Plasma Fibrinogen and Coronary Heart Disease in Urban Japanese
Shinichi Sato1,2,
Masakazu Nakamura1,
Minoru Iida1,
Yoshihiko Naito1,2,
Akihiko Kitamura1,
Tomonori Okamura1,
Yuko Nakagawa1,
Hironori Imano1,
Masahiko Kiyama1,
Hiroyasu Iso3,
Takashi Shimamoto3 and
Yoshio Komachi2
1 Department of Epidemiology and Mass Examination, Osaka Medical Center for Cancer and Cardiovascular Diseases, 133 Nakamichi, Higashinari-ku, Osaka 5378511, Japan.
2 Osaka Prefectural Institute of Public Health, 1369 Nakamichi, Higashinari-ku, Osaka 5370025, Japan.
3 Institute of Community Medicine, University of Tsukuba, 111 Tennodai, Tsukubashi, Ibaraki-ken 3058575, Japan.
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ABSTRACT
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There is little information on the relation of plasma fibrinogen concentration to the risk of coronary heart disease in Asians, including Japanese, whose plasma fibrinogen concentration has been reported to be low by Western standards. The authors conducted a prospective study with 4.8 years of follow-up of 11,977 men and women aged 2189 years (mean value of fibrinogen = 267 mg/dl) living or working in Osaka, Japan, in 19901996 to examine the relation of plasma fibrinogen with the incidence of coronary heart disease (myocardial infarction and angina pectoris). Mean fibrinogen concentration was 293.6 mg/dl for men who developed coronary heart disease (n = 35) compared with 261.6 mg/dl for men free of coronary heart disease (n = 8,094; difference, p < 0.01), and 355.2 mg/dl for women who developed coronary heart disease (n = 6) compared with 276.8 mg/dl for women free of coronary heart disease (n = 3,842; difference, p < 0.01). With a Cox proportional hazards model to adjust for cardiovascular risk factors, the relative risk for the highest fibrinogen quartile (
295 mg/dl) compared with the lowest (<228 mg/dl) was 4.8 (95% confidence interval: 1.4, 16.8, p = 0.01) for coronary heart disease, and 3.8 (95% confidence interval: 1.1, 13.4, p = 0.04) for myocardial infarction. Plasma fibrinogen is useful to predict the risk of coronary heart disease among urban Japanese, whose mean plasma fibrinogen is relatively low. Am J Epidemiol 2000;152:4203.
coronary disease; fibrinogen; myocardial infarction; prospective studies
Abbreviations:
>ARIC, Atherosclerosis Risk in Communities; SD, standard deviation
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INTRODUCTION
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There is growing evidence from prospective studies in Europe and the United States that higher plasma fibrinogen concentrations are associated with greater incidence and mortality from coronary heart disease (1








11
). Two cross-sectional studies of Japanese (12
, 13
) showed that plasma fibrinogen levels were higher in patients with coronary heart disease than in controls and that the degree of coronary artery atherosclerosis was positively associated with plasma fibrinogen concentrations. Yet, no prospective data have been available in Asian countries, including Japan, where mean plasma fibrinogen concentrations were reported to be lower than among Caucasians (14
).
We conducted a prospective study among Japanese men and women to examine the relation of plasma fibrinogen concentrations to the incidence of coronary heart disease.
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MATERIALS AND METHODS
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The subjects were population-based samples of 7,261 men aged 30 years and over who worked for eight industrial companies in Osaka Prefecture and 4,973 men and women aged 20 years and over who lived in Yao City in Osaka Prefecture, Japan. Their age range was 21 89 years, and only 3 percent of the participants were under age 34 or over age 76 years. They participated in cardiovascular risk surveys between 1990 and 1996. A total of 257 persons with a history of either coronary heart disease (n = 179) or stroke (n = 72) or both (n = 6) were excluded. The remaining 11,977 persons were followed to ascertain the incidence of coronary heart disease through March 31, 1998.
Blood was drawn from nonfasting, seated participants into citrated and siliconized glass tubes according to the protocol of Atherosclerosis Risk in Communities (ARIC) Study (15
). The plasma was separated and stored at -70°C for 2 weeks until the measurement. Fibrinogen was measured by the clotting assay of Clauss (16
), using reagents obtained from General Diagnostics (Organon-Technika Co., Morris Plains, New Jersey) in the laboratory of the Osaka Medical Center for Cancer and Cardiovascular Diseases. The internal quality control was conducted according to the protocol of the ARIC Study. The external quality control was performed by comparison of fibrinogen values for split specimens from 50 Japanese and 50 Caucasians in our laboratory and the ARIC laboratory at University of Texas Health Center at Houston. We found no difference in mean fibrinogen, with 276 mg/dl in our laboratory and 275 mg/dl in the ARIC laboratory. The Pearson correlation coefficient between fibrinogen values obtained by the two laboratories was 0.69 (p < 0.001).
The serum was separated and stored at -70°C for 2 weeks. Serum total cholesterol was measured by enzymatic methods, and high density lipoprotein cholesterol was measured after heparin-manganese precipitation using the Liebermann-Burchard method; our laboratory was standardized by the Lipid Standardization Program, Centers for Disease Control and Prevention, Atlanta, Georgia (17
). Serum glucose was measured by enzymatic methods. Diabetes mellitus was defined as serum glucose of 140 mg/dl or more fasting and/or blood glucose of 200 mg/dl or more nonfasting and/or taking hypoglycemic medication.
Height in stocking feet and weight in light clothing were measured, and body mass index was calculated as weight (kg)/height (m)2. Systolic and diastolic blood pressures were measured with a standard mercury sphygmomanometer on the right arm of seated participants after a 5-minute rest. Blood pressure technicians were trained according to American Heart Association methods (18
). Hypertension was defined as systolic pressure of 160 mmHg or more and/or diastolic pressure of 95 mmHg or more and/or taking antihypertensive medication.
An interview was conducted to ascertain the smoking status, the number of cigarettes smoked per day, and the usual alcohol intake per week. Current smokers were defined as persons who smoked more than one cigarette regularly, and those who quit smoking more than 3 months previously were defined as ex-smokers. Current drinkers were defined as persons who drank more than 3 g ethanol per day and more than once a week. Ex-drinkers were defined as those who quit drinking more than 3 months previously.
Follow-up was terminated at the occurrence of coronary heart disease, retirement, emigration, or death. The criteria for coronary heart disease were modified from those of a World Health Organization Expert Committee (19), which we described elsewhere (20
). "Definite" myocardial infarction was indicated by typical chest pain (lasting for 30 minutes or longer) with the appearance of abnormal and persistent Q or QS waves, changes in cardiac enzyme levels, or both. "Suspect" myocardial infarction was indicated by typical chest pain without a positive electrocardiogram or enzyme findings. Angina pectoris was defined as reported episodes of chest pain during effort, especially when walking, usually disappearing rapidly after the cessation of effort or upon use of sublingual nitroglycerin. In this report, definite and suspect myocardial infarctions were combined and presented as myocardial infarction, and myocardial infarction and angina pectoris were combined and presented as coronary heart disease.
Differences in age-specific and sex- and age-adjusted mean values and proportions of baseline characteristics were compared between people who developed coronary heart disease or myocardial infarction and those who remained free of coronary heart disease by using a t test or a chi-square test. Proportional hazards regression models were used to examine the relations of plasma fibrinogen with the incidence of coronary heart disease and myocardial infarction. All probability values were two-tailed.
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RESULTS
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The mean value of plasma fibrinogen was 267 mg/dl (standard deviation (SD), 59) in this cohort. During the 4.8 years of follow-up, 41 incident coronary heart disease events occurred (21 definite myocardial infarctions, 11 suspect myocardial infarctions, and nine angina pectoris). The baseline age distribution of incident coronary heart disease was two subjects aged 2149 years, 24 aged 5059, nine aged 6069, and six aged 7089, while that of the participants was 4,770, 4,631, 1,973, and 603 in the four age categories, respectively.
Table 1 shows mean values of risk characteristics at baseline for incident cases of coronary heart disease and for those who remained free of the disease. Cases of coronary heart disease and myocardial infarction had higher mean values of plasma fibrinogen for both men and women than did noncases, a difference that was statistically significant after adjustment for age and sex. For men, incident cases had higher mean values of systolic pressure, serum total cholesterol, and serum glucose and lower mean values of serum high density lipoprotein cholesterol and usual alcohol intake. For women, the prevalence of current smokers was higher for incident cases than for noncases.
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TABLE 1. Mean values (standard deviations) and proportions of risk characteristics at baseline among Japanese developing coronary heart disease or myocardial infarction and those remaining free of coronary heart disease, Osaka, Japan, 19901998
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Table 2 provides adjusted relative risks of coronary heart disease and myocardial infarction according to quartiles of plasma fibrinogen concentration. For both coronary heart disease and myocardial infarction, the age- and sex-adjusted relative risks were lowest in the lowest fibrinogen quartile and increased with higher fibrinogen quartiles. After further adjustment for major confounding variables, i.e., smoking status (never, ex-, and current smokers) and quartile of serum total cholesterol levels, the positive association with fibrinogen remained statistically significant for both coronary heart disease and myocardial infarction. The multivariate relative risks for the highest fibrinogen quartile compared with the lowest were 4.8 (95 percent confidence interval: 1.4, 16.8, p = 0.01) for coronary heart disease and 3.8 (95 percent confidence interval: 1.1, 13.4, p = 0.04) for myocardial infarction. The multivariate relative risk associated with 1 SD increment of fibrinogen (59 mg/dl) was 1.5 (95 percent confidence interval: 1.2, 1.9, p = 0.001) for coronary heart disease and 1.4 (95 percent confidence interval: 1.0, 1.9, p = 0.02) for myocardial infarction.
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TABLE 2. Adjusted relative risks and 95% confidence intervals of coronary heart disease or myocardial infarction by quartiles of plasma fibrinogen concentration, Osaka, Japan, 19901998
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The positive association between plasma fibrinogen and risk of coronary heart disease was similarly observed between younger and older age subgroups. The multivariate relative risk of coronary heart disease associated with 1 SD increment of fibrinogen was 1.4 (95 percent confidence interval: 1.0, 2.0, p = 0.03) for ages 2157 years (number of cases = 24) and 1.5 (95 percent confidence interval: 1.0, 2.2, p = 0.03) for ages 5889.
The positive association between plasma fibrinogen and risk of coronary heart disease was examined according to the time of followup split by the mean. The multivariate relative risk of coronary heart disease associated with 1 SD increment of fibrinogen was 1.3 (95 percent confidence interval: 0.8, 2.0, p = 0.27) within 4.8 years of follow-up (number of cases = 14) and 1.6 (95 percent confidence interval: 1.2, 2.1), p = 0.001) (number of cases = 22) thereafter.
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DISCUSSION
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We found that plasma fibrinogen was higher in Japanese men and women who developed coronary heart disease than in persons free of the disease. This relation remained statistically significant even after adjustment for major covariates, such as age, sex, smoking status, and serum total cholesterol. The positive association was similarly observed in younger and older age groups and was not confined to the early follow-up periods. To our knowledge, this is the first report to raise plasma fibrinogen as a significant predictor of increased risk of coronary heart disease in Japanese individuals.
Prospective studies in Caucasians have indicated that a raised plasma fibrinogen concentration is positively associated with the risk of coronary heart disease (1








11
). It is noteworthy that baseline mean values of plasma fibrinogen in studies of Caucasians were higher than those in our study. In the meta-analysis of 18 studies with 4,018 coronary heart disease events conducted by Danesh et al. (21
), baseline mean plasma fibrinogen was 300 mg/dl (SD, 80) at a mean age of 56 years, whereas our baseline mean plasma fibrinogen was 267 mg/dl (SD, 59) at a mean age of 52 years. Our previous cross-cultural study (14
), which measured fibrinogen in a single laboratory, showed that plasma fibrinogen levels were lower in Japanese than in US Caucasians.
A drawback of our study is that we had few incidence cases, and only three cases occurred in the lowest quartile of plasma fibrinogen. When we conducted the tertile analyses such as the reported meta-analysis (21
), the multivariate relative risk for the highest fibrinogen tertile (
280 mg/dl) compared with the lowest (<238 mg/dl) was 2.8 (95 percent confidence interval: 1.1, 7.1, p = 0.03) for coronary heart disease and 2.0 (95 percent confidence interval: 0.8, 5.4, p = 0.15) for myocardial infarction. These estimates were similar to the pooled relative risk in the meta-analysis (relative risk = 1.8, 95 percent confidence interval: 0.6, 2.0).
Fibrinogen is one of the acute-phase reactant proteins and increases in response to the inflammatory process of atherosclerosis (22
). However, there are several direct mechanisms by which increased fibrinogen causes coronary heart disease. Fibrinogen is a major contributor of increased blood viscosity, stimulates smooth muscle cell proliferation and migration, and increases platelet aggregability, all of which may contribute to development of coronary heart disease (2
, 7
, 9
, 11
, 21
).
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ACKNOWLEDGMENTS
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Supported by a Japan Heart Foundation Research grant for 1996.
The authors thank Prof. Aaron R. Folsom for his valuable comments and Mina Morita, Misako Yukami, Emiko Yabuuchi, Sumie Kuruma, Kouzo Misu, and Emiko Sugiyama for plasma fibrinogen measurement. They also thank for Miyoko Ueda, Sanae Nomura, Tei Takemori, Kazuyo Kakehashi, Kazuyo Kamei, Yoshimi Yamamoto, Reiko Suzuki, Yoshiko Oowada for helping to obtain information on coronary heart disease events.
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NOTES
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Reprint requests to Dr. Shinichi Sato, Department of Epidemiology and Mass Examination, Osaka Medical Center for Cancer and Cardiovascular Diseases, 133 Nakamichi, Higashinari-ku, Osaka 5378511, Japan.
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Received for publication May 24, 1999.
Accepted for publication October 11, 1999.