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(Circulation. 1997;96:1102-1108.)
© 1997 American Heart Association, Inc.

Articles

Prospective Study of Hemostatic Factors and Incidence of Coronary Heart Disease

The Atherosclerosis Risk in Communities (ARIC) Study

Aaron R. Folsom, MD; Kenneth K. Wu, MD; Wayne D. Rosamond, PhD; A. Richey Sharrett, MD, DrPH; ; Lloyd E. Chambless, PhD

From the Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis (A.R.F.); Division of Hematology, University of Texas Medical School, Houston (K.K.W.); Collaborative Studies Coordinating Center, Chapel Hill, NC (W.D.R., L.E.C.); and NHLBI, NIH, Bethesda, Md (A.R.S.).

Correspondence to Dr Aaron R. Folsom, Division of Epidemiology, School of Public Health, University of Minnesota, Suite 300, 1300 S 2nd St, Minneapolis, MN 55454-1015. E-mail folsom{at}epivax.epi.umn.edu

	Abstract

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Background Although hemostatic factors contribute to acute coronary syndromes and atherogenesis, few studies have prospectively evaluated the association between multiple hemostatic factors and coronary heart disease incidence.

Methods and Results The Atherosclerosis Risk in Communities Study recruited 14 477 adults from 45 to 64 years of age who were initially free of coronary heart disease. Coronary disease risk factors and several plasma hemostatic factors were measured, and incidence of coronary heart disease was ascertained during an average follow-up of 5.2 years. Age-, race-, and field center–adjusted relative risks of coronary heart disease were significantly elevated (P.05) per higher value of fibrinogen (relative risk: men, 1.76; women, 1.54), white blood cell count (men, 1.68; women, 2.23), factor VIII coagulant activity (women, 1.25), and von Willebrand factor antigen (men, 1.20; women, 1.18). Adjustment for other risk factors attenuated these associations for fibrinogen (adjusted relative risk: men, 1.48; women, 1.21), and it eliminated the white blood cell count, factor VIII, and von Willebrand factor associations, consistent with the other risk factors either confounding or partly operating through their effects on the hemostatic variables. Adjusted standardized relative risks of total mortality, ranging from 1.13 to 1.37, were also elevated (P<.05) in relation to these four factors. There was no association of coronary disease incidence with factor VII, protein C, antithrombin III, or platelet count.

Conclusions Elevated levels of fibrinogen, white blood cell count, factor VIII, and von Willebrand factor are risk factors and may play causative roles in coronary heart disease. However, their measurement in healthy adults appears to add little to prediction of coronary events beyond that of more established risk factors.

Key Words: coagulation • coronary disease • von Willebrand factor • fibrinogen • leukocytes

	Introduction

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Considerable evidence indicates that the hemostatic system plays an important role in the pathogenesis of atherosclerotic vascular diseases. Yet few prospective epidemiological studies have examined whether plasma levels of hemostatic factors among initially healthy individuals can predict the subsequent incidence of CHD. An increased plasma fibrinogen concentration^{1 2 3 4 5 6} and WBC^{4 7 8 9} are consistent risk factors for cardiovascular disease, and WBC effects may interact with the effects of fibrinogen.⁴ Prospective evidence for roles in CHD of factor VII,^{2 5 10} factor VIII,^{2 10} von Willebrand factor,^{10 11 12} platelet count,¹³ aPTT, and two anticoagulation factors, protein C 10 and AT-III,^{14 15} is more limited and inconsistent. Few prior studies have included women or ethnically diverse populations.

The ARIC Study¹⁶ measured hemostatic factors in a large sample of middle-aged adults. This report details the association of these factors with CHD incidence after an average follow-up of 5 years.

	Methods

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Study Population
The ARIC Study^{16 17} included a cohort totaling 15 792 persons between 45 and 64 years of age at recruitment in 1987 through 1989. Population samples were selected from Forsyth County, North Carolina; Jackson, Miss (blacks only); the northwest suburbs of Minneapolis, Minn; and Washington County, Maryland. Participants underwent reexamination in 1990 through 1992 (93% return rate) and in 1993 through 1995 (86% return rate).

Baseline Measurements
Blood was drawn after an 8-hour fasting period with minimal trauma from an antecubital vein. Detailed methods for hemostatic variables have been published.^{18 19} In brief, fibrinogen was measured by the thrombin-time titration method²⁰ with reagents and calibration materials (Fibriquik) obtained from General Diagnostics (Organon-Technika Co). Factor VII and VIII activities were measured by determining the ability of the tested sample to correct the clotting time of human factor VII– or factor VIII–deficient plasma obtained from George King Biomedical Inc. von Willebrand factor antigen and protein C antigen were determined by ELISA kits from American Bioproducts Co. AT-III activity was measured by a chromogenic substrate method. aPTT was measured on an automated coagulometer (Coag-A-Mate X-2, General Diagnostics). The reference material for assays was the Universal Coagulation Reference Plasma (Thromboscreen, Pacific Hemostasis, Curtin Matheson Scientific, Inc). Reliability coefficients (method variance plus intraindividual variance divided by total variance) obtained from repeated testing of individuals over several weeks were 0.72 for fibrinogen, 0.78 for factor VII, 0.86 for factor VIII, 0.68 for von Willebrand factor, 0.56 for protein C, 0.42 for AT-III, and 0.92 for aPTT.²¹

Plasma total cholesterol²² and triglycerides²³ were measured by enzymatic methods, and LDL cholesterol was calculated.²⁴ HDL cholesterol was measured after dextran-magnesium precipitation of non-HDL lipoproteins.²⁵ Prevalent diabetes mellitus was defined as a fasting glucose level 140 mg/dL, nonfasting glucose level 200 mg/dL, and/or a history of or treatment for diabetes. Platelet counts and WBCs were measured by Coulter counters in laboratories in each study community.

The ratio of waist (umbilical level) and hip (maximum buttocks) circumferences was calculated as a measure of fat distribution. Three blood pressure measurements were taken with a random-zero sphygmomanometer. The mean of the last two measurements was used. Physical activity was expressed as a sport index ranging from 0 (low) to 5 (high).²⁶ Average carotid intima-media thickness was assessed by use of a standardized B-mode ultrasonographic technique.^{27 28} Prevalent CHD at baseline was defined, for exclusion, as a reported history of a physician-diagnosed heart attack, prior MI by ECG, or prior cardiovascular surgery or coronary angioplasty. Persons with exertional angina by questionnaire²⁹ (4% of the cohort) were not excluded because doing so had no impact on results.

Ascertainment of Incident Events
CHD incidence in ARIC was identified as previously described.^{17 30} For hospitalized patients, trained abstractors recorded the presenting signs and symptoms, including chest pain, cardiac enzymes, and related clinical information. Up to three 12-lead ECGs were visually coded with the Minnesota Code,³¹ and waveform evolution was evaluated by use of side-by-side comparisons. Out-of-hospital deaths were investigated by means of the death certificate and, in most cases, an interview with next of kin and questionnaires completed by the patient's physicians. Coroner reports and autopsy reports, when available, were used for validation.

CHD incidence was defined for this article as a definite, probable, or silent MI or definite CHD death by use of published criteria.³⁰ Unrecognized MI was defined by the appearance between the first and subsequent ARIC examinations of a major Q wave or a minor Q wave with ischemic ST-T changes or an MI by computerized NOVACODE³² criteria confirmed by side-by-side visual ECG comparison.

Data Analysis
Of the 15 792 ARIC participants, 14 477 were free of CHD at baseline, were not taking anticoagulants, and had at least one hemostatic factor measured. Sex-specific and age-, race-, and ARIC field center–adjusted mean baseline values of hemostatic factors were compared by ANCOVA for participants who did versus did not develop an incident CHD event during follow-up. Incidence rates were calculated by dividing the number of events by the person-years of follow-up, within thirds of the distributions of hemostasis variables, on the basis of tertiles of the entire sample distribution. Quintiles were also used sometimes. Length of follow-up was calculated for clinically recognized cases as the time elapsed from the baseline examination to the first CHD event. The date of unrecognized MI, being unknown, was assigned arbitrarily as the midpoint between the ARIC examination at which an ECG revealed it and the immediately prior examination. For noncases, follow-up continued until the date of death, date of last contact (if lost), or through December 31, 1993. Age-, race-, and field center–adjustment of rates was accomplished by use of sex-specific Poisson regression models using 5-year age groupings.

Multivariate modeling to obtain relative risks of incident CHD and total mortality in relation to hemostasis factors was performed by use of proportional hazards regression. Hemostatic factors were stratified by thirds or treated as continuous variables. Curvilinear associations were tested by including a quadratic term in each continuous variable model, retaining it when significant (P<.05). Correlates of hemostatic factors, which might serve as determinants of the effects of hemostatic factors or as potential confounders in the analysis, had been detailed in previous ARIC publications.^{33 34 35 36 37 38} We chose to adjust for age, race (black, other), ARIC field center (three dummy variables), LDL cholesterol, HDL cholesterol, systolic blood pressure, antihypertensive medication use (yes, no), diabetes (yes, no), cigarette smoking (current, former, never), pack-years of cigarettes, waist-to-hip ratio, and sport index. Relative risks and 95% CIs were computed for the highest versus lowest third or per SD of study variables (standardized relative risks). In the case of a quadratic association, the standardized relative risk was calculated for an increment of 1 SD centered at the mean of the study variable. In a supplemental analysis, we also corrected standardized relative risks for measurement error in hemostatic factors with the formula SSRcorrected=e_^(SD)/R, where ß is the regression coefficient and R is the reliability coefficient. Reliability data were not available for WBC and platelet count.

	Results

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The ARIC cohort included 27% blacks; almost all other participants were white. Several of the baseline hemostatic factors were interrelated: factor VIII with von Willebrand factor (Pearson r=.71), factor VIII or von Willebrand factor with aPTT (r=-.31 and -.46), factor VIII or von Willebrand factor with fibrinogen (r=.26 and .29), WBC with fibrinogen (r=.29), WBC with platelet count (r=.24), and factor VII with protein C (r=.40).

Over the 4 to 7 years of follow-up, 238 men developed incident CHD events (169 nonfatal or fatal clinically recognized MI, 40 other fatal CHD, 29 "silent" MI), as did 110 women (87 clinical MI, 11 fatal CHD, and 12 "silent" MI). Men who developed incident CHD had higher (P<.05) age-, race-, and ARIC field center–adjusted mean baseline values of fibrinogen, von Willebrand factor, and WBCs than did men who remained free of CHD (Table 1). Women who developed CHD also had elevations in these three parameters and in mean factor VII and VIII coagulant activities. The adjusted mean values of these variables in those who developed CHD were approximately 1/5 to 1/2 SD higher than in those who did not develop CHD. There was no significant difference in mean protein C, AT-III, aPTT, or platelet count between these two groups.

View this table: [in this window] [in a new window]   Table 1. Adjusted Mean Values1 of Hemostatic Factors in Participants Who Did and Did Not Develop a First CHD Event in the ARIC Study

Age-, race-, and field center–adjusted incidence rates of CHD rose significantly from the lowest to highest thirds of the fibrinogen distribution: 2.77-fold in men and 2.63-fold in women (the Figure). For the highest versus lowest fifth of the fibrinogen distribution (not shown), relative risks were 3.66 and 3.50, respectively. Relative risks of CHD rose 1.22- to 1.53-fold across thirds of factor VIII or von Willebrand factor in men and women (the Figure). Relative risks for the highest versus lowest third of platelet count were 1.28 in men and 1.52 in women, although neither trend was statistically significant. Relative risks were significantly elevated for the highest versus lowest third of WBC: 2.62 in men and 4.24 in women. Incidence rates of CHD were not appreciably associated with factor VII, protein C, AT-III, or aPTT. Although some of the associations depicted in the Figure appeared to differ between men and women, sex differences in relative risks were not statistically significant.

View larger version (44K): [in this window] [in a new window]   Figure 1. Age-, race-,and ARIC field center–adjusted incidence of CHD by thirds of hemostasis variables in the ARIC Study. Bar height depicts CHD incidence according to thirds of the distribution of hemostasis variables. Tertile cutting points are indicated. Values within the bars represent the relative risk of CHD for that third referenced to the first third. SRR indicates the relative risk (95% CI) per 1-SD increment of the factor (in the case of fibrinogen in men and WBC in both men and women for which a quadratic relation pertained, the SD increment was centered at the mean); SRRcorr, the SRR corrected for measurement error; and PTT, partial thromboplastin.

The Figure also provides the relative risks of CHD per each SD-higher level of the hemostatic factors (standardized relative risks) derived from proportional hazards regression analysis. For three associations that required a quadratic term in addition to a linear term (fibrinogen in men and WBC in both sexes), the standardized relative risk is for an increment of 1 SD centered at the mean. Thus, in women, the age-, race-, and field center–adjusted incidence of CHD was 54% higher per SD increment (65 mg/dL) of fibrinogen. In men, CHD incidence was 76% higher for a fibrinogen of 335 versus 270 mg/dL. CHD incidence was 10% to 25% higher per each SD increment in factor VIII or von Willebrand factor. These standardized relative risks were somewhat higher when corrected for measurement error. CHD incidence was 68% higher in men and 123% higher in women for a WBC of 7000 versus 5100 cells/mm³. Although the factor VII standardized relative risk in women was 1.25 (P=.02), there was no evidence of a monotonic trend in incidence across thirds (the Figure) or fifths (not shown) of the factor VII distribution. Furthermore, after adjustment for other major risk factors, there was no statistically significant association of factor VII with CHD incidence or CHD mortality (data not shown).

Table 2 shows that for the most part, fibrinogen and WBC were CHD risk factors in blacks and whites, older and younger participants, smokers and nonsmokers, and in those individuals above and below the median carotid intima-media wall thickness. Although CIs mostly overlapped 1.0, relative risks for factor VIII and von Willebrand factor were also elevated for these subgroups and were especially elevated for blacks compared with whites. These associations also generally held within strata on the basis of a median split of other major risk factors (not shown). Tests for two-way interactions (and specifically of fibrinogen with WBC⁴ and LDL cholesterol^{5 12} ) were not statistically significant.

View this table: [in this window] [in a new window]   Table 2. Age-, Race-, and Field Center–Adjusted1 Relative Risk and 95% CI of Incident CHD for the Highest Versus Lowest Third of the Distribution of Hemostatic Factors According to Levels of Other Factors in the ARIC Study

A number of accepted CHD risk factors, eg, cigarette smoking, hypertension, diabetes, and physical inactivity, may exert their effects through elevations of plasma fibrinogen, factor VIII, von Willebrand factor, or WBCs. To determine whether this could have occurred in these data, we computed multivariate-adjusted relative risks (Table 3) for comparison with the age-, race-, and field center–adjusted relative risks (the Figure). The multivariate-adjusted relative risks of CHD per SD-higher fibrinogen concentration were 1.48 in men and 1.21 in women (P<.05). The standardized relative risks for factor VIII, von Willebrand factor, and WBC were no longer statistically significantly different from 1.0 after multivariate adjustment. Attenuation of the relative risks with adjustment suggests that the accepted risk factors partially accounted for the positive association of fibrinogen with CHD and almost totally accounted for the factor VIII, von Willebrand factor, and WBC associations. The risk factor covariates that most attenuated the associations of fibrinogen and WBC with CHD were smoking (both sexes), HDL cholesterol (men), and LDL cholesterol (women); the factor VIII and von Willebrand factor associations with CHD were attenuated most by the inclusion of diabetes.

View this table: [in this window] [in a new window]   Table 3. Multivariate Relative Risk1 and 95% CI of Incident Events in Relation to 1-SD-Higher Level of Hemostatic Factors in the ARIC Study

Higher levels of plasma fibrinogen, factor VIII, von Willebrand factor, and WBC were also associated with increased all-cause mortality. Adjusted relative risks of death ranged from 1.13 to 1.37 per SD increment of these factors. Insufficient numbers precluded detailed analyses by underlying cause of death, but generally all four hemostatic factors were associated positively with cardiovascular deaths and noncancer/noncardiovascular deaths, and fibrinogen was associated with cancer deaths.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The ARIC Study assessed whether levels of hemostatic factors in middle-aged adults free of CHD predict the incidence of CHD during an average of 5.2 years of follow-up. We found that CHD incidence was associated positively with fibrinogen, WBC, factor VIII, and von Willebrand factor. This was true for women and men and for blacks and whites. CHD was not associated with factor VII, AT-III, protein C, or platelet count.

The associations of fibrinogen with CHD were moderately strong in both men and women. Smaller studies, primarily of men, also have found fibrinogen associated positively with CHD incidence^{1 2 3 4 5 6} and with other atherosclerotic vascular diseases.⁶ In a pooled analysis,⁶ the odds ratio of CHD for the highest versus lowest tertile of fibrinogen among six studies was 2.3 (95% CI, 1.9 to 2.8) versus age-, race-, and field center–adjusted relative risks of 2.77 and 2.63 in ARIC men and women, respectively. Fibrinogen is correlated positively with most other CHD risk factors.³³ Thus, in ARIC, as in other studies, multivariate adjustment reduced the relative risks. This suggests that fibrinogen could mediate some of the effect of other risk factors (in ARIC, primarily smoking and plasma lipids). However, even in nonsmokers and most other subgroups (Table 2), fibrinogen proved to be a CHD risk factor.

Elevated fibrinogen could predict incident CHD because it may reflect the inflammatory activity of progressing atherosclerosis. Yet there are also direct mechanisms by which fibrinogen may contribute to acute coronary events.² Fibrinogen stimulates smooth muscle migration and proliferation, is a component of atherosclerotic plaques, promotes platelet aggregation, and is a major contributor to blood viscosity and thrombi,² all of which may contribute to coronary disease.

The association of WBC with CHD was moderately strong in ARIC, corroborating prior studies,^{4 7 8 9} but it was reduced substantially by controlling for other risk factors (primarily smoking and lipids). We did not find a statistical interaction between the association of fibrinogen and WBC with CHD incidence as was reported previously.⁴ Oxidant-generating stimuli (eg, smoking) may raise the WBC, but WBC proved to be a CHD risk factor even in nonsmokers and most other subgroups (Tables 2 and 3). WBC contributes to blood viscosity and participates in endothelial injury,⁹ both of which may increase risk of CHD. However, as with fibrinogen, WBC elevations also may reflect the inflammatory activity of atherosclerosis.

A few prospective clinical studies have linked higher von Willebrand factor antigen levels with a greater risk of acute events among patients with CHD.^{10 11 12} However, to the best of our knowledge, no previous prospective study of healthy adults has reported a positive association between von Willebrand factor and subsequent CHD incidence. Elevated von Willebrand factor levels are believed to indicate endothelial dysfunction and vascular inflammation,³⁹ may promote platelet adhesion to damaged arterial walls, and may enhance platelet aggregation under sheer stress.⁴⁰ In women, factor VIII was also positively associated with CHD incidence, which might be expected because factor VIII is bound to von Willebrand factor in plasma and there is a correlation of 0.71 between these two factors. The Northwick Park Heart Study also reported a positive association of factor VIII with CHD in men during early follow-up,⁴¹ but it did not persist with longer follow-up.² Despite their univariate predictions, which were especially strong in blacks, neither von Willebrand factor nor factor VIII was associated independently with CHD in ARIC. The likely risk factor, diabetes, elevates von Willebrand factor and factor VIII.³⁵

We found that fibrinogen, factor VIII, von Willebrand factor, and WBC also were associated positively with total mortality; this appeared to include both noncardiovascular and cardiovascular deaths. Others have reported similar associations between these factors and mortality.^{2 41} A number of chronic conditions elevate hemostatic factors, especially those that are acute-phase reactants, so the observed associations with total mortality may not be totally causal.

The Northwick Park Heart Study reported a strong positive association between factor VII coagulant activity and CHD incidence in middle-aged men.² The Prospective Cardiovascular Münster Study also found a positive association, although it did not quite achieve statistical significance.⁵ In contrast, other investigators have found no association of factor VII with CHD.^{4 42} A role for factor VII is plausible because it plays a key role in coagulation. A possible reason for discrepancies among studies is the factor VII assay used. The Northwick Park Heart Study used a factor VII assay that seems to be more sensitive than the assay used in ARIC Study in detecting the activated form of factor VII.⁴³

The Northwick Park Heart Study investigators reported a significant U-shaped association between AT-III, an inhibitor of thrombin, and CHD; risks were elevated for both low and high AT-III levels.¹⁴ In contrast, AT-III activity was associated inversely with cardiac events in patients with angina.¹⁵ We found a U-shaped association only in women (the Figure), but it was not statistically significant. Protein C, an inhibitor of factors V and VIII, also was not associated with CHD. Measurement error, however, is excessive for AT-III and protein C,²¹ substantially reducing our chances of showing an association with CHD, if one exists.

A previous study found platelet count to be associated positively with CHD incidence,³ but Meade et al⁴¹ did not. We observed a suggestive but statistically insignificant positive association in both men and women. Four separate laboratories, using automated methods, measured the platelet counts in ARIC participants; nonstandardization could have obscured associations of the platelet count with CHD.

Other potential limitations of this study warrant consideration. ARIC made a single assessment of hemostatic factors, which may lead to misclassification of the habitual hemostatic factor levels of some individuals. Correction for measurement unreliability strengthens the relative risk estimates (the Figure). The accumulated follow-up was relatively short, and there were too few CHD events for the detection of small effects, especially in subgroup analyses. Although participants with clinical CHD at baseline were excluded, a large number of participants may have had alterations of hemostasis because of subclinical disease. Although this could weaken cause-effect inferences from these data, it does not diminish the predictive capacity of elevated levels of fibrinogen and WBC, particularly for CHD. Finally, the interpretation of the weaker associations of hemostatic factors with CHD after multivariate adjustment is complicated. If the adjusting factors were merely confounding variables, then the multivariate relative risks are the most informative. However, if, as is suspected, several risk factors operate through hemostatic mechanisms, then the relative risks adjusted only for age, race, and field center represent the mechanistic aspects of these hemostatic variables on CHD.

From a preventive-medicine point of view, only measurement of fibrinogen (and not the other hemostatic factors) contributed anything beyond traditional risk factors in the prediction of CHD. A fibrinogen measurement costs approximately the same as a lipid profile, so it could be considered for risk factor screening. However, there is no universal standardization system for the fibrinogen assay, and the independent contribution of fibrinogen to prediction of risk appears to be modest (Table 3). There also has been no clinical trial yet to demonstrate that lowering fibrinogen will prevent CHD. These facts suggest that routine screening for elevated fibrinogen in healthy adults is currently not warranted.

	Selected Abbreviations and Acronyms

 

aPTT = activated partial thromboplastin time ARIC = Atherosclerosis Risk in Communities AT-III = antithrombin III CHD = coronary heart disease CI = confidence interval MI = myocardial infarction WBC = white blood cell count

	Acknowledgments

 
The ARIC study was funded by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. We appreciate the important contributions of the following ARIC personnel: Phyllis Johnson, Marilyn Knowles, Catherine Paton, Dawn Scott, Nadine Shelton, Carol Smith, and Pamela Williams from the University of North Carolina, Chapel Hill; Betty Warren, Dorothy Washington, Mattye Watson, and Nancy Wilson from the University of Mississippi Medical Center, Jackson; Paul McGovern, Fangzi Liao, Susan Winkhart, Laura Kemmis, Maxine Dammen, Caryl DeYoung, Jaci Dion, and Lowell Hedquist from the University of Minnesota, Minneapolis; Joyce Chabot, Carol Christman, Mary Ann Cocodrilli, and Dorrie Costa from Johns Hopkins University, Baltimore, Md; Valarie Stinson, Pam Pfile, Hoang Pham, and Teri Trevino from the University of Texas Medical School, Houston; Wanda Alexander, Doris Harper, Charlie Rhodes, and Selma Soyal from the Atherosclerosis Clinical Laboratory, Methodist Hospital, Houston, Tex; Mary Lauffer, Suzanne Pillsbury, Tiffany Robertson, and Anne Safrit from the Ultrasound Reading Center, Bowman-Gray School of Medicine, Winston-Salem, NC; and Debbie Rubin-Williams, Climmon Walker, Louis Wijnberg, and Kiduk Yang from the ARIC Coordinating Center, University of North Carolina, Chapel Hill.

	Footnotes

 
Guest editor for this article was James H. Chesebro, MD, Cardiovascular Institute, New York, NY.

Received September 24, 1996; revision received March 25, 1997; accepted March 26, 1997.

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