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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:893-899.)
© 1999 American Heart Association, Inc.

Original Contributions

Hormone Replacement Therapy, Inflammation, and Hemostasis in Elderly Women

Mary Cushman; Elaine N. Meilahn; Bruce M. Psaty; Lewis H. Kuller; Adrian S. Dobs; Russell P. Tracy

From the Departments of Medicine and Pathology (M.C.) and the Department of Pathology (R.P.T.), University of Vermont, Burlington; the London School of Hygiene and Tropical Medicine, Department of Public Health, London, UK (E.N.M.); the Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle (B.M.P.); the Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pa (L.H.K.) and the Department of Medicine, The Johns Hopkins University, Baltimore, Md (A.S.D.).

Correspondence to Mary Cushman, MD, MSc, Assistant Professor of Medicine, University of Vermont, 55A South Park Drive, Colchester, VT 05446. E-mail mcushman{at}salus.uvm.edu

	Abstract

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Abstract—Lipid-lowering by postmenopausal hormone therapy (HRT) explains only partly the assumed coronary risk reduction associated with therapy. To explore other possible mechanisms, we studied associations of HRT use with inflammation and hemostasis risk markers in women 65 years of age. Subjects were selected from 3393 participants in the fourth year examination of the Cardiovascular Health Study, an observational study of vascular disease risk factors. After excluding women with vascular disease, we compared levels of inflammation and hemostasis variables in the 230 women using unopposed estrogen and 60 using estrogen/progestin, with those of 196 nonusers selected as controls. Compared with nonusers, unopposed estrogen use was associated with 59% higher mean C-reactive protein (P<0.001), but with modestly lower levels of other inflammation indicators, fibrinogen, and alpha-1 acid glycoprotein (P<0.001). Factor VIIc was 16% higher among estrogen users (P<0.001), but this was not associated with higher thrombin production (prothrombin fragment 1-2), or increased fibrin breakdown (D-dimer). Concentration of plasminogen activator inhibitor-1 was 50% lower in both using groups (P<0.001) compared with nonusers, and this was associated with higher plasmin-antiplasmin complex: 8% higher in estrogen and 18% higher in estrogen/progestin users (P<0.05). Relationships between the markers and hormone use were less pronounced in estrogen/progestin users, with no association for C-reactive protein except in women in upper 2 tertiles of body mass index (P for interaction, 0.02). The direction and strength of the associations of HRT use with inflammation markers differed depending on the protein, so it is not clear whether HRT confers coronary risk reduction through an inflammation-sensitive mechanism. Associations with hemostasis markers indicated no association with evidence of procoagulation and a possible association with increased fibrinolytic activity.

Key Words: blood coagulation • inflammation • hormone replacement therapy • elderly • women

	Introduction

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The preponderance of observational epidemiological evidence suggests that hormone replacement therapy (HRT), either as estrogen or combined estrogen/progestin, reduces the risk of cardiovascular events, although a few studies have suggested no protection,^{1 2 3 4 5 6 7} and a recent clinical trial in women with coronary disease showed an increase in coronary events in the first year of combined therapy.⁸ Compared with unopposed estrogen, effects of combined therapy on risk factors such as HDL cholesterol may differ.⁹ Though clinical trials of HRT are ongoing, understanding its associations with newly described coronary risk markers may elucidate hypotheses about its nonlipid and nonvasoactive mechanisms.

C-reactive protein, fibrinogen, albumin, and alpha-1 acid glycoprotein are hepatically-derived acute phase reactant proteins.¹⁰ At concentrations below those indicative of clinical inflammation, C-reactive protein was associated with future coronary events in studies of those with unstable or stable angina,¹¹ healthy middle-aged men and women,^{12 13} and healthy elderly men and women.¹⁴ Fibrinogen, a marker of inflammation and coagulation, predicted coronary events,¹⁵ and levels declined with HRT.⁹ Low albumin predicted coronary risk in several studies,^{16 17 18 19} and this was more prominent in women in 2 studies.^{17 19} Potential biological roles for albumin include enhanced fibrinolytic function,²⁰ vasodilation, antioxidant effects, and reduced platelet aggregability.²¹ Alpha-1 acid glycoprotein has not been widely studied, and was not associated with increased coronary risk in the all-male MRFIT study.¹⁸ However, because alpha-1 acid glycoprotein is regulated by similar cytokines as C-reactive protein during the acute phase response, its relationship to HRT is of interest. The relationship between inflammation markers and atherosclerosis is not understood at this time. The association may be related to arterial wall inflammation due to preclinical atherosclerosis, low grade infections, genetic, or unknown environmental factors. Defining the relationship between HRT and these markers may provide useful information concerning modification of cardiovascular disease (CVD) risk by HRT.

We studied cross-sectional associations of estrogen use with markers of inflammation in female participants of the Cardiovascular Health Study, a cohort study of risk factors for CVD in 5888 free-living men and women age 65 and over. Women with clinical vascular disease were excluded to minimize confounding by disease on the markers.²² Coagulation and fibrinolysis markers, some which have been previously reported in prospective studies of hormone use,^{23 24 25} were also studied to (1) extend previous findings to an older age group and (2) simultaneously study a number of related markers.

	Methods

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Subjects
The Cardiovascular Health Study is a longitudinal population-based cohort of 5888 men and women recruited in 1989 to 1990 or 1992 to 1993 from 4 field centers.²⁶ Subjects were examined yearly at each field center. Subjects for this analysis were selected from among 3393 women participating in the fourth clinical examination of the study (1992 to 1993). Associations of HRT with CVD risk factors, clinical, and subclinical CVD at the baseline examination have been previously reported.²⁷ All participants provided informed consent with procedures approved by the institutional review committees at each site.

Women were excluded from analysis if they had a history of clinical vascular disease, were taking warfarin or transdermal estrogen, or did not have a plasma sample available from the 1992 to 1993 examination. All hormone users remaining were studied. History of clinical vascular disease was defined in the following 3 ways: (1) baseline presence of cardiovascular, cerebrovascular, or peripheral vascular disease using previously published criteria²⁸ ; (2) incident vascular disease events identified between the baseline and 1992 to 1993 examination years, and adjudicated by committee²⁹ ; and (3) discovery, during adjudication of incident events, of the presence of previously unknown prestudy vascular diagnoses. Women were divided into the following 3 exposure groups: 230 taking unopposed estrogen, 60 taking estrogen with progestin, and a comparison group of 196 women randomly selected from the remaining women not currently using hormones and frequency matched with estrogen-takers on 5-year age strata, clinic site, and race.

Definitions
Hormone use was established by medication inventory. Past use and duration of current or past use, hysterectomy and oophorectomy status, pregnancy history, smoking status, and alcohol use (drinks per week) were established by interview. Osteoporosis was defined by the question, "Has a doctor told you that you currently have osteoporosis?" Blood pressure, ankle-brachial index, waist-hip ratio, and body mass index were measured as previously reported.²⁶ Hypertension was defined as absent, borderline (systolic pressure 140 to 160 mm Hg or diastolic pressure 90 to 95 mm Hg), or definite (systolic pressure >160 mm Hg or diastolic >95 mm Hg, or self-reported hypertension in association with use of antihypertensive medication). Diabetes was defined as fasting glucose >140 mg/dL or use of insulin or oral hypoglycemic agents. Physical activity was defined as the weekly kilocalories of energy expenditure as measured by questionnaire.²⁶

Laboratory Analyses
A fasting morning blood sample was collected with minimal stasis as previously described.³⁰ C-reactive protein and alpha-1 acid glycoprotein were measured by colorimetric competitive immunoassays (C-reactive protein antibodies and antigens from Calbiochem) with respective coefficients of variation (CVs) of 4.8% and 14.2%.³¹ Plasminogen activator inhibitor-1 (PAI-1) antigen was measured by a sandwich immunoassay.³² Prothrombin fragment 1-2 (Baxter-Dade), fibrin fragment D-dimer, and plasmin-antiplasmin complex (PAP) were measured by enzyme-linked immunosorbent assays.^{33 34} The respective CVs for values in the range of our results were 11.8%, 10.1%, 18.5%, and 4.2%. Lipid levels, blood cell counts, albumin, fibrinogen, and factor VIIc were measured as previously described.³⁰

Statistical Analysis
SPSS 6.1.3 was used for data analysis, using the CHS database from the 1992 to 1993 examination, updated October 3, 1996. Baseline characteristics between study groups were compared using ² tests or Fisher's exact test for categorical data and t tests for continuous data. Log transformation was done when necessary to achieve gaussian distributions. Because many biomarkers had skewed distributions, crude associations between hormone use and the markers were determined by the Wilcoxon rank sum test. To assess the independence of relationships between hormone use and the markers, multivariable linear models were developed using each marker (untransformed for simplicity of interpretation) as the dependent variable, with hormone use status forced into the model and covariates entered in stepwise fashion (P value for entry 0.10, for removal 0.15). Including only blacks and whites, interaction by race was assessed (there were too few subjects of other races). Because it has been suggested that relationships between HRT and hemostasis are explained in large part by obesity,³⁵ interaction by body mass index was assessed. In this hypothesis-generating analysis, we set the statistical significance level for all analyses at 0.05.

	Results

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Among estrogen users 227 of 247 (92%) were taking conjugated equine estrogens (Premarin). Among combined therapy users 56 of 62 (90%) were taking Premarin, with 24 of 62 (39%) using continuous progestin, 13 of 62 (21%) using 11 to 29 days per month, 16 of 62 (26%) using 10 days per month, and 7 of 62 (11%) using <10 days per month.

Characteristics of the HRT use groups are shown in Table 1, and were similar to results from the baseline CHS examination.²⁷ There were 17 estrogen users and 2 combined therapy users (mean age 73.9) without available blood samples; 2 of 19 (11%) had diabetes and 9 of 19 (47%) had hypertension. Characteristics of unopposed estrogen versus combined estrogen-progestin users were similar, but estrogen users had a longer duration of use, and a much higher prevalence of hysterectomy and oophorectomy. Compared with nonusers, users of either estrogen or combined therapy had lower body size, higher income, younger age at menopause, and were more likely to have had hysterectomy, oophorectomy, and osteoporosis. Lipid levels were more favorable in users, with HDL levels similar in estrogen compared with combined therapy users. There were 10 users and 5 nonusers taking regular aspirin, and there were 19 users and 18 nonusers taking lipid-lowering drugs. More women in both using groups reported hormone use for osteoporosis prevention (206 of 285, 72%) than for coronary disease prevention (50 of 271, 19%). There were no differences between users and nonusers in the other factors shown in Table 1.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Study Groups

Table 2 shows levels of the study variables in the 3 exposure groups. The largest difference between users and nonusers was for C-reactive protein, with 59% higher median C-reactive protein levels in estrogen users than nonusers (3.49 mg/L versus 2.20 mg/L). Median C-reactive protein in estrogen/progestin users was similar to nonusers (2.41 mg/L). For albumin the difference also suggested increased inflammation in users. Fibrinogen and alpha 1-acid glycoprotein were lower in both groups of users compared with nonusers, but the fibrinogen difference was not significant in combined therapy users. For all 3 latter analytes representing inflammation, the magnitudes of the differences between users and nonusers were much smaller (3% to 17%) than for C-reactive protein.

View this table: [in this window] [in a new window]   Table 2. Median and Interquartile Range of Study Markers by Hormone Use

In unopposed estrogen and combined therapy users, median PAI-1 levels were lower than nonusers by 48% and 56% respectively, with respective values of 14 ng/mL and 12 ng/mL, compared with 27 ng/mL in nonusers. This was associated with less PAI-1-mediated plasmin suppression, measured as higher PAP, by 8% and 18%, respectively, in estrogen and combined therapy users (5.4 nmol/L nonusers, 5.9 nmol/L estrogen, 6.4 nmol/L combined therapy). A marker of procoagulant activity and fibrinolytic response, D-dimer, did not differ among the groups. In assessment of procoagulation, estrogen users had 16% higher factor VIIc levels than nonusers (137% versus 118%), and this was not observed in estrogen-progestin users. This difference did not translate to higher thrombin production, as measured by fragment 1-2.

Because preanalytical factors and variability due to minor illness may affect the values of some markers, unusually high values were excluded for all analyses, resulting in no substantial difference in bivariate relationships with hormone use status (data not shown). Additionally, exclusion of women using either regular aspirin or nonsteroidal anti-inflammatory drugs had no effect on results with the exception that the statistical significance of the difference in fibrinogen between combined therapy users and nonusers was improved (P=0.03; data not shown).

In the control group, 67 of 196 (34%) women reported past use of estrogen for a median duration of 3 years (range 1 month to 34 years). These past users had lower body mass index and waist-hip ratio, and higher prevalence of osteoporosis, hysterectomy, and oophorectomy compared with never users, with levels intermediate between current and never users (data not shown). Lipid levels and the other variables in Table 1 were similar between past and never users (data not shown). Most variables in Table 2 were similar between past and never users. Levels of C-reactive protein were slightly higher and PAI-1 slightly lower in past versus never users, but these differences were not statistically significant. D-dimer level was lower in past users compared with never users (121 versus 164 µg/L, P=0.01). Exclusion of past users from the control group did not alter the differences between nonusers and users for any of the hemostasis and inflammation markers.

For both groups of current hormone users there were no significant relationships between age-adjusted duration of use and levels of the study variables, except for factor VIIc, with a 1.8% absolute increase for every 5 years of current use of unopposed estrogen (P<0.05). For past users in the control group there were no associations of current level of any study analyte to age-adjusted past duration of use.

Comparing women using hormones for 5 years (36 estrogen/16 estrogen/progestin) with the 196 nonusers, relationships were similar to those in Table 2 with a nonsignificantly lower C-reactive protein in estrogen/progestin users compared with nonusers (1.77 versus 2.30 mg/L, P=0.27). Although PAP was higher in these short-term users, the difference was not statistically significant. In analysis of the 77 women reporting unopposed estrogen use for >20 years, there were similar relationships of study variables compared with nonusers. These long-term users had higher levels of C-reactive protein (4.20 mg/L), factor VIIc (142%), PAP (6.2 nmol/L), and lower fibrinogen (2.93 g/L) and alpha-1 acid glycoprotein (571 mg/L) than the entire group of current estrogen users (see Table 2 for values).

There were 30 estrogen users and 23 nonusers who were black. Relationships of study variables to use were similar to those in whites, except that black users had higher fibrinogen levels than nonusers (3.62 versus 3.02 g/L, P=0.003), a relationship opposite to that in whites (2.97 g/L users versus 3.17 g/L nonusers, P<0.001; P for race interaction=0.03). Adjusting for confounders (hypertension, LDLc), values were similar but the interaction term was no longer statistically significant (P=0.23). Overall, C-reactive protein concentration was higher in blacks than whites (4.06 versus 2.90 mg/L, P=0.02), with black estrogen users having the highest values: 4.52 mg/L black users versus 3.40 mg/L black nonusers (P=0.41); 3.92 mg/L white users versus 2.18 mg/L white nonusers (P<0.001, P for interaction by race >0.05).

Associations between estrogen use and the study variables, with and without adjustment for confounders, are shown in Table 3. The covariates that entered each model generally reflected lipid status and obesity. Comparing estrogen users with nonusers, for C-reactive protein and fibrinogen, income level also remained in the final model. There was mild attenuation of most relationships after adjustment, but use of unopposed estrogen remained associated with higher C-reactive protein and factor VIIc and lower fibrinogen, alpha-1 acid glycoprotein, albumin, and PAI-1 concentrations. Comparing combined hormone therapy users to nonusers, relationships between study variables also persisted after adjustment, except for loss of statistical significance for lower PAI-1, adjusted for HDLc and body mass index.

View this table: [in this window] [in a new window]   Table 3. Crude and Adjusted Differences in the Study Variables By Hormone Use Status

In analyses stratified by body mass index, C-reactive protein was higher with unopposed estrogen in all 3 body mass index tertiles (Figure 1). For combined users, C-reactive protein was higher than nonusers among those in the second and third BMI tertiles, even though C-reactive protein was not higher in the overall combined therapy group (P for interaction=0.02 adjusted for LDL and income). Women in the lowest body mass index tertile, who were nonusers or on combined therapy, had the lowest C-reactive protein levels.

View larger version (81K): [in this window] [in a new window]   Figure 1. C-reactive protein by hormone use status and body mass index tertiles. Sample size of each group is shown in the bars. Adjusting for income and LDLc, for estrogen compared with nonusers the P for interaction by BMI was 0.71, and for combined users versus nonusers the P for interaction was 0.02. Unadjusted geometric mean values are shown, as there was little difference between crude and adjusted mean values within subgroups. BMI tertile values: first tertile, 14.5 to 24.2; second tertile, 24.2 to 27.7; third tertile, 27.7 to 46.3. BMI indicates body mass index.

Figure 2 shows that PAI-1 level also differed by use status and body mass index (P for interaction=0.0003 for combined use; 0.04 for estrogen, adjusted for HDL). Within body mass index tertiles, all using groups had lower PAI-1 levels than nonusers. Nonusers in the highest body mass index tertile had the highest PAI-1 concentration, and unopposed estrogen users in the highest tertile had lower PAI-1 level, but only with a concentration similar to nonusing women in the lowest tertile.

View larger version (78K): [in this window] [in a new window]   Figure 2. Plasminogen activator inhibitor-1 (PAI-1) level by hormone use status and body mass index tertiles. Sample size of each group is shown in the bars. Adjusting for HDLc, for estrogen compared with nonusers the P for interaction by BMI was 0.04, and for combined users versus nonusers the P for interaction was 0.0003. Unadjusted geometric mean values are shown, as there was little difference between crude and adjusted mean values within subgroups. Note that the z-axis showing use status is reversed in order compared with Figure 1. BMI tertile values: first tertile, 14.5 to 24.2; second tertile, 24.2 to 27.7; third tertile, 27.7 to 46.3. BMI indicates body mass index.

	Discussion

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The main findings of this cross-sectional study of HRT users age 65 and over were (1) unopposed estrogen use was associated with higher levels of the new risk marker, C-reactive protein and lower levels of albumin; both differences were consistent with increased inflammation. However, (2) use was associated with modestly lower levels of 2 other inflammation indicators, fibrinogen and alpha-1 acid glycoprotein; (3) the previously reported higher factor VIIc level with use was confirmed, but we demonstrated lack of association with higher thrombin production; (4) the previously reported reduction in PAI-1 with estrogen use was confirmed, and we demonstrated less PAI-1-mediated plasmin suppression; (5) relationships between hormone use and the study variables were less pronounced in users of combined estrogen/progestin; and (6) relationships of hormone use to novel risk markers may differ in blacks compared with whites, and by body mass index.

Associations of HRT with inflammation differed among the markers with respect to direction, suggesting complexity in inflammation regulation. These differing relationships may be related to differential influences of HRT on transcriptional control, clearance, or cytokine regulation of these proteins. Our results agree with an experimental study of 15 women, where an 18% decline in alpha-1 acid glycoprotein over 4 weeks,³⁶ was observed. Alpha-1 acid glycoprotein and albumin are also lower in pregnancy,³⁷ suggesting decreased synthesis or increased clearance by estrogen.

Our data indicate that hormone use was associated with higher C-reactive protein, a recently recognized vascular risk marker. To our knowledge no other study has assessed C-reactive protein in relation to HRT, using a sensitive assay. Because C-reactive protein is a powerful risk marker, and might influence progression of atherosclerosis, confirmation of our findings is necessary.

Our results suggest any increase of factor VIIc observed with HRT does not translate to a procoagulant tendency, as assessed by the thrombin marker prothrombin 1-2. We previously reported in healthy subjects that factor VIIc level was not cross-sectionally associated with prothrombin 1-2 or fibrinopeptide A, another marker of thrombin.³⁸ Two small prospective crossover studies showed short-term increase of fragment 1-2 on HRT,^{23 24} and a larger prospective study is indicated.

The relationship between fibrinolysis markers and coronary risk has not been clarified, and few data specific to older women are available. Our results suggest that the large decline of PAI-1 observed experimentally,²⁵ and confirmed here cross-sectionally, translates to a modestly higher plasmin-antiplasmin complex. In different settings, increased plasmin-antiplasmin may be a response to either decreased PAI-1 inhibition, or increased fibrin formation. The differences in PAI-1 and plasmin-antiplasmin by hormone use were not associated with higher D-dimer, suggesting the higher plasmin-antiplasmin reflects the lower PAI-1 concentration. One small randomized study showed a nonsignificant increase of D-dimer with HRT²⁵ and larger studies are warranted to fully understand the significance of fibrinolytic effects of HRT.

Our data support a hypothesis that body mass index, as a measure of obesity, may modify the associations of HRT with PAI-1³⁵ and C-reactive protein. Women with the highest body mass index had the greatest difference in PAI-1 between users and nonusers, with lower concentration in users. However, this same group had the highest C-reactive protein level with use. One explanation for these findings relates to evidence that adipocytes synthesize and secrete inflammatory cytokines and PAI-1, and that this secretion is upregulated in obesity.³⁹ In the setting of obesity, it is possible that hormone therapy has effects on both inflammation and fibrinolysis through adipocyte function. Prospective clinical studies and animal model research may clarify these relationships.

The primary limitation of the study is the cross-sectional design. The study shares other limitations with the majority of observational research on HRT; it is possible that healthier women, at lowest risk for CHD, were prescribed estrogen, which might influence results.⁴⁰ The women studied were long-term users on average, so other health-conscious behaviors were probably more likely in users, although not all our findings suggested beneficial health effects. Multivariate methods were used to attempt to adjust for confounding factors that may relate to these sources of bias. The CHS cohort is healthier than the general elderly population, possibly limiting generalizability. Results are limited by the relatively small number of combined hormone users and the small number of black users, so cautious interpretation of results for those groups is indicated. Findings related to fibrinogen and PAI-1 agree with other prospective studies,^{9 25} supporting the validity of the remaining new findings; however, prospective randomized trials are required to confirm these findings.

In conclusion, HRT use in older women was associated with differences in newer risk markers that might translate to increased as well as reduced risk of arterial occlusion. Taken together, the findings related to procoagulation and fibrinolysis suggest overall beneficial effects of HRT on hemostatic balance, at doses usually used by older women. Use of HRT may have differential effects on components of the inflammatory response. The influence on vascular disease risk of these differences in relationships of HRT to inflammation markers, especially in light of recent reports,^{8 13} requires further study. Before specific treatment recommendations may be made on the basis of these new risk markers, effects of therapy on the markers need to be confirmed in ongoing clinical trials. Any effects observed should include assessment of effect modification by obesity and race, and the relationship between changes in markers with therapy and subsequent ischemic events.

	Acknowledgments

 
The study was supported by NIH contracts NO1-HC-85079-85086 (L.H.K., B.M.P., R.P.T.) and RO1-HL-46696 (R.P.T.), AHA Beginning Grant-in-Aid, 9606258S (New Hampshire-Vermont Affiliate, M.C.), and K08-HL-03618 (M.C.). We are grateful to Drs P. DeClerck and D. Collen for providing PAI-1, D-dimer, and PAP reagents and to our colleagues at the following participating institutions of the Cardiovascular Health Study: Forsyth County, NC–Bowman Gray School of Medicine of Wake Forest University: Gregory L. Burke, Sharon Jackson, Alan Elster, Walter H. Ettinger, Curt D. Furberg, Gerardo Heiss, Dalane Kitzman, Margie Lamb, David S. Lefkowitz, Mary F. Lyles, Cathy Nunn, Ward Riley, John Chen, Beverly Tucker; EKG Reading Center–Bowman Gray School of Medicine: Farida Rautaharju, Pentti Rautaharju; Sacramento County, CA–University of California, Davis: William Bommer, Charles Bernick, Andrew Duxbury, Mary Haan, Calvin Hirsch, Lawrence Laslett, Marshall Lee, John Robbins, Richard White; Washington County, MD–The Johns Hopkins University: M. Jan Busby-Whitehead, Joyce Chabot, George W. Comstock, Linda P. Fried, Joel G. Hill, Steven J. Kittner, Shiriki Kumanyika, David Levine, Joao A. Lima, Neil R. Powe, Thomas R. Price, Jeff Williamson, Moyses Szklo, Melvyn Tockman; MRI Reading Center–The Johns Hopkins University: R. Nick Bryan, Norman Beauchamp, Carolyn C. Meltzer, Naiyer Iman, Douglas Fellows, Melanie Hawkins, Patrice Holtz, Michael Kraut, Grace Lee, Larry Schertz, Cynthia Quinn, Earl P. Steinberg, Scott Wells, Linda Wilkins, Nancy C. Yue; Allegheny County, PA–University of Pittsburgh: Diane G. Ives, Charles A. Jungreis, Laurie Knepper, Peg Meyer, Roberta Moyer, Anne Newman, Richard Schulz, Vivienne E. Smith, Sidney K. Wolfson; Echocardiography Reading Center (Baseline)–University of California, Irvine: Hoda Anton-Culver, Julius M. Gardin, Margaret Knoll, Tom Kurosaki, Nathan Wong; Echocardiography Reading Center (Follow-Up)–Georgetown Medical Center: John Gottdiener, Eva Hausner, Stephen Kraus, Judy Gay, Sue Livengood, Mary Ann Yohe, Retha Webb; Ultrasound Reading Center–Geisinger Medical Center: Daniel H. O'Leary, Joseph F. Polak, Laurie Funk; Central Blood Analysis Laboratory–University of Vermont: Edwin Bovill, Elaine Cornell; Respiratory Sciences–University of Arizona-Tucson: Paul Enright; Coordinating Center–University of Washington-Seattle: Alice Arnold, Annette L. Fitzpatrick, Bonnie K. Lind, Richard A. Kronmal, David S. Siscovick, Lynn Shemanski, Will Longstreth, Patricia W. Wahl, David Yanez, Paula Diehr, Maryann McBurnie, Chuck Spiekerman, Scott Emerson, Cathy Tangen, Priscilla Velentgas; NHLBI Project Office: Diane E. Bild, Robin Boineau, Teri A. Manolio, Peter J. Savage, Patricia Smith.

Received June 25, 1998; accepted October 13, 1998.

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