© 1996 American Heart Association, Inc.
Articles |
Plasma Fibrinogen and Coronary Heart Disease in Elderly Japanese-American Men
From the Honolulu Epidemiology Research Section, Epidemiology and Biometry Program, National Heart, Lung, and Blood Institute, Hawaii (D.S.S., C.M.B.); the Honolulu Heart Program, Kuakini Medical Center, Hawaii (R.D.A., B.L.R., K.Y., J.D.C.); the Department of Medicine, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu (R.D.A., B.L.R., J.D.C.); the Departments of Pathology and Biochemistry, University of Vermont, Burlington (R.P.T.); and the Division of Biostatistics, University of Virginia School of Medicine, Charlottesville (R.D.A.).
Correspondence to Dr Dan S. Sharp, National Heart, Lung, and Blood Institute, Honolulu Heart Program, 347 North Kuakini Street, Honolulu, HI 96817. E-mail dan@hhs.cba.hawaii.edu.
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Abstract |
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Abstract Clinical and epidemiological studies consistently indicate that elevations in plasma fibrinogen concentration are associated with the presence and development of coronary heart disease (CHD). These elevations are strongly correlated with smoking behavior and may play a significant role in mediating a relation of smoking to CHD. This cross-sectional survey of 3571 elderly Japanese-American men, aged 71 through 93 years, represents survivors of the Honolulu Heart Program cohort. Active smokers are almost twice as likely to be represented in the highest quintile of the fibrinogen distribution compared with the lowest quintile (9.8% versus 5.3%, respectively). The highest prevalence of CHD (34%) was noted in past and current smokers who were in the highest quintile of fibrinogen. The age-adjusted relative odds of prevalent CHD comparing the average fibrinogen levels in the first and fifth quintiles were 1.36 (95% confidence interval, 1.13 to 1.64). After adjustment for smoking status, blood pressure, total and HDL cholesterol, diabetes status, hematocrit, and white cell count, the association between fibrinogen and CHD was changed slightly and remained statistically significant (P<.05). These findings in an elderly cohort of Japanese-American men are consistent with previous studies among middle-aged adults demonstrating fibrinogen to be associated with indicators of clinical CHD and CHD risk factors. Because of the cross-sectional nature of this study, it is not possible to distinguish whether the observed relation of fibrinogen to prevalent CHD is causal or whether it represents a marker of active and progressive disease.
Key Words: coronary heart disease • fibrinogen • non–insulin-dependent diabetes mellitus • smoking • erythrocyte indices
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Introduction |
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Since the publication of preliminary results of the Northwick Park Heart Study,1 there appears to be little doubt that an elevated plasma fibrinogen concentration is associated with increased risk of cardiovascular disease.2 A number of epidemiological studies of population groups in Sweden,3 the United Kingdom,1 4 5 the United States,6 and Germany7 have demonstrated that baseline measurements of plasma fibrinogen predict subsequent coronary events in men 40 to 65 years old. The Framingham study has also demonstrated such associations in women.4
Ernst2 has suggested that the epidemiological and clinical evidence consistently indicates an elevated plasma concentration of fibrinogen is related to cardiovascular events. Elevated fibrinogen has been associated with smoking and serum cholesterol level, as well as diabetes, obesity, low levels of HDL cholesterol, and high white blood cell count.2 Whether fibrinogen represents a causal risk factor or an associated risk marker remains unresolved. At the least, fibrinogen plays a significant role as a marker for chronic inflammatory processes reflecting active atherogenesis and possibly may play an active role in the development and progression of atherosclerotic lesions.2 Both roles are consistent with the coronary artery disease pathogenesis model proposed by Fuster et al.8 9
Recent comparisons of plasma fibrinogen and its correlates among 45- through 64-year-old men and women between Japanese and American populations indicate Japanese of the Akita, Japan Study have significantly lower fibrinogen levels than either European or African Americans participating in the Atherosclerosis Risk in Communities Study.10 There is little information on fibrinogen distributions in the elderly. The Cardiovascular Health Study is the only epidemiological study to examine population characteristics of plasma fibrinogen concentration by age, race, and sex among subjects older than 65 years, and results suggest that fibrinogen concentration continues to increase with age, with little difference between men and women.11 Meade,12 however, has reported little association of fibrinogen with cardiovascular risk in the elderly.
The purpose of this study was to provide the first description of the relation between fibrinogen and prevalent coronary heart disease (CHD) in an elderly Japanese-American cohort. Data from the Honolulu Heart Program will demonstrate that among survivors of the cohort, distinct relations exist between prevalent CHD, smoking status, alcohol intake, blood pressure, serum cholesterol, hematological indices, and diabetes. The nature of those relations, although reflecting the survivor status of the cohort, is consistent with what might be expected from past prospective studies of younger men or the results reported among older African and European Americans participating in the Cardiovascular Health Study.
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Methods |
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Study Population
The Honolulu Heart Program is a population-based longitudinal study initiated in 1965 to identify risk factors for cardiovascular disease in Japanese-American men living in Hawaii. A baseline examination of 8006 men who were living on the island of Oahu and were born between 1900 and 1919 was conducted between 1965 and 1968. The men's ages ranged between 45 and 68 at the time of that examination. Subjects were identified through Selective Service records, and the results of recruitment and methods of data collection are described in previous publications.13 14
Of the 8006 men, 4678 were still living and thereby eligible for participation in the fourth examination that occurred between 1991 and 1993. A total of 3741 examinations were conducted among the survivors, including 3194 clinic visits, 485 home visits, and 62 nursing home visits. Of the 3741 subjects participating in some form of examination, 3571 had measurements of plasma fibrinogen concentration.
Laboratory Analyses, Baseline Interview, and Clinical
Examination
Participants were asked to fast for 12 hours before the
clinic
visit. Blood specimens were collected after measurements of sitting
blood pressure and an electrocardiogram. Plasma
fibrinogen was measured as rate of clot formation by a semiautomated
modification of the Clauss method,15 using a BBL
Fibrometer (Becton Dickinson). Standardization was accomplished using
Data-Fi fibrinogen calibration reference plasma (Baxter
Healthcare Corp) and confirmed by participation in the College of
American Pathologists' comprehensive coagulation quality assurance
program. During the course of the study, internal reference plasma
specimens were used to assess reproducibility, revealing an average
monthly coefficient of variation of 
3.1%.
Other laboratory procedures included the measurement of total cholesterol, HDL cholesterol, and red cell indices. Total and HDL cholesterol were measured at the University of Vermont,16 17 using an Olympus Demand system (Olympus Corp), which had been standardized in the Centers for Disease Control Lipid Standardization program. Red cell indices were measured on whole-blood specimens collected in a standard 5-mL EDTA tube with a Coulter Counter S Plus (Coulter Corp). This device directly measures red blood cell count and mean corpuscular volume and calculates hematocrit as a scaled product of the two.
In addition to laboratory studies, blood pressure determinations included two sitting measurements using a conventional mercury sphygmomanometer and a separate measurement of the ankle/arm blood pressure. Technicians were trained to use standardized blood pressure measurement techniques, which included (1) measurement of midarm circumference and selection of appropriate-sized cuffs, (2) stethoscope placement, (3) determination of peak inflation level, (4) appropriate deflation rate (2 mm Hg/s), (5) identification of first-phase (systolic) and fifth-phase (diastolic) Korotkoff sounds, and (6) avoidance of digit preference. Technicians were certified initially and recertified 1 month later and then every 6 months thereafter. An average of the two measurements was used as the measure of blood pressure.
The ankle/arm index was determined as the ratio of the systolic pressure measured at the posterior tibial artery divided by the pressure at the brachial artery, using a Doppler stethoscope. Measurements of the posterior tibial artery were made on the right and left sides, but only one measurement was made from the right brachial artery. The average of the two posterior tibial measurements was used in constructing the index.
Men were defined to have diabetes on the
basis of a reported history or
the use of diabetic medication. On the basis of blood specimens from
the fourth examination, diabetes was also considered to be present
when fasting serum glucose was 
140 mg/dL or when 2-hour postload
serum glucose was 200 mg/dL.
Prevalent CHD
Two levels of CHD prevalence were assessed,
definite and
possible. These classifications were made by the Honolulu Heart Program
Surveillance Conference Committee, which periodically reviews all
clinical information collected from hospital admissions, past
examinations, and death certificates.18
Definite CHD was determined from a variety of end points. These included (1) prior myocardial infarction, as detected by hospital surveillance, (2) silent myocardial infarction, from electrocardiographic data collected by surveillance and from examinations, (3) acute coronary insufficiency or angina pectoris resulting in surgical intervention, and (4) temporal changes in electrocardiograms diagnostic of myocardial infarction.
Possible CHD reflected a categorization of men with less certain clinical evidence for coronary conditions (vague anginal complaints not requiring surgical intervention, equivocal electrocardiographic and cardiac enzyme findings), indicating they could not be classified as free from CHD with certainty.
Statistical Analyses
To describe the prevalence of CHD in the
elderly Honolulu
cohort, the percent of men with definite and possible CHD was derived
for three age groups; 71 through 74, 75 through 79, and 80 through 93
years. These three groupings were chosen in order to have comparable
numbers of men in each group. A grouping of 85 years and older had too
few men to reliably estimate relations with fibrinogen or prevalent CHD
among other joint combinations of covariates. Age was used as a
continuous variable when adjusting for confounding. The
age-adjusted percent of men with CHD was also calculated by
quintiles of fibrinogen by using logistic regression
models.19 For the purpose of describing how other factors
differ across quintiles of fibrinogen, age-adjusted mean levels of
each factor were compared across the quintiles by using
analysis of covariance and logistic regression
models.19
To assess the relation between fibrinogen and CHD, logistic models20 were used to provide estimates of CHD prevalence and the relative odds of disease between the average fibrinogen levels in the top versus bottom quintiles of fibrinogen. Based on the models, 95% confidence intervals (CIs) for the relative odds were calculated. Adjustments were made for age and other risk factors and for age alone. All reported probability values were based on two-sided tests of statistical significance.
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Results |
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Because of the elderly status of this cohort, CHD is common, yet its prevalence showed little relation to increasing age (Table 1
). There was a slight increase in prevalence of
possible CHD with age (P<.01), rising from 12.3% in men 71
through 74 years to 15.1% in men 80 through 93 years. There was no
significant change in prevalence of definite CHD with age. Fibrinogen
also increased modestly with increasing age (P<.05).
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Between quintiles of fibrinogen, CHD prevalence remained constant at
27% to 28% for the three lowest groups but increased to 30% and 35%
in the fourth and fifth quintiles, respectively (Table 2).
Similar patterns were noted for possible and
definite CHD. The increase in definite and total CHD prevalence with
increasing fibrinogen was statistically significant
(P<.01). It was not significant for possible CHD.
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Among the risk factors associated with CHD, average systolic
blood pressure, total cholesterol, prevalence of diabetes,
and white blood cell count significantly increased in magnitude across
increasing quintiles of fibrinogen (Table 3). Average
ankle/arm index, HDL cholesterol, red blood cell count,
mean corpuscular volume, and hematocrit significantly decreased. In
some cases, J-shaped or hockey stick–shaped relations were
suggested across quintiles. No relation was noted for body mass
index.
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Smoking status was also associated with fibrinogen. For never smokers
the distribution of plasma fibrinogen concentrations was shifted to the
left compared with the distribution for current smokers (Fig
1). The proportion of current cigarette smokers
increased significantly with increasing quintiles of fibrinogen, while
the proportion of past cigarette smokers was constant (Table
4). Among current smokers, there appeared to be no
significant relation between the number of cigarettes smoked per day
and quintile of fibrinogen, although with only 236 active smokers, the
statistical power to detect a relation was low. Among past smokers, an
increasing trend in the average number of cigarettes smoked per day was
noted across quintiles of fibrinogen (P<.05).
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The joint relation of smoking status and fibrinogen with the prevalence
of any CHD indicates that the highest prevalence was among men who had
smoked (past and current) and who had the highest levels of fibrinogen
(Fig 2). A test for interaction was not significant,
however, nor did the proportion of possible or definite CHD appear to
vary with smoking status and fibrinogen.
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Use of alcohol tended to have an opposite relation with fibrinogen
compared with the use of cigarettes. A significant decrease in the
proportion of men currently drinking alcohol was noted across
increasing quintiles of fibrinogen (Table 4
). This contrasts
with a
significant increase in the proportion of men consuming alcohol in the
past with increasing levels of fibrinogen. No trend in ounces of
alcohol consumed per month was noted among current users, but an
increasing trend in past amounts of alcohol consumed was observed with
increasing fibrinogen.
Adjustment for other factors had only modest effects on the relation
between fibrinogen and CHD prevalence. Multivariate
analysis indicated a relation independent of age, smoking
status, blood pressure, total and HDL cholesterol,
diabetes, hematocrit, and white blood cell count (Table 5).
Adjusted relations involving alcohol data also had
no effect, but this variable was not included in statistical models
in order to minimize the number of covariates. With adjustment for age
alone, the relative odds of prevalent CHD comparing the first and fifth
quintiles of fibrinogen is 1.36 (95% CI, 1.13 to 1.64). After
adjustment for the other risk factors, the relative odds was only
slightly reduced. Among smokers (past and current), the highest
age-adjusted relative odds of CHD was noted as 1.46 (95%
CI, 1.14 to 1.86). The relative odds among never smokers was smaller,
at 1.30, although there was no significant evidence for statistical
interaction. After taking into account simultaneous
relations with other risk factors, these respective relative odds
decreased in magnitude, with odds among past or current smokers
remaining statistically significant.
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Discussion |
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The relation between fibrinogen and CHD has been documented in epidemiological studies of incident disease.1 3 4 5 6 7 If an elevated plasma fibrinogen is correlate to a hypercoagulable condition, then the mechanism by which fibrinogen plays a role in the development of CHD may be via thrombotic, hemostatic, and rheological mechanisms.2 An increased level of fibrinogen is a direct determinant of increased plasma viscosity as well as induced reversible red blood cell aggregation, thereby significantly decreasing whole-blood fluidity. Such rheologic impacts could significantly alter in situ flow patterns at vascular sites predisposed to developing atherosclerotic lesions or enhance thrombotic potential. Also, fibrinogen has been directly implicated in the early formation of atherosclerotic plaques via mechanisms whereby fibrinogen and its degradation products are noted to stimulate smooth muscle cell proliferation and migration,2 although it is not clear whether increases in plasma fibrinogen concentration reflect this mechanism of action.
About 30% of men among the three age strata reported in Table
1 have
some evidence of CHD. Prevalence figures reported for participants of
the Cardiovascular Health Study21 are not
strictly comparable with those of the Honolulu Heart Program cohort
because myocardial infarction and angina pectoris are reported as
separate, although not necessarily mutually exclusive, categories in
that study. However, between 20% and 30% of men within similar age
strata are reported to have had a myocardial infarction or to have
angina.
Studies of prevalent relations have focused on the correlation of fibrinogen levels with other cardiovascular risk factors and demographic characteristics.10 11 22 23 24 25 26 Relations of fibrinogen with prevalent disease have not been considered appropriate in establishing the nature of a causal relation because sustained elevations in fibrinogen measured in the years following a cardiovascular event are well documented.2 27 28
In our study, elevations in plasma fibrinogen concentration coexist with a past history of CHD. This relation may reflect ongoing atherosclerosis, which in turn is more prevalent and of greater severity among men with long-standing clinical evidence of CHD.2 However, there was no suggestion that CHD diagnosed as of 1988, when date of incident CHD is completely enumerated, demonstrated a different relationship with fibrinogen than CHD diagnosed after 1988 when incident CHD is incompletely enumerated.
In middle-aged men6 10 23 24 29 30 and the elderly men of the Cardiovascular Health Study,11 fibrinogen is consistently higher in older age groups. This pattern is not noted in 1724 younger subjects (23 to 35 years) from the Chicago and Minneapolis centers of the Coronary Artery Risk Development in Young Adults Study,31 although among the 4193 members of the cohort from all centers, higher fibrinogen levels are noted for subjects >30 years old in joint categories of sex and race (white/black).32 In all of the aforementioned studies, as in our study, fibrinogen is strongly and consistently related to smoking status. The lowest fibrinogen levels are noted in never smokers, the highest in current smokers, and intermediate in past smokers. In our study, this pattern was also noted on stratification by alcohol intake status, particularly within past drinkers, less so in current drinkers, and much less so among never drinkers.
The Japanese Akita Study and the Atherosclerosis Risk in Communities Study10 did not demonstrate a relation between fibrinogen and grams of alcohol intake per week. The Northwick Park Heart Study29 and the Scottish Heart Health Study24 showed significantly lower fibrinogen levels in current drinkers compared with nondrinkers. These findings are consistent with our demonstration of a higher prevalence of current users of alcohol among the lower quintiles of fibrinogen. This observation may represent a survivor effect, whereby heavy drinkers with vascular disease have not survived to this examination and current drinkers in this elderly age range are more moderate in their consumption and are healthier. In contrast, the demonstration of the highest prevalence of past alcohol users and the highest amounts (ounces per month) in the highest quintile of fibrinogen may reflect past heavy alcohol consumption as a marker for diseases or other causal factors associated with elevated fibrinogen. The highest fibrinogen levels (mean±SD) were noted in past alcohol users who currently smoked (340±59 mg/dL), while the lowest were in current alcohol users who had never smoked (299±61 mg/dL).
Fewer studies have compared fibrinogen levels between nondiabetic and diabetic subjects. Two that have are consistent with our findings of higher levels in men with diabetes.6 23 In our study, joint relations of diabetes status and fibrinogen with prevalent CHD suggested no effect modification. Across the range of fibrinogen, the highest prevalence was noted among men with diabetes; and within strata of diabetic status, the highest prevalence was noted among men with the highest levels of fibrinogen.
Other risk factors, such as indicators of high blood pressure, adiposity, white blood cell count, red blood cell mass, and serum lipids, have been inconsistently related to fibrinogen in previous studies. In the Prospective Cardiovascular Münster study,7 incident CHD appeared to be the highest among people with the highest levels of fibrinogen (>277 mg/dL), and within this fibrinogen range incident CHD increased the most dramatically with increasing LDL cholesterol levels. In our study, there was no suggestion of an effect modification between fibrinogen and either LDL or HDL cholesterol in the prediction of prevalent CHD. However, the distribution of fibrinogen in our study is notably higher, and a comparison of incident with prevalent CHD may not be appropriate.
Only the Framingham study has reported significant relations between fibrinogen and hematocrit, but only in women, and in that study fibrinogen increased with increasing hematocrit.6 This contrasts with our results. Not only hematocrit but also red blood cell count and mean corpuscular volume were inversely and significantly related to fibrinogen. A combination of low red blood cell count (<4.33x1012/L) and low mean corpuscular volume (<92.5 fL) was associated with a significantly higher (P<.001) fibrinogen level (362 mg/dL) compared with other combinations of red blood cell count and mean corpuscular volume (295 to 324 mg/dL).
These findings are consistent with the clinical condition called "anemia of chronic disorders"33 and suggest that the chronic inflammatory and neoplastic conditions identified with this disorder are associated with a low-grade anemia and elevated fibrinogen. In the Honolulu cohort, the prevalence of either chronic bronchitis, emphysema, active tuberculosis, hepatitis, cirrhosis, thyroid disease, kidney disease, or cancer was highest among men with red blood cell counts less than 4.33x1012/L compared with men with higher counts (13% versus 8%, respectively; P<.001). It may be that elevated fibrinogen in this group characterized by low red blood cell count and low mean corpuscular volume is a reflection of chronic inflammatory conditions directly related to these disease processes. However, it is also conceivable that such patients are under closer medical scrutiny and the ascertainment of coronary heart disease, with its concomitant elevation of fibrinogen, is more likely in the subgroup.
Data from the Framingham study suggest a positive relation between
clinical peripheral artery disease and
fibrinogen.34 Men and women with fibrinogen concentrations
311 mg/dL demonstrated an incidence of peripheral artery
disease 1.6 and 1.7 times higher, respectively, than people with
measurements of 
264 mg/dL. Among elderly participants of the
Cardiovascular Health Study,35 the average
age- and sex-adjusted fibrinogen concentrations systematically
increased with decreasing ankle/arm index, consistent with the
findings presented in this report (Table 3).
There was no attempt to take into account use of nonsteroidal anti-inflammatory drugs (NSAIDs) that are known to affect the development of myocardial events and that may impact on plasma fibrinogen level. Although attempts were made to collect data on the general use of nonprescription medications, these efforts did not produce a thorough enumeration of their use, let alone the specific use of NSAIDs. Clinical trials examining the impact of short-term36 and long-term37 aspirin treatment have not demonstrated statistically significant impacts on plasma fibrinogen concentration, although these studies did not have the statistical power to detect relatively small impacts.
In summary, findings from this study of elderly Japanese-American survivors of the Honolulu Heart Program cohort are consistent with previous results among middle-aged adults that demonstrate fibrinogen is associated with indicators of cardiovascular disease and their risk factors. Strong and consistent relations with smoking, seen in all previous studies, appear to be confirmed in this elderly sample. Of course, the conclusion of a relation between fibrinogen and indicators of prevalent CHD suffers from the inferential dilemma of temporal sequence, ie, that fibrinogen may be elevated as a consequence of active disease or that elevated fibrinogen may mediate continued development of cardiovascular disease.
From an epidemiological perspective, this dilemma may be immaterial. As Ernst38 has suggested, the "final test for the hypothesis that fibrinogen is a cardiovascular risk factor would be a randomized trial to therapeutically lower it in patients and determine the subsequent cardiovascular outcome." The consistent results of studies and the development of a fundamental understanding of the role of fibrinogen in the molecular basis of atherosclerosis and thrombosis suggest the time may be near to progress to such trials. However, no known drug safely and selectively reduces fibrinogen.38 The discovery of such a substance could herald a new and fundamentally different therapeutic modality in the treatment of cardiovascular events, particularly in elderly persons who already have a significant prevalence of established disease and in whom the efficacy of therapeutic efforts may be limited to the more proximate thrombotic and hemostatic mechanisms of an infarction event.
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Acknowledgments |
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This study was supported by contract N01-HC-05102 (to the Honolulu Heart Program, Kuakini Medical Center, Hawaii) from the National Heart, Lung, and Blood Institute, Bethesda, Md. The authors thank Dr Kamal Masaki, who provided useful comments and input into assessing the clinical basis for relations between fibrinogen and red blood cell indices.
Received August 10, 1995; accepted November 21, 1995.
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