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(Circulation. 1996;94:952-956.)
© 1996 American Heart Association, Inc.

Articles

Fish Intake May Limit the Increase in Risk of Coronary Heart Disease Morbidity and Mortality Among Heavy Smokers

The Honolulu Heart Program

Beatriz L. Rodriguez, MD, PhD; Dan S. Sharp, MD, PhD; Robert D. Abbott, PhD; Cecil M. Burchfiel, PhD; Kamal Masaki, MD; Po-Huang Chyou, PhD; Boji Huang, MD, PhD; Katsuhiko Yano, MD; Jess David Curb, MD

the John A. Burns School of Medicine, The University of Hawaii at Manoa, Divisions of Clinical Epidemiology and Geriatric Medicine (B.L.R., R.D.A., K.M., B.H., K.Y., J.D.C.), Honolulu, Hawaii; The Honolulu Heart Program, National Heart, Lung, and Blood Institute, National Institutes of Health (D.S.S., C.M.B.), Honolulu, Hawaii; Department of Biostatistics, University of Virginia (R.D.A.), Charlottesville; and The Honolulu Heart Program, Kuakini Medical Center (B.L.R., P.-H.C., B.H., K.Y., J.D.C.), Honolulu, Hawaii.

Correspondence to Beatriz L. Rodriguez, MD, PhD, Coprincipal Investigator, The Honolulu Heart Program, 347 N Kuakini St, Honolulu, HI 96817. E-mail beatriz@hhs.cba.hawaii.edu.

	Abstract

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Background Research has shown that fish consumption limits damage to the lungs caused by cigarette smoking, possibly by the effects of fish on arachidonic acid metabolism. We explored this fish-smoking interaction using coronary heart disease (CHD) incidence and mortality as the outcome.

Methods and Results The Honolulu Heart Program began in 1965 to follow a cohort of 8006 Japanese-American men aged 45 to 65 years who lived on Oahu, Hawaii, in 1965. Fish intake was measured at baseline by use of a questionnaire. For current smokers at baseline (n=3310) who reported low fish intake (<2 times/wk), age-adjusted 23-year CHD mortality rates increased with the number of cigarettes smoked per day (2.3, 3.1, and 6.9 per 1000 person-years for men who smoked <20, 20 to 30, and >30 cigarettes/d, respectively; trend test P<.0001). Among current smokers whose fish intake was high (2 times/wk), CHD mortality rates showed no relation with cigarettes/d (3.7, 3.2, and 3.7 per 1000 person-years for the corresponding levels of smoking). A Cox proportional hazards model based on current smokers, adjusted for age, years in Japan, calories/d, alcohol intake, physical activity index, years smoked, hypertension, and serum cholesterol, blood glucose, and uric acid levels, was examined. In the high-smoking group, the risk factor–adjusted relative risk (RR) for CHD mortality among those with high fish intake was half that of those with low fish consumption (RR=0.5, 95% confidence interval=0.28 to 0.91). A Cox model that adjusted for similar risk factors confirmed a significant interaction of cigarettes/d and fish intake (P<.01) on CHD mortality. Analyses for CHD incidence showed similar results.

Conclusions Despite the findings of this investigation, the public health message for smokers continues to be to stop smoking. However, an interaction between fish intake and cigarette smoking is biologically plausible and deserves further investigation. The study of this phenomenon may shed light on the biological mechanisms by which cigarette smoking leads to CHD.

Key Words: coronary disease • smoking • fatty acids • follow-up studies • epidemiology

	Introduction

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Recent cross-sectional¹ and longitudinal analyses from the Honolulu Heart Program have shown that fish intake protects the lung from the deleterious effects of cigarette smoking.² Similarly, the Atherosclerosis Risk in Communities study investigators³ reported an inverse and graded relation between fish consumption and chronic obstructive lung disease among current and past smokers. These relations are biologically plausible because 3 fatty acids may inhibit inflammatory mechanisms in the lung involving arachidonic acid metabolism. We have explored further this hypothetical biological interaction between fish intake and cigarette smoking using coronary heart disease (CHD) incidence and mortality as the outcome.

Various observational studies^{4 5 6 7 8} have found an inverse relation between fish consumption and CHD. Others^{9 10 11 12} find no association. A randomized controlled trial¹³ conducted in men who had recovered from a myocardial infarction showed a 29% reduction in 2-year all-cause mortality among subjects who were advised to eat fish compared with subjects not so advised. In addition, some trials^{14 15} suggest a protective effect of fish oil supplementation on the recurrence of coronary stenosis after angioplasty, but others^{16 17} have shown no benefit. It is conceivable that the lack of consistency in the relation between fish intake and CHD observed in epidemiological studies could be explained in part by a fish-smoking interaction similar to that observed for lung disease.

In the present study, we tested the hypothesis that high fish intake limits the increase in risk of CHD among heavy smokers. Our biological model postulates that fish intake counteracts some of the adverse effects produced by cigarette smoking, such as platelet aggregation, cell proliferation, and other inflammatory processes that occur in response to the endothelial injury.

	Methods

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Study Population
The Honolulu Heart Program began on Oahu, Hawaii, in 1965 to 1968 to follow 8006 men of Japanese ancestry, then aged 45 to 68 years, for the development of CHD and stroke. Details of the selection process and procedures of the baseline examination and subsequent follow-up for this cohort have been published previously.^{18 19 20} Prevalent cases of CHD, stroke, and cancer at baseline (491 of the 8006 men) were excluded from the analyses because the presence of these conditions may have affected eating and smoking behavior as well as subsequent morbidity and mortality. Analyses presented here are limited to 3310 current smokers at baseline.

Data Collection
Baseline Examination
During the first examination of this cohort in 1965 to 1968, data on cardiovascular risk factors were collected by use of a standard protocol. These data included demographic information, anthropometric and blood pressure measurements, ECG, alcohol intake, physical activity, blood chemistries (including a 1-h nonfasting 50-g postload glucose test), medical history, smoking habits, and dietary fish intake, among other variables. An examination by a physician was also conducted. Habitual fish consumption was assessed by asking: How often do you eat fish? Five response categories were initially coded: almost never, <2 times/wk, 2 to 4 times/wk, almost daily, and more than once per day. The distribution of fish intake in the overall cohort as well as for current smokers is shown in Table 1. Fish intake data were recorded into two categories: low (<2 times/wk) and high (2 times/wk) fish intake. Fish consumption data were also available from a 24-h dietary recall interview; however, this type of information was not considered a good measure of habitual diet and would have led to the misclassification of over 3500 cohort members who did not consume fish the day before the interview but who reported eating fish regularly.¹

View this table: [in this window] [in a new window]   Table 1. Frequency of Dietary Fish Intake at Baseline: The Honolulu Heart Program

Surveillance Methods
A surveillance system was established in 1965 that continues to identify cases of CHD and stroke. It is based on selected discharge diagnoses at all major medical facilities on the island of Oahu. The ascertainment of death is primarily made from obituaries in island newspapers, supplemented with listings of death certificates filed with the State Department of Health. The medical records are then requested and reviewed by a panel of Honolulu Heart Program physicians to identify incident cases of heart disease and stroke as well as to determine the cause of death on the basis of standardized criteria. Incident cases of CHD include fatal CHD and nonfatal myocardial infarction as well as sudden deaths (within 1 hour) among asymptomatic or apparently healthy subjects.²¹ Analyses are based on 23 years of follow-up. The out-migration rate from Oahu has been less than 1 in 1000 per year. After participants for the fourth examination in 1991 to 1993 were contacted, only 4 of the original 8006 men were lost to follow-up. All hospitalizations reported by participants at the third and fourth examinations had been independently confirmed by the hospital surveillance process.

Data Analysis
Age-adjusted incidence rates per 1000 person-years for CHD were calculated by fish intake category (<2 times/wk or "low" versus 2 times/wk or "high") and smoking status (never, past, and current) in the overall cohort. Similar rates were calculated among current smokers for six groups based on fish intake category (low versus high) and number of cigarettes smoked per day (<20, 20 to 30, >30). Age-adjusted mean values (or percentages) for selected risk factors were calculated by fish intake category by smoking status. Cox regression models were used that adjusted for age, years lived in Japan, total calories/d, alcohol intake, physical activity, years smoked, hypertension, and serum cholesterol, glucose, and uric acid levels for past and current smokers separately. Estimates of relative risk for CHD morbidity and mortality were also obtained with the low fish–high smoking group used as a reference. Use of the Cox model was considered appropriate on the basis of an evaluation of the underlying assumption of proportionality.

	Results

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At baseline, 44% of the cohort members were current smokers, 26% were past smokers, and 30% were never smokers. Table 2 shows the incidence and mortality rates for CHD by smoking status and fish intake. There was no significant association between fish intake and CHD incidence and mortality within smoking strata (past, current, or never). However, as we examined this relation among current smokers more closely, we observed that for those who had low fish intake, incidence rates increased with the number of cigarettes smoked per day. The incidence rates were 4.5, 8.0, and 11.6 per 1000 person-years among men who smoked <20, 20 to 30, and >30 cigarettes/d, respectively. In contrast, among current smokers whose fish intake was high, CHD incidence rates showed no relation with number of cigarettes/d.

View this table: [in this window] [in a new window]   Table 2. Age-Adjusted Incidence Rates per 1000 Person-Years for Coronary Heart Disease Morbidity and Mortality by Fish Intake and Smoking Status: The Honolulu Heart Program

Similar results were observed for CHD mortality rates. For current smokers who reported low fish consumption, the CHD mortality rates increased with increasing number of cigarettes/d (2.3, 3.1, and 6.9 deaths per 1000 person-years, respectively). Among current smokers with high fish intake, no association was observed between cigarettes/d and CHD mortality.

Table 3 shows the age-adjusted mean values or percentages of selected risk factors among current smokers by fish intake category. Subjects who had a high fish intake smoked more cigarettes per day, lived more years in Japan, consumed more calories and alcohol per day, were more physically active, and had higher serum uric acid levels than subjects who had a low fish intake (P<.05).

View this table: [in this window] [in a new window]   Table 3. Age-Adjusted Mean Values (or Percentages) of Risk Factors at Baseline Among Current Smokers by Fish Intake: The Honolulu Heart Program

Fig 1 shows the risk factor–adjusted relative risk for CHD incidence. Because the highest 23-year incidence rate of CHD was found among the low fish–high smoking group, it was used as reference. A Cox model that adjusted for age, years lived in Japan, total calories/d, alcohol intake, physical activity, years smoked, hypertension, and serum cholesterol, glucose, and uric acid levels was utilized. Among subjects with low fish intake, the relative risk increased with increasing number of cigarettes/d. The relative risks were 0.38, 0.61, and 1.0 for subjects who smoked <20, 20 to 30, and >30 cigarettes/d, respectively. No relation was observed between CHD incidence and number of cigarettes/d among subjects with high fish intake.

View larger version (27K): [in this window] [in a new window]   Figure 1. Fish intake, smoking, and incidence of coronary heart disease (CHD) among current smokers: the Honolulu Heart Program. *Adjusted for age, years in Japan, total calories/d, physical activity, years smoked, hypertension, and serum cholesterol, glucose, and uric acid levels.

Similar relations were observed for CHD mortality (Fig 2). The risk factor–adjusted relative risk among subjects in the high fish–high smoking group was 0.50 (95% CI=0.28 to 0.91). That is, after adjustment for possible confounders, heavy smokers (>30 cigarettes/d) with high fish intake had half the risk of CHD death compared with heavy smokers with low fish intake. In addition, a Cox model based on current smokers, adjusted for the risk factors previously mentioned, confirmed a significant interaction of cigarettes/d and fish intake for CHD incidence (P=.01) as well as for CHD mortality (P=.02). Similar analyses were conducted among past smokers; however, no significant interaction was evident in this group (P=.6 and P=.8, respectively).

View larger version (25K): [in this window] [in a new window]   Figure 2. Fish intake, smoking, and coronary heart disease (CHD) mortality among current smokers: the Honolulu Heart Program. *Adjusted for age, years in Japan, total calories/d, physical activity, years smoked, hypertension, and serum cholesterol, glucose, and uric acid levels.

	Discussion

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Previous research by Honolulu Heart Program investigators^{1 2} and others³ suggests that fish intake may protect the lung against damage caused by cigarette smoking. A similar protective effect of fish intake was evident for CHD incidence and mortality in this population.

Despite the fact that the epidemiological evidence to support a positive association between cigarette smoking and CHD is very strong, not all populations in which smoking is common have high rates of CHD.²² The Japanese are an illustrative example, which suggests that high fish intake relative to other populations may account for the lower CHD rates observed. Other factors such as diet and physical activity also may contribute significantly to the low rates observed. One could speculate that differences in the intensity of smoking across populations may have contributed to the lack of consistency in the relation between fish intake and CHD observed in various epidemiological studies.^{4 5 6 7 8 9 10 11 12}

Fish oils have been reported to have many beneficial effects. Intake of 3 fatty acids alters the metabolism of arachidonic acid, which results in a change in the hemostatic balance maintained by the counterbalancing effects of thromboxane A₂, a potent vasoconstrictor and proaggregator of platelets, and prostaglandin I₂ (prostacyclin), a vasodilator and platelet antiaggregator. 3 Fatty acids also inhibit the synthesis of thromboxane A₂ and leukotriene B₄, a chemoattractant. Instead, a physiologically inactive thromboxane A₃ is produced, while prostaglandin I₂ continues to be synthesized. In addition, a new prostaglandin, prostaglandin A₃, is synthesized from eicosapentaenoic acid. These changes may lead to a more vasodilatory state, with less platelet aggregation and a reduced inflammatory response to the endothelial injury caused by cigarette smoking.^{23 24 25 26}

Many other cardiovascular effects of 3 fatty acids have been reported. Fish oils reduce levels of triglycerides and VLDL cholesterol among patients with hypertriglyceridemia.^{27 28} Fish oils may suppress the formation of fibrinogen,^{29 30 31 32} which is an independent risk factor for CHD and is also a major component of the adverse effects of cigarette smoking.^{33 34} Fish oils also reduce the viscosity of the blood, increase the deformability of red cells,³⁵ increase fibrinolytic activity,³⁶ and produce a reduction in blood pressure among normotensive and mildly hypertensive subjects.^{37 38}

The results of the present study suggest that high fish intake may limit the increase in risk of CHD morbidity and mortality among heavy smokers (>30 cigarettes/d) in this population of middle-aged Japanese-American men. The observed relation is independent of other measured risk factors. The 3 fatty acids contained in fish may mediate this protective effect by limiting the response to the endothelial injury caused by smoking, decreasing platelet aggregation, and possibly reducing the inflammatory reaction to such an insult, as well as reducing smooth muscle cell proliferation.³⁹ However, it is possible that the effects observed in the present study could also be due to components of fish other than 3 fatty acids. The findings of this investigation need to be confirmed in other populations.

In this cohort, we did not observe an inverse relation between fish intake and CHD in the overall population nor within smoking status strata. However, as we further explored the associations within current smokers, the interaction between the number of cigarettes smoked per day and fish intake on the risk of CHD incidence and mortality became evident. It is possible that this study did not show a protective effect of fish on CHD in the overall cohort because almost everyone in the study ate some fish regularly.

Subjects who smoked <30 cigarettes/d did not show a protective effect of fish on their risk of CHD. It is not clear why subjects who smoked <20 cigarettes/d and who had a high fish intake had a higher incidence of CHD than those with low fish intake and similar smoking habits. This could be explained by random error. However, no significant differences were observed for CHD mortality in this group.

Analyses conducted among current smokers in this population showed a significant interaction between pack-years of smoking and fish intake on the development of 23-year CHD incidence and mortality. However, when this relation was examined more closely, it became apparent that it was driven by the number of cigarettes smoked per day and not the number of years smoked, which suggests a pronounced effect at high daily doses of smoking (>30 cigarettes/d) as opposed to long-term exposure to smoking. These findings strengthen the hemostasis hypothesis presented, suggesting perhaps that fish oils may counteract the prothrombotic effects associated with high levels of tobacco smoke.

The analyses contained in the present study are based on a crude measure of fish intake. Detailed descriptions of the type of fish consumed were not obtained, and changes in fish intake over time could not be considered because similar data were not collected in subsequent examinations of the cohort. However, misclassification of fish intake is likely to be nondifferential. It is conceivable that the associations reported here may underestimate the magnitude of the true relations.

Despite the findings of this investigation, the public health message for smokers continues to be to stop smoking. Cigarette smoking has many other adverse effects on health in addition to CHD. Nonsmokers still have the lowest CHD mortality rate regardless of their fish intake. However, the interaction between fish intake and cigarette smoking is biologically plausible and deserves further investigation. The study of this phenomenon may shed light on the biological mechanisms by which cigarette smoking leads to CHD.

	Acknowledgments

 
This research was supported by contract No. NO1-HC-05102 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.

Received September 12, 1995; revision received March 6, 1996; accepted March 13, 1996.

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