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Circulation. 1996;94:1809-1811

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(Circulation. 1996;94:1809-1811.)
© 1996 American Heart Association, Inc.

Articles

Estrogen Therapy, Atherosclerosis, and Clinical Cardiovascular Events

H. Vernon Anderson, MD

the University of Texas Health Science Center, Houston.

Correspondence to H. Vernon Anderson, MD, Department of Internal Medicine, UT Health Science Center–Houston, 6431 Fannin, PO Box 20708, Houston, TX 77225.


Key Words: Editorials • hormones • atherosclerosis


*    Introduction
up arrowTop
 *Introduction
down arrowVascular Effects of Estrogen
 down arrowAnatomic Atherosclerosis Versus...
 down arrowReferences
 
In this issue of Circulation, Nabulsi and coworkers1 from the Atherosclerosis Risk in Communities (ARIC) Study Group report their findings on the association of age, menopause status, and hormone replacement therapy with a single measure of atherosclerosis: the average carotid artery intima-media thickness determined by B-mode ultrasound. What they discovered in the ARIC cohorts was this: there was little or no relation between menopausal staus and carotid thickness in women aged 45 to 54 who had never used hormonal therapy and who had no evidence of coronary heart disease at entry. Furthermore, for slightly older (aged 55 to 64 years) postmenopausal women, there was no relation between the number of years since menopause and carotid thickness nor between hormone use and carotid thickness. All of these findings were unexpected. Data that have been accumulated over the past few years demonstrate strong clinical benefits from estrogen use for postmenopausal women. The ARIC investigators quite logically hypothesized that there would be significant relations between carotid thickness, menopause, and hormone therapy (or lack of it) in this community-wide study, but in fact their data did not provide support for this. The investigators speculate that the association of estrogen replacement therapy with a reduction in clinical cardiovascular events after menopause may not necessarily be due to a reduction in the amount of anatomic atherosclerotic disease or inhibition of its formation, at least during the early years after menopause, but might instead be more attributable to other beneficial physiological changes brought about by estrogen compounds.

The present ARIC study has a number of limitations, as the authors themselves recognize. First, the upper age limit for ARIC was 64 years, and it was revealed that the duration of hormone use in women currently using hormones at entry was 9 years. It is possible that both the number of years since menopause and the duration of hormone use in these women were too brief to find any measurable effects on carotid thickness. If older women had been included in ARIC, the results might have been different. Another large-scale screening study2 that measured carotid thickness and which included women >64 years old noted average values that were greater than those described here (in the range of 0.9 versus 0.7 mm), and furthermore, there was a relation noted with estrogen use after menopause. Second, ARIC was a cross-sectional study, so no randomizations were performed. Consequently, there may be biases present in the subgroups of premenopausal and postmenopausal women and those using or not using hormones, inasmuch as they were self-selected. For example, some researchers3 4 have noted that postmenopausal hormone users tend to have healthier lifestyles than nonusers, and this presumably could bias measures of atherosclerosis as well as clinical events, including coronary events such as sudden death, myocardial infarctions, and anginal syndromes. The ARIC investigators measured carotid artery thickness, and although the association of carotid disease with coronary disease is accepted by many,5 there are differences of opinion on this point.6 It is possible that the presence or absence of carotid disease is not the correct marker to use for what ultimately boils down to a coronary risk. Finally, the current report from the ARIC investigators does not include any clinical outcomes data, so it is not possible to know whether the equality of the atherosclerosis burden found here was matched by an equality of later clinical events. One hopes that this large and valuable prospective study will eventually yield outcomes data, too.


*    Vascular Effects of Estrogen
up arrowTop
 up arrowIntroduction
 *Vascular Effects of Estrogen
down arrowAnatomic Atherosclerosis Versus...
 down arrowReferences
 
Is it possible, as the ARIC authors speculate, that clinical benefits of estrogen use are derived mainly via mechanisms other than anatomic ones, that is, other than by inhibiting the accumulation of atherosclerotic plaque in arteries? The evidence certainly is clear that hormonal therapy after menopause results in a decrease in clinical cardiovascular events. The precise mechanisms by which this reduction is achieved are unknown. Could these mechanisms be largely physiological? The answer to this question likely is yes. Estrogen has a number of immediately apparent vascular effects that do not depend on any change in the amount of atherosclerosis, which itself must require months or years to bring about. Studies of brachial7 as well as coronary8 arterial blood flow reveal that estrogen administration quickly enhances endothelium-dependent vasodilatation. Additionally, some investigators9 10 have reported both antioxidant and calcium-channel antagonist properties of estrogens. When sustained, these properties might provide physiological benefits leading to reduced clinical events but with little change in atherosclerotic substrate. Estrogen also alters a number of plasma constituents, including lipid components and fibrinogen. Lowering of fibrinogen levels by estrogen is only modest but is probably important. However, the influence of estrogen on lipid profiles is likely its most important effect. Estrogen administration reduces both LDL cholesterol and lipoprotein(a) and raises HDL cholesterol and triglycerides. As recently proposed by Guetta and Cannon in Circulation,9 the vascular protective benefits derived from estrogen may be due entirely to this favorable alteration in lipid profiles. Others11 have previously suggested that the lipid effect of estrogen accounts for only a small to moderate proportion of its clinical benefit. Changes in lipid profiles of the type and degree that are seen with estrogen use have been associated with a reduction in clinical cardiovascular events of approximately the same amount as that reported in recent studies of lipid-lowering agents. For example, a large meta-analysis of estrogen studies by Grady and colleagues12 revealed an estimated relative risk of coronary events of 0.65 for women who had ever used estrogen versus those who never had. In the Scandinavian Simvastatin Survival Study (4S),13 the relative risk of a major coronary event in women assigned to the cholesterol-lowering drug versus those assigned to a placebo was also 0.65.


*    Anatomic Atherosclerosis Versus Clinical Events
up arrowTop
 up arrowIntroduction
 up arrowVascular Effects of Estrogen
 *Anatomic Atherosclerosis Versus...
down arrowReferences
 
Nabulsi and colleagues from the ARIC study suggest there is a dissociation between anatomic measures of atherosclerosis and clinical events. Three similar situations come to mind wherein this same dissociation has been noted. The first is the conversion from chronic to acute coronary disease syndromes; second, the effect of lipid-lowering therapies on atherosclerosis progression; and third, restenosis after coronary interventions.

Acute Coronary Syndromes
The pathophysiology of the acute coronary syndromes of unstable angina pectoris and myocardial infarction involves complex structural changes in atherosclerotic plaques. These variously involve splitting, fissuring, or rupture of the plaque cap with in situ formation of thrombus.14 In a majority (50% to 80%) of cases, the culprit coronary plaque is not severe enough to be considered hemodynamically significant. It has been demonstrated repeatedly that thrombotic occlusion does not necessarily develop on the most severe lesions seen on angiography.15 More often, thrombosis develops on insignificant lesions that rapidly progress (or rather, degenerate) biologically. In fact, angiographic studies suggest that progression to infarction correlates with development of new, insignificant coronary lesions rather than worsening of old lesions.16 17 Thus, there is a dissociation here between angiographic disease severity seen at one time point and the clinical events that develop subsequently.

Regression
Several excellent clinical studies have examined the influence of diet, lifestyle, and drug therapies on general health indexes, lipid profiles, and long-term clinical outcomes. Many of these studies have included arteriographic measures of disease, generally with serial coronary angiograms. Furthermore, a wide variety of patient groups has been included.18 19 20 In virtually all lipid and lifestyle trials conducted to date, the improvement in clinical outcomes, that is, the reduction in death, myocardial infarction, and revascularization procedures, far exceeds the amount of change in atherosclerosis seen on angiography. In most trials, the reductions in total cholesterol, LDL cholesterol, and triglycerides range from 10% to 50%, with average reductions of {approx}30% in each, while HDL cholesterol rises on average by {approx}15% to 20%. These changes are accompanied by reductions in clinical events of 25% to 80%. Yet angiography reveals only modest changes in coronary lesions. Average stenosis diameter of lesions identified at baseline examination drops by only 2 to 5 percentage points at follow-up. When global measures of coronary disease presence, such as severity scores, are used, more progression and less regression are noted in control patients in these studies, whereas treated patients exhibit the reverse phenomenon. However, in many studies, disease progression by angiography occurs in both control and treated patients. The treated patients have slightly less progression than the control patients and yet have far fewer clinical events. A variety of explanations have been advanced to explain this dissociation. Most revolve around the inaccuracies of angiography for measuring atherosclerosis, even when sophisticated quantitative angiographic imaging techniques are used.21 One conclusion from these data is that serum lipid alterations must produce physiological changes in normal and atherosclerotic vessels that render them less likely to undergo rapid degeneration and produce untoward clinical events. A similar beneficial influence might be obtained from estrogen. In fact, if the estrogen-lipid hypothesis mentioned above is correct, then it would be expected that estrogen would produce significant reductions in clinical events with no change in anatomic measures of disease, because the same lipid physiology would apply to both.

Restenosis
The final parallel situation is the case of restenosis after coronary interventions. Investigators have struggled during the past 15 years to develop logical and useful definitions of restenosis on the basis of comparisons of angiograms from treatment to follow-up. The angiogram, in fact, has been the reference standard for determining restenosis. But a dissociation exists here, too, because of the presence of "significant" lesions without any clinical events occurring during the follow-up interval. Patients with this asymptomatic or "silent" restenosis have clinical courses not unlike patients without angiographic restenosis.22 23 24 It may be possible, as suggested by Meier and Ramamurthy,25 that angioplasty causes plaque "sealing," which renders the plaque much less likely to produce clinical events regardless of its measurement on an angiogram. Again, the physiological behavior of the plaque may be changed while the anatomy is not, or at least not much. Seen from this perspective, the speculations of the ARIC investigators do not seem out of line.

What do the results of ARIC mean? Should investigators not bother to measure anatomic disease at all but focus only on physiological parameters and clinical events? Definitely not, even though clinical events are perhaps the more relevant indexes and really are the final arbiters of any disease. Anatomic measures still have much to teach us about atherosclerosis. As an example, witness the blossoming of new thinking that has occurred as the concept of arterial remodeling has grown from the numerous measurements of coronary lesions, especially those made by intravascular ultrasound, at baseline and follow-up exams. On the other hand, it now seems likely that anatomic measures are probably not as important as previously believed. The biological and physiological behavior of the anatomic lesion apparently can be influenced in favorable ways.

In conclusion, the ARIC results that are described here represent one negative study of modest size and statistical power drawn from a relatively young group of women with only a few years' duration of menopause and hormone usage. If anything, these results tell us only that some anatomic measures of atherosclerosis do not show up very early after menopause. The clinical importance of these observations has yet to be determined. However, the authors' final speculations on the possible dissociation between the anatomic and physiological benefits of estrogen use after menopause are noteworthy, congruent with other observations, and deserve further attention.


*    Footnotes
 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.


*    References
up arrowTop
 up arrowIntroduction
 up arrowVascular Effects of Estrogen
 up arrowAnatomic Atherosclerosis Versus...
 *References
 

  1. Nabulsi AA, Folsom AR, Szklo M, White A, Higgins M, Heiss G, for the Atherosclerosis Risk in Communities (ARIC) Investigators. No association of menopause and hormone replacement therapy with carotid artery intima-media thickness. Circulation. 1996;94:1857-1863.[Abstract/Free Full Text]
  2. Manolio TA, Furberg CD, Shemanski L, Psaty BM, O'Leary DH, Tracy RP, Bush TL. Associations of postmenopausal estrogen use with cardiovascular disease and its risk factors in older women. Circulation.. 1993;88:2163-2171.[Abstract/Free Full Text]
  3. Barrett-Connor E. Postmenopausal estrogen and prevention bias. Ann Intern Med.. 1991;115:455-456.
  4. Posthuma WFM, Westendorp RGJ, Vandenbroucke JP. Cardioprotective effect of hormone replacement therapy in postmenopausal women: is the evidence biased? Br Med J.. 1994;308:1268-1269.[Abstract/Free Full Text]
  5. Craven TE, Ryu JE, Espeland MA, Kahl FR, McKinney WM, Toole JF, McMahan MR, Thompson CJ, Heiss G, Crouse JR. Evaluation of the associations between carotid artery atherosclerosis and coronary artery stenosis. Circulation.. 1990;82:1230-1242.[Abstract/Free Full Text]
  6. Adams MR, Nakagomi A, Keech A, Robinson J, McCredie R, Bailey BP, Freedman SB, Celermajer DS. Carotid intima-media thickness is only weakly correlated with the extent and severity of coronary artery disease. Circulation.. 1995;92:2127-2134.[Abstract/Free Full Text]
  7. Gilligan DM, Badar DM, Panza JA, Quyyumi AA, Cannon RO. Acute vascular effects of estrogen in postmenopausal women. Circulation.. 1994;90:786-791.[Abstract/Free Full Text]
  8. Gilligan DM, Quyyumi AA, Cannon RO. Effects of physiological levels of estrogen on coronary vasomotor function in postmenopausal women. Circulation.. 1994;89:2545-2551.[Abstract/Free Full Text]
  9. Guetta V, Cannon RO. Cardiovascular effects of estrogen and lipid-lowering therapies in postmenopausal women. Circulation.. 1996;93:1928-1937.[Free Full Text]
  10. Jiang C, Sarrel PM, Lindsay DC, Poole-Wilson PA, Collins P. Endothelium-independent relaxation of rabbit coronary artery by 17-ß-oestradiol in vitro. Br J Pharmacol.. 1991;104:1033-1037.[Medline] [Order article via Infotrieve]
  11. Bush TL, Barrett-Connor E, Cowan LD, Criqui MH, Wallace RB, Suchindran CM, Tyroler HA, Rifkind BM. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program follow-up study. Circulation.. 1987;75:1102-1109.[Abstract/Free Full Text]
  12. Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, Ernster UL, Cummings SR. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med.. 1992;117:1016-1037.
  13. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet.. 1994;344:1383-1389.[Medline] [Order article via Infotrieve]
  14. Fuster V, Badimon JJ, Badimon L. Clinical-pathological correlations of coronary disease progression and regression. Circulation. 1992;86(suppl III):III-1-III-11.
  15. Little WC, Constantinescu M, Applegate RJ, Kutcher MA, Burrows MT, Kahl FR, Santamore WP. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease? Circulation.. 1988;78:1157-1166.[Abstract/Free Full Text]
  16. Giroud D, Li JM, Urban P, Meier B, Rutishauser W. Relation of the site of acute myocardial infarction to the most severe coronary arterial stenosis at prior angiography. Am J Cardiol.. 1992;69:729-732.[Medline] [Order article via Infotrieve]
  17. Lichtlen PR, Nikutta P, Jost S, Deckers J, Wiese B, Rafflenbeul W. Anatomical progression of coronary artery disease in humans as seen by prospective, repeated, quantitated coronary angiography. Circulation.. 1992;86:828-838.[Abstract/Free Full Text]
  18. Superko HR, Krauss RM. Coronary artery disease regression: convincing evidence for the benefit of aggressive lipoprotein management. Circulation.. 1994;90:1056-1069.[Abstract/Free Full Text]
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  20. Gotto AM. Lipid lowering, regression, and coronary events. Circulation.. 1995;92:646-656.[Free Full Text]
  21. Hong MK, Mintz GS, Popma JJ, Kent KM, Pichard AD, Satler LF, Leon MB. Limitations of angiography for analyzing coronary atherosclerosis progression or regression. Ann Intern Med.. 1994;123:348-354.
  22. Gershlick A, Brack MJ, More RS, Syndercombe-Court D, Balcon R. Angiographic restenosis after angioplasty: comparison of definitions and correlation with clinical outcome. Coron Artery Dis.. 1993;4:73-81.[Medline] [Order article via Infotrieve]
  23. Hernandez RA, Macaya C, Iniquez A, Alfonso F, Goicolea J, Fernandez-Ortiz A, Zarco P. Midterm outcome of patients with asymptomatic restenosis after coronary balloon angioplasty. J Am Coll Cardiol.. 1992;19:1402-1409.[Abstract]
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