED-FMD; B, EI-FMD; C, vessel diameter; and D, hyperemia.

In response to tamoxifen, there was a substantial increase in ED-FMD to 7.5±0.7% (P<0.0001) by 28 days for the treated TVD group that did not change significantly at 56 days (8.0±0.6%) (Figure 1A). In contrast, there was no significant change in the control TVD group at any time point. There was also an increase in ED-FMD for the NCA group in response to tamoxifen at 28 days (7.9±1.0%; P<0.0001) and at 56 days (9.2±0.9%; P<0.0001) to a level similar to that of the TVD group. Each of the treated TVD and NCA patients showed an increase in ED-FMD in response to tamoxifen (range 0.7% to 8.8% from day 0 to day 28 for the TVD group and 1.6% to 7.0% for the NCA group). No control TVD patient showed an increase in ED-FMD of >0.8% or a decrease of >0.2% over the same period. There were no significant changes in EI-FMD, vessel diameter, or hyperemia at any visit from the levels at day 0 for the tamoxifen-treated TVD group or the NCA group (Figure 1B, 1C, and 1D). The mean hyperemia values, as measured and defined, were consistent with those reported previously.¹⁹ Changes in vessel diameter or hyperemia did not therefore contribute significantly to the increases in ED-FMD in response to tamoxifen.

Blood Parameters
Treatment of the TVD group with tamoxifen caused increases in estradiol, testosterone, and FSH of 40% (P<0.0001), 82% (P<0.0001), and 44% (P=0.001), respectively, by day 28, with only small further changes at 56 days of treatment (Figure 2A through 2C), as for all other blood parameters. A similar pattern of hormone responses to tamoxifen treatment was observed for the NCA group. Although the hormone responses to tamoxifen varied widely between the treated patients, all responses remained within the normal ranges. Each of the treated patients showed increases in each hormone at day 28 and day 56, except for 1 TVD patient who showed an increase only in testosterone.

View larger version (18K): [in this window] [in a new window]   Figure 2. Effects of tamoxifen treatment on hormone levels in patient groups. Percent change from baseline for (A) estradiol, (B) testosterone, and (C) FSH. Baseline values for TVD control and tamoxifen-treated groups and NCA group were as follows: estradiol 166±7.9, 162±9.0, and 164±5.9 pmol/L; testosterone 15.5±1.1, 16.2±2.0, and 14.6±2.6 nmol/L; and FSH 5.7±0.8, 6.7±0.7, and 3.5±0.5 IU/L, respectively.

Total cholesterol decreased significantly in response to tamoxifen to a similar extent in both TVD (-10.9±2.4%; P=0.05) and NCA (-13.3±2.9%; P=0.024) groups compared with the control TVD group, which also showed a small but not significant decrease (-4.0±2.5%; P=0.133) (Figure 3A). The decrease in total cholesterol in response to tamoxifen in the TVD group was in addition to the effect of the statins, because all the TVD patients had been treated with statin for 6 weeks before starting tamoxifen treatment. Comparison with the NCA patients who were not treated with statins suggests that the effects of tamoxifen and statins on total cholesterol levels were approximately additive. The decreases in LDL-C in the treated TVD and NCA groups did not reach significance compared with the untreated TVD group, whereas decreases in HDL-C were significant (P=0.05 and P=0.015, respectively; Figure 3A). Overall, there was no significant effect of tamoxifen on LDL:HDL ratio. Triglyceride levels showed substantial decreases in response to tamoxifen, reaching significance in the NCA group (-23.9±6.6%; P=0.05); Lp(a) decreased significantly in the treated TVD group (-24.5±6.5%; P=0.05) compared with the control group (Figure 3A).

View larger version (26K): [in this window] [in a new window]   Figure 3. Effects of tamoxifen treatment on (A) lipid and (B) other cardiovascular risk factors. *P<0.05 vs control TVD group.

There were significant decreases in fibrinogen, which is an independent risk factor for thrombosis,²¹ in the tamoxifen-treated TVD (-14.2±5.0%; P=0.006) and NCA (-17.1±5.9%; P=0.004) groups compared with the untreated TVD group (Figure 3B). In contrast, there was no change in PAI-1, which is also a risk factor for thrombosis, although PAI-1 is reduced by oral estrogen in postmenopausal women. There were no significant changes in leukocyte number (Figure 3B) or other blood cells in response to tamoxifen.

The level of alkaline phosphatase decreased significantly in response to tamoxifen (Figure 3B) in both TVD (-19.5±3.6%; P=0.002) and NCA groups (-20.1±3.3%; P=0.0005), with smaller, significant decreases in phosphate (-12.1±3.2; P=0.006) and Ca²⁺ (not shown) in the TVD group and a similar trend in the NCA group (Figure 3B). Similar changes have been associated with the protective effects of tamoxifen on bone mineral density.⁴

There were no significant correlations between ED-FMD and estradiol (r=0.032; P=0.795) or any other parameter measured for the untreated TVD group that were sustained when data for each visit were analyzed separately and were therefore likely to be robust. Furthermore, there were no correlations between the ED-FMD and estradiol (r=0.206; P=0.307) or any other parameter at 28 or 56 days after tamoxifen treatment (when the changes in blood parameters had stabilized) that were observed in both the TVD and NCA treatment groups.

	Discussion

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The average ED-FMD for asymptomatic adult men is constant at 7% below age 40 years but declines to 5% at 51 years (the average age of the NCA group) and to 3.5% at 63 years (the average age of the TVD group).²⁰ Both the NCA and TVD groups in the present study had baseline ED-FMD values before tamoxifen treatment below the corresponding values for asymptomatic men of the same age. The increases in %ED-FMD in response to tamoxifen occurred in each patient in both the TVD and NCA groups and raised the mean levels to those observed in the asymptomatic men below age 40 years.²⁰ The constant ED-FMD for the untreated TVD group and the absence of any changes in EI-FMD, vessel diameter, or hyperemia in either of the tamoxifen-treated groups provide strong internal controls for the observed ED-FMD responses to tamoxifen.

The increase in plasma estradiol concentration in the tamoxifen-treated groups suggested a possible indirect mechanism for the improvement in endothelial function. However, there was no significant correlation between estradiol levels and ED-FMD for the TVD or NCA groups before or after treatment with tamoxifen, which suggests that the estradiol response to tamoxifen is unlikely to be a major determinant of the enhanced endothelial function. The data for tamoxifen can be compared with 2 important studies^{8 9} of long-term, high-dose therapy in male-to-female transsexuals that demonstrated >2-fold higher ED-FMD values and higher EI-FMD responses to nitroglycerine compared with matched male controls. In the present study, tamoxifen resembled estrogen in enhancing ED-FMD but, in contrast to estrogen, did not affect EI-FMD. Triglyceride levels were greater in transsexuals than in a control group of men,⁹ and increases in triglycerides in response to hormone replacement therapy have been reported in women.²² Tamoxifen also causes an increase in triglycerides²³ in women but caused a significant reduction in men in the present study.

Several studies have shown that statins enhance ED-FMD in hypercholesterolemic patients,²⁴ which suggests that the reduction in cholesterol levels in response to tamoxifen is a potential indirect mechanism for the endothelial response. However, the large increase in ED-FMD in the TVD group occurred on a background of 6 weeks of statin therapy before tamoxifen treatment. The mean ED-FMD value for the 2 TVD groups at baseline before tamoxifen treatment was only 1.8±0.3%, which suggests that treatment of the TVD patients with statin had only small effects on %ED-FMD compared with the response to tamoxifen. Similar levels of ED-FMD to those of the treated TVD group were achieved for the NCA patients after 28 days of treatment with tamoxifen and, unlike the TVD group, none of the NCA group was taking statin medication. These data are therefore consistent with a much larger effect of tamoxifen compared with statins on ED-FMD, at least in these patient groups. Simvastatin was the HMG-CoA reductase inhibitor taken by the majority of the TVD patients. However, the effect of tamoxifen on cholesterol levels in men was much smaller than the effects reported for simvastatin in the 4S study²⁵ (81.5% of whose participants were men) of 25% and 35% reductions in total and LDL cholesterol, respectively. We conclude that the ED-FMD response to tamoxifen is unlikely to be due mainly to the reduction in plasma cholesterol level.

In conclusion, it should be noted that although estrogen clearly improves endothelial function in women, it has not been shown in randomized clinical trials to lessen cardiovascular risk, perhaps owing to worsening coagulation and/or inflammation. All of these effects are mediated in part by the endothelium. Thus, although ED-FMD improves with estrogen, this effect does not translate clearly into clinical benefit. The present data show that in addition to its effects on endothelial function, tamoxifen has similar effects on some but not all blood cardiovascular risk factors in men as reported for women,^{22 23} and therefore it also acts as an SERM on the cardiovascular system in men. The data provide strong evidence to support clinical evaluation of SERMs for the treatment of men with CAD.

View this table: [in this window] [in a new window]   Table 11. Baseline Clinical Data

	Acknowledgments

 
This work was supported by a program grant from the British Heart Foundation to Dr Metcalfe, a grant from NeoRx Corporation, Seattle, Wash, to Dr Metcalfe, and a grant from the Dr Scholl Foundation, Chicago, Ill, to Dr Schofield. Dr Grace is a British Heart Foundation Senior Research Fellow.

Received September 29, 2000; revision received November 21, 2000; accepted November 28, 2000.

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