(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
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
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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
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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 males8 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
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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.
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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.
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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.
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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.
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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).
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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.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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 studies8 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.
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Acknowledgments |
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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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I. Mercier, S. Mader, and A. Calderone Tamoxifen and ICI 182,780 negatively influenced cardiac cell growth via an estrogen receptor-independent mechanism Cardiovasc Res, October 1, 2003; 59(4): 883 - 892. [Abstract] [Full Text] [PDF]
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T. Simon, P. Boutouyrie, J.M. Simon, B. Laloux, C. Tournigand, A.I. Tropeano, S. Laurent, and P. Jaillon Influence of Tamoxifen on Carotid Intima-Media Thickness in Postmenopausal Women Circulation, December 3, 2002; 106(23): 2925 - 2929. [Abstract] [Full Text] [PDF]
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M. A. Sader and D. S. Celermajer Endothelial function, vascular reactivity and gender differences in the cardiovascular system Cardiovasc Res, February 15, 2002; 53(3): 597 - 604. [Full Text] [PDF]
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M. Cattaneo, D. N. Kiortsis, M. S. Elisaf, K.M. English, P.J. Pugh, K.S. Channer, S. C. Clarke, P. M. Schofield, A. A. Grace, J. C. Metcalfe, et al. Does Tamoxifen Enhance Endothelial Function by Lowering the Plasma Levels of Homocysteine? Effects of Tamoxifen on Endothelial Function and Cardiovascular Risk Factors in Men With Advanced Atherosclerosis Effects of Tamoxifen on Endothelial Function and Cardiovascular Risk Factors in Men With Advanced Atherosclerosis Response Circulation, December 11, 2001; 104 (24): e146 - e147. [Full Text] [PDF]
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M. E. Mendelsohn and R. H. Karas The Time Has Come to Stop Letting the HERS Tale Wag the Dogma Circulation, November 6, 2001; 104(19): 2256 - 2259. [Full Text] [PDF]
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