Estrogen and atherothrombosis editorial22

READERS’ COMMENTS Estrogen and Atherothrombosis Editorial

The recent editorial by Blumenthal et al in the AJC (April 15, 2000, pages 1015 to 1017) analyzing the estrogen/coronary heart disease hypothesis might have made some sense if published just after the Heart and Estrogen Replacement (HERS) trial,1 but there is in June 2000, significant evidence and published scientific statements that indicate estrogen should have a very small, if any, role in atherosclerosis therapy or prevention. The editorial does not mention these guidelines and omits much of the very recent data. After the HERS study, the American Heart Association/American College of Cardiology (AHA/ACC) empowered a prestigious panel to analyze existing data on coronary artery disease (CAD) and women and make recommendations. Preventive Cardiology Guidelines for Women was published and endorsed by several prestigious organizations including The American College of Obstetrics and Gynecology. In essence, the committee made hormone replacement therapy (HRT) a “no start” in women with CAD (secondary prevention) and a no “stand alone” drug in primary prevention (must coadminister a statin, which is supported by clinical trial data in primary prevention).2 The committee recognized that there are no primary prevention data with estrogen, and that there has never been a previous drug that has failed in the secondary prevention of CAD that has subsequently succeeded in primary prevention. It is also remiss to keep mentioning the “lipid benefits” of estrogen without reporting the lipid adversities. All one keeps hearing about is estrogen’s ability to lower Letters (from the United States) concerning a particular article in The American Journal of Cardiology姞 must be received within 2 months of the article’s publication, and should be limited (with rare exceptions) to 2 doublespaced typewritten pages. Two copies must be submitted.

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low-density lipoprotein (LDL) cholesterol and raise high-density lipoprotein (HDL) cholesterol: There are many things going on with lipids when estrogen replacement therapy (ERT) or HRT is administered. Total and LDL cholesterol decrease and HDL cholesterol increases. However, triglycerides elevate, LDL particle size diminishes, very low density lipoprotein size increases, and apolipoprotein B levels (LDL particle concentration) are minimally reduced.3–5 These are currently thought to be not beneficial or potentially atherogenic. The HERS and recent Estrogen Replacement and Atherosclerosis (ERA) trials showed no clinical or angiographic benefit to the HRT or ERT despite LDL cholesterol decreasing and HDL cholesterol increasing. The HDL cholesterol increase in the HERS trial (8%) was greater than that in the VA-HIT trial (6%), which did have successful clinical outcomes with gemfibrozil therapy.6 The editorial mentions that the subset analysis of HERS may help us understand the study. Although not mentioned, I have to presume the authors are very aware of the lipoprotein(a) data from the trial since it was presented at AHA last November and published in April. It would seem that the only women who had any late benefit and no early harm from HRT were those with significantly elevated lipoprotein(a), which is a small percentage of American women.7 The C-reactive protein (CRP) data are extremely alarming. The data supporting high-sensitivity (hs) CRP as an independent risk factor in women are significant.8 Results of the Cholesterol And Recurrent Events (CARE) trial demonstrated that patients had a significantly better outcome if the hs-CRP was elevated and they received pravastatin (which lowered CRP 37% over 5 years).9 We now have prospective data revealing that either ERT or HRT equally, significantly, and rapidly elevates hs-CRP (thus removing progesterone from the blame). Authors of such studies hypothesize

©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 86 August 15, 2000

that HRT may destabilize plaque and cause endothelial dysfunction (which makes one wonder how estrogen would ever succeed in primary prevention).10,11 Is it a coincidence that hs-CRP increases in 4 to 8 months and that most of the adverse effects in HERS occurred over that same time period? Let us hope the investigators are analyzing hs-CRP data from the HERS trial. The editorialists suggest that the disappointing results may be due medroxyprogesterone acetate (MPA) in the HERS trial. The hsCRP data make that hypothesis doubtful. Much of adverse effects of MPA have been thought to be through a negative HDL cholesterol benefit, yet the HERS treatment cohort had a significant 8% HDL elevation (hardly aggravated by MPA).1 Finally, the data available this year from the ERA (a negative angiographic trial that included a Conjugated Equine Estrogens– only arm),12 Healthy Women’s Study (a trial showing no HRT benefit on carotid intimal thickening)13 and the Women’s Health Initiative (a primary prevention trial in which there has again been early adverse outcomes) are not mentioned.14 All of these trials are randomized and prospective. The results, like HERS, continue to be negative or null to HRT or ERT in atherosclerotic disease treatment or prevention. Finally, until the Raloxifene Use in The Heart trial is completed, we will have no outcome data on where selective estrogen receptor modulators fit in this scenario. However, I know of no adverse effects of raloxifene on any clinical outcomes in humans or on CAD risk factors. With respect to hs-CRP, triglycerides, apolipoprotein B, and fibrinogen, raloxifene has a more beneficial profile than estrogen. Both drugs affect HDL-2 (thought to be the important HDL subfraction involved with reverse cholesterol transport) and lipoprotein(a) beneficially.5,15 At this point in time, outside of clinical trials, estrogen has no

place in the prevention or treatment of atherosclerosis, with the possible exception of women with elevated lipoprotein(a) levels. Physicians should adhere to the AHA/ ACC guidelines and use proven therapies. I believe CAD in women can be very successfully impacted or treated with lifestyle changes, statins, fibrates, niacin, angiotensin-converting enzyme inhibitors, and antiplatelet therapy. Estrogen is not needed. At this time, selective estrogen receptor modulators, such as raloxifene, cannot be recommended pending the Reloxifene Use in The Heart trial. However, based on the above-mentioned surrogate data, raloxifene would seem to be a more appropriate therapy for women with CAD or CAD risk factors who require treatment for osteopenia or osteoporosis. Thomas Dayspring,

MD

Wayne, New Jersey 7 June 2000 1. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605– 612. 2. Mosca L, Grundy S, Judelson D, King K, Limacher M, Oparil S, Pasternak R, Pearson T, Redberg R, Smith S, Winston M, Zinberg S. AHA/ACC Scientific Statement: Consensus Panel Statement Guide to Preventive Cardiology for Women. J Am Coll Cardiol 1999;33:1751–1755. 3. The Writing Group for the PEPI Trial. Effects of estrogen and estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995;273:199 –208. 4. Wakatsuki A, Nobuo I, Sagara Y. Effect of estrogen on the size of low density lipoprotein particles in postmenopausal women. Obstet Gynecol 1997;90: 22–25. 5. Walsh B, Kuller L, Wild R, Paul S, Farmer M, Lawrence J, Shah A, Anderson P. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 1998;279: 1445–1451. 6. Rubins H, Robbins SJ, Collins D, Fye CL, M, Anderson JW, Elam MB, Faas FH, Laneres E, Schaefer EJ, Schectman G, Wilt T, Wittes J, for the Veterans Affairs HDL Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of HDL cholesterol. N Engl J Med 1999;341:410 – 418. 7. Shlipak M, Simon J, Vittinghoff E, Lin F, BarrettConnor E, Knopp R, Levy R, Hulley S. Estrogen and progestin, lipoprotein (a), and the risk of recurrent coronary heart disease events after menopause. JAMA 2000;283:1845–1852. 8. Ridker P, Hennekens C, Buring J, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in Women. N Engl J Med 2000;342:836 – 843. 9. Sacks F, Pfeffer M, Moye L, Rouleay J, Rutherford J, Cole T, Warnica W, Arnold J, Wun C, Davis B, Braunwald E. The Effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335:1001–1009. 10. Cushman M, Legault C, Barrett-Connor E, Ste-

fanick ML, Kessler C, Judd HL, Sakkinen PA, Tracey RP. Effect of postmenopausal hormones on inflammatory-sensitive proteins. Circulation 1999; 100:717–722. 11. Ridker P, Hennekens C, Rifai N, Buring J, Manson J. Hormone replacement therapy and increased plasma concentration of C-reactive protein. Circulation 1999;100:713–716. 12. Gottlieb S. News extra: study throws doubt on protective effects of HRT for heart disease. Br Med J 2000;320:826. 13. Mackey R, Kuller L, Mathews K, Sutton-Tyrrel K, Evans R. Does HRT Affect Associations Between Carotid Atherosclerosis and Lipoprotein Subclasses?—The Healthy Women’s Study Presented at AHA Council of Epidemiology & Prevention Meeting San Diego, CA: March 2000. 14. New York Times Interview of Jacques Rossouw (WHI Lead Investigator), April 6, 2000. (http:// www.nytimes.com/). 15. Walsh B, Paul S, Wild R, Dean R, Tracy R, Cox D, Anderson P. The Effects HRT and Raloxifene on C-Reactive Protein and Homocysteine in Healthy Postmenopausal Women: A Randomized Controlled Trial. J Clin Endocrinol Metab 2000;85:214 –218. PII S0002-9149(00)01152-8

Possible Mechanisms of Increased Blood Viscosity in Systemic Hypertension

Devereux et al1 found a higher whole blood viscosity (WBV) in patients with mild essential hypertension than in age- and sexmatched controls. Although hematocrit is the most important determinant of WBV,2 an increase in hematocrit was not an explanation for the higher WBV in hypertensive subjects because the hematocrit was similar in the 2 groups. Further, although WBV was positively correlated with hematocrit in normotensive subjects, there was no correlation between the WBV and the hematocrit in patients with hypertension. In an attempt to explain these findings, the authors postulate 2 mechanisms by which an increase in WBV in patients with hypertension could occur independently of hematocrit (there being an increase in plasma viscosity or a reduction in red cell deformability). Hematocrit is the product of red cell concentration and mean corpuscular volume, and although the hematocrit was not related to the increase in WBV in hypertensive subjects,1 there are reasons to also consider the relation of WBV to the individual components of hematocrit. First, red cell size may have effects on viscosity independent of hematocrit, because signif-

icant reductions in WBV can occur with decreases in mean corpuscular volume at a constant hematocrit.3 Second, individual variability in the red cell concentration may have effects on blood pressure. Thus, red cell concentration has been found to be a positive correlate of diastolic blood pressure in elderly men with hypertension, with the most likely mechanism being via an effect on WBV.4 Third, there appears to be an inverse relation between red cell concentration and mean corpuscular volume in population studies,4 – 6 which is of unknown cause, but could act to regulate viscosity in subjects with a high normal red cell concentration. In summary, the foregoing suggests that further studies investigating the relation between WBV and hypertension should also take the relatively simple extra step of measuring red cell concentration and mean corpuscular volume. Roger E. Peverill,

MB, BS, PhD

Melbourne, Australia 20 June 2000 1. Devereux RB, Case DB, Alderman MH, Pickering TG, Chien S, Laragh JH. Possible role of increased blood viscosity in the hemodynamics of systemic hypertension. Am J Cardiol 2000;85:1265– 1268. 2. Lowe GD, Fowkes FG, Dawes J, Donnan PT, Lennie SE, Housley E. Blood viscosity, fibrinogen and activation of coagulation and leukocytes in peripheral arterial disease and the normal population in the Edinburgh Artery Study. Circulation 1993;87: 1915–1920. 3. Chen D, Kaul DK. Rheologic and hemodynamic characteristics of red cells of mouse, rat and human. Biorheology 1994;31:103–113. 4. Sharp DS, Curb JD, Schatz IJ, Meiselman HJ, Fisher TC, Burchfiel CM, Rodriguez BL, Yano K. Mean red cell volume as a correlate of blood pressure. Circulation 1996;93:1677–1684. 5. Strazzullo P, Cappuccio FP, Iacoviello L, Cipollaro M, Varriale V, Giorgione N, Farinaro E, Mancini M. Erythrocyte volume and blood pressure in a cross-sectional population-based study. J Hypertens 1990;8:179 –183. 6. Sharp DS, Bath PM, Martin JF, Beswick AD, Sweetnam PM. Platelet and erythrocyte volume and count: epidemiological predictors of impedance measured ADP-induced platelet aggregation in whole blood. Platelets 1994;5:252–257. PII S0002-9149(00)01153-X

Arrhythmic Right Ventricular Cardiomyopathy

We appreciated the interesting study by Bauce et al1 reporting on a familial form of polymorphic ventricular arrhythmias triggered by effort. We agree that the auREADERS’ COMMENTS

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