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(Stroke. 1995;26:368-372.)
© 1995 American Heart Association, Inc.

Articles

The Impact of Alcohol and Hypertension on Stroke Incidence in a General Japanese Population

The Hisayama Study

Yutaka Kiyohara, MD; Isao Kato, MD; Hiromitsu Iwamoto, MD; Keizo Nakayama, MD Masatoshi Fujishima, MD

From the Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Japan.

Correspondence to Yutaka Kiyohara, MD, Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka City, 812 Japan.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose The relationship between alcohol intake and stroke has been inconsistent in previous studies. We examined the separate and combined effects of drinking habits and hypertension on stroke incidence in a prospective survey of a general Japanese population.

Methods A total of 1621 stroke-free Hisayama residents aged 40 years or older were classified by their alcohol intake into nondrinkers, light drinkers (<34 g of ethanol per day), and heavy drinkers (34 g of ethanol per day) and followed up prospectively for 26 years from 1961.

Results During the follow-up period, cerebral infarction developed in 244 subjects and cerebral hemorrhage in 60. For men, the incidence of cerebral hemorrhage increased significantly with rising alcohol consumption. In contrast, the incidence of cerebral infarction was slightly lower in light drinkers than in nondrinkers, while it increased significantly in heavy drinkers compared with light drinkers. Female drinkers had a lower incidence of cerebral infarction but a slightly higher incidence of cerebral hemorrhage than nondrinkers, as did male light drinkers. Among the hypertensive subjects, the age- and sex-adjusted relative risk of cerebral hemorrhage was significantly elevated in heavy drinkers versus abstainers (3.13; 95% confidence interval [CI], 1.08 to 9.10), but the increase was not significant for light drinkers. In contrast, the relative risk did not significantly increase for normotensive light and heavy drinkers. Compared with hypertensive light drinkers, the relative risk of cerebral infarction significantly increased in hypertensive heavy drinkers (1.96; 95% CI, 1.08 to 3.57) but remained unchanged in normotensive heavy drinkers. Significant associations between alcohol intake and stroke were substantially the same even after controlling for other risk factors in multivariate analysis.

Conclusions Among hypertensive individuals, heavy alcohol consumption leads to a significant increase in the risk of cerebral hemorrhage, suggesting a synergistic effect of alcohol and hypertension, while light alcohol consumption significantly reduces the risk of cerebral infarction.

Key Words: alcohol drinking • cerebral hemorrhage • cerebral infarction • epidemiology • hypertension

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Moderate alcohol consumption has been suggested to have a preventive effect on coronary heart disease.^{1 2} However, studies on the relationship between alcohol intake and stroke have shown inconsistent results, ranging from no association^{3 4} to a dose-dependent increase in risk^{5 6 7 8} or a so-called J-shaped relationship^{9 10 11} (ie, a decrease in risk with a small amount of alcohol but an increase with a large amount). It is well known that alcohol consumption is closely associated with hypertension,¹² which is the most powerful risk factor for both cerebral infarction (CI) and hemorrhage (CH).^{13 14} Thus, the net effect of alcohol on stroke should be evaluated after taking hypertension into consideration.

The Japanese population is characterized by high morbidity and mortality from both CI and CH.¹³ Previous epidemiological studies have shown that alcohol consumption is a significant risk factor for CH but not for CI in Japan.^{5 6 7 14 15} However, these studies, including our previous reports,^{14 15} have not adequately clarified the role of alcohol in the development of stroke, since the effects of major confounding factors such as hypertension were not controlled for or the number of subjects examined, especially those with CH, was small.

In the present article we report the findings of a long-term prospective survey of a general Japanese population that examined the relationship between drinking habits and stroke occurrence by multivariate analysis, especially focusing on the independent and combined effects of alcohol and hypertension on the development of CI and CH.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The Hisayama Study is a prospective epidemiological study of cardiovascular disease in the residents of Hisayama Town, a suburban community adjacent to Fukuoka City, a metropolitan area on Kyushu Island in Japan. The study design and characteristics of the subject population have been described in detail elsewhere.^{16 17} In 1961, 1658 of the residents aged 40 years or older (90.1% of the total population in that age group) underwent a screening examination. After exclusion of 37 individuals who died or moved out of town during the examination period or who had a history of stroke, 1621 subjects were entered into the study. This population was followed up for 26 years between November 1, 1961, and October 30, 1987, by repeated health examinations every 2 years. During the follow-up period, 184 subjects (11.4%) moved out of town. However, more than 92% of the surviving subjects regularly participated in the follow-up examination until 1967. After that, more than 80% of the survivors returned for examination until 1978, and thereafter more than 71% of the surviving subjects continued until 1988. For all subjects who did not undergo regular examination or who moved out of town, health status was checked every year by mail or telephone to determine whether stroke had occurred. Only two subjects were lost to follow-up. In addition, a daily monitoring system was established by the study team and local physicians or members of the local health and welfare office. When stroke was suspected, an evaluation was done by a study physician either at the patient's home or in the hospital to which the subject had been admitted. When necessary, the patient was transferred to our university or affiliated hospitals to undergo further examination. Subjects who died underwent autopsy examination at the Department of Pathology of our university to morphologically evaluate brain lesions and confirm the cause of death. During the follow-up period we did autopsies on 704 (82.6%) of 852 deceased subjects. The clinical diagnosis of stroke and its nature were determined on the basis of a detailed history, neurological examination, and ancillary diagnostic procedures such as lumbar puncture, cerebral angiography, and recently, computed tomography. Findings were also confirmed by autopsy. During the follow-up period, CI developed in 244 subjects (120 men and 124 women) and CH developed in 60 subjects (40 men and 20 women).

At the initial examination, information on alcohol consumption was obtained by interview based on a questionnaire that ascertained the usual weekly intake of alcoholic beverages over the previous several months. A total of 558 subjects reported drinking habits, of whom the majority consumed sake (rice wine, 80.8%), and the remainders consumed shochu (distilled liquor, 15.1%), beer (3.6%), or whisky (0.5%). Alcohol intake was converted into a daily equivalent in terms of the number of go, a traditional Japanese unit of volume for sake (1 go=0.18 L and contains 23 g of ethanol). Subjects were classified as follows: nondrinkers, light drinkers consuming less than 1.5 go (34 g of ethanol) per day, and heavy drinkers consuming 1.5 go or more per day.

To assess the independent effect of alcohol intake on stroke occurrence, the following factors in addition to age and sex were used for analysis as confounding factors: (1) blood pressure measured with a standard sphygmomanometer at the right arm with the patient in a supine position after resting for at least 5 minutes (a systolic pressure 160 mm Hg or a diastolic pressure 95 mm Hg was defined as hypertension); (2) heart rate per minute calculated from the recordings of the electrocardiogram (ECG); (3) ECG abnormalities indicating evidence of left ventricular hypertrophy or ischemic changes (Minnesota code 3-1 and/or 4-1,2,3); (4) glucose intolerance as revealed by an oral glucose tolerance test in subjects with glycosuria; (5) serum cholesterol level determined by the Zak-Henly method with a modification by Yoshikawa¹⁸ ; (6) body mass index (weight in kilograms per height in meters squared) as an indicator of obesity; and (7) data on smoking habits obtained by interview at the same time as the data on alcohol consumption.

The SAS computer package¹⁹ was used for all statistical analyses. Mean values for the possible risk factors were adjusted for age with use of the covariance method and were compared among different alcohol intake levels by Fisher's least significant difference method. The frequencies of risk factors were compared by the Mantel-Haenszel ² test after adjusting for age by the direct method. The incidence of stroke was calculated by the person-year method, and its difference among drinking levels was analyzed by means of the Cox proportional hazards model.²⁰ The age- and sex-adjusted probability of stroke incidence and the risk factor–adjusted relative risks were also estimated by means of the Cox proportional hazards model. We used all the study subjects as a standard population for adjustment by age and by age and sex.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Table 1 shows the age-adjusted mean values or frequencies of possible risk factors for stroke in relation to drinking habits at the initial examination. In men, the mean values for age decreased significantly with rising alcohol consumption, but the systolic and diastolic blood pressures as well as body mass index increased significantly. Male heavy drinkers had a significantly higher heart rate than nondrinkers. In men, hypertension and glucose intolerance also became significantly more common with rising alcohol intake. Female subjects were divided into nondrinkers and drinkers because of the small number of heavy drinkers. Female drinkers had a higher cigarette consumption than nondrinkers.

View this table: [in this window] [in a new window]   Table 1. Age-Adjusted Mean Values or Frequencies of Risk Factors for Stroke

For men, the age-adjusted incidence of CH significantly increased with rising alcohol intake (Fig 1). The incidence of CI was slightly lower in light drinkers than in nondrinkers, but it significantly increased in heavy drinkers compared with light drinkers. Female drinkers had a slightly higher incidence of CH but a lower incidence of CI than did nondrinkers. This pattern was similar to that observed in male light drinkers compared with nondrinkers.

View larger version (17K): [in this window] [in a new window]   Figure 1. Bar graphs show age-adjusted 26-year incidence (per 1000 person-years) of cerebral infarction and hemorrhage according to initial alcohol intake.

To clarify the separate and combined effects of alcohol and hypertension on stroke, the age- and sex-adjusted probability of stroke incidence was compared among six groups of subjects classified according to their drinking and hypertension status (Fig 2). Among the alcohol consumers, the incidence of CH was significantly higher in hypertensives than in normotensives. With an elevation of alcohol intake, the incidence of CH increased in both normotensives and hypertensives, but the increase was more marked in hypertensives than in normotensives. Among the hypertensives, the age- and sex-adjusted relative risk (RR) of CH was significantly elevated in heavy drinkers compared with that of abstainers (RR, 3.13; 95% confidence interval, 1.08 to 9.10), but it did not significantly increase in light drinkers (Table 2). In contrast, the risk did not significantly increase in either normotensive light or heavy drinkers. The age- and sex-adjusted incidence of CI was significantly higher for hypertensives than for normotensives at each drinking level (Fig 2). In both hypertensives and normotensives, the incidence of CI was lowest for light drinkers, but only hypertensives showed a significant difference between light and heavy drinkers: the risk of CI was twofold higher for hypertensive heavy drinkers than for light drinkers (RR, 1.96; 95% confidence interval, 1.08 to 3.57; Table 2).

View larger version (19K): [in this window] [in a new window]   Figure 2. Bar graphs show age- and sex-adjusted probability of incidence of cerebral hemorrhage and infarction in nonhypertensives and hypertensives according to initial alcohol intake.

View this table: [in this window] [in a new window]   Table 2. Age- and Sex-Adjusted Relative Risk of Stroke Occurrence According to Alcohol Intake and Hypertension Status

The net effect of alcohol consumption on the incidence of CH and CI was also assessed after correction for age, sex, hypertension, heart rate, ECG abnormalities, glucose intolerance, smoking, serum cholesterol, and body mass index by multivariate analysis (Fig 3). With an increase in alcohol intake, the risk of CH also increased significantly and independent of other risk factors (RR, 2.66; 95% confidence interval, 1.07 to 6.62), while the risk of CI was significantly higher in heavy drinkers than in light drinkers (RR, 1.56; 95% confidence interval, 1.02 to 2.38). Among other risk factors assessed, hypertension was a significant independent risk factor for both CH and CI, and age, male sex, ECG abnormalities, and glucose intolerance were significant for CI.

View larger version (16K): [in this window] [in a new window]   Figure 3. Bar graphs show multivariate relative risk of occurrence of cerebral hemorrhage and infarction according to alcohol intake. Age, sex, hypertension, electrocardiographic abnormalities, heart rate, glucose intolerance, serum cholesterol, body mass index, and smoking were adjusted by means of Cox's proportional hazards model.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The present study showed that regular heavy intake of alcohol significantly increased the risk of CH. The increase of risk with rising alcohol intake was more marked in hypertensives than in normotensives, suggesting a synergistic effect of alcohol and hypertension on CH. The risk of cardiovascular disease including stroke has been reported to show a substantial increase with the combination of multiple risk factors.^{21 22} The 30-year follow-up survey of the Framingham Study²² showed that the probability of stroke occurrence within 10 years was 13% in 70-year-old men with a systolic blood pressure of 180 mm Hg. However, when five other risk factors such as diabetes mellitus were also present, the probability of stroke increased to nearly 90%. Very few studies have evaluated the combined effect of various risk factors on CH, and the present report appears to be the first description of the potentiating effect of alcohol and hypertension on the development of CH.

Several pathophysiological mechanisms by which alcohol intake might contribute to CH have been proposed. Alcohol intake has been shown to be closely associated with hypertension.¹² Chronic alcohol consumption is also associated with platelet and clotting abnormalities.^{23 24 25 26} Moderate alcohol intake decreases the number of platelets and impairs their function,^{23 24} and it promotes fibrinolysis.²⁵ In alcoholics with hepatic damage, there is decreased production of coagulation factors in the liver.²⁶ Persistent hypertension promotes cerebral atherosclerosis and particularly induces fibrinoid necrosis and microaneurysm formation in the small penetrating cerebral arteries, leading to weakening of the blood vessel wall.²⁷ The changes in the coagulation system caused by alcohol promote a bleeding tendency and may thus markedly increase the risk of CH when combined with arteriosclerosis caused by hypertension.

In the present study the incidence of CI was slightly lower in light alcohol drinkers than in abstainers, but it significantly increased in heavy drinkers compared with light drinkers. After reviewing in detail 62 reports (in English) concerning the association between moderate alcohol consumption and stroke, Camargo²⁸ proposed that the effect of alcohol on CI differs between whites and Japanese. Among whites, the risk of CI decreases significantly with a small alcohol intake, but it increases with a higher intake, showing a J-shaped relationship. In contrast, Japanese do not show this J-shaped relationship, since no preventive effect of light drinking is observed. The findings of the present study initially seemed to support Camargo's opinion. However, when this association was analyzed further by classifying the subjects according to their hypertension status, the risk of CI was significantly reduced (by 50%) in light-drinking hypertensives compared with that in heavy drinkers. This suggests that a small amount of alcohol may also have a significant protective effect against CI in Japanese with hypertension.

There is evidence indicating a difference in the distribution of cerebral atherosclerosis between Japanese and whites, with more marked changes being reported in small intracranial arteries of Japanese and in large extracranial neck arteries of whites.²⁹ Among the various types of CI, lacunar infarction due to small-vessel disease was the most common among Hisayama residents,³⁰ while reports from Western countries indicate that the frequency of cortical infarction or cerebral embolism was higher than that of lacunar infarction.^{31 32} In addition, a pathological study revealed that moderate alcohol intake has a weak inverse association with atherosclerosis in large, but not small, cerebral arteries.³³ Therefore, it is tempting to speculate that there may be also a racial difference in the protective effect of a small amount of alcohol. Several mechanisms, as described above, by which alcohol could increase the risk of CH may exert a preventive effect against CI. In Japanese, especially among hypertensives, light drinking is presumed to reduce the risk of CI by decreasing platelet hyperaggregability or hypercoagulability, both of which are closely associated with hypertension.^{34 35} In addition, light alcohol intake has been shown to reduce insulin resistance³⁶ and to improve lipid metabolism by decreasing low-density lipoprotein cholesterol and increasing high-density lipoprotein cholesterol.³⁷ However, lipid abnormalities are closely associated with atherosclerosis of large, but not small, cerebral arteries.³³ Therefore, light drinking may play an important role in the prevention of CI through the improvement of lipid metabolism, mainly among whites.

Alcohol has reciprocal effects on CI according to the amount consumed. Heavy drinking is suggested to increase the risk of CI by several mechanisms, including embolism due to arrhythmia and cardiomyopathy,^{38 39} a vasopressor effect,¹² and a decrease in cerebral blood flow due to vascular smooth muscle contraction⁴⁰ or altered cerebral metabolism.⁴¹ Since heavy drinking may also have some of the intrinsic preventive effects of light drinking on CI, the risk of CI may increase less than otherwise even in hypertensives.

We assume that some degree of underreporting of drinking habits occurred, especially among those consuming large amounts of alcohol. However, this bias should be small. We observed significant effects of drinking habits on stroke, namely the increased risk of CH in heavy drinkers and the preventive effect of light drinking on CI in hypertensives. It is unlikely that these reciprocal effects were related to underreporting or inaccuracy of self-reported drinking habits by hypertensives only. During the long follow-up period, the frequency of alcohol consumption for men decreased slightly from 67% in 1961 to 54% of the subjects who returned for examination in 1983, and it decreased from 8% to 7% for women. These factors would have tended to lessen the true effect of alcohol intake, suggesting the possibility that our data underestimated the net effect of alcohol consumption on stroke.

In Japan, the morbidity and mortality from stroke, especially CH, were higher among men than among women.¹⁵ Our results suggest that the much higher frequency of drinking among men compared with that among women may be included in the factors causing this disease in our country. Men also had much higher frequency of cigarette smoking, which is a potential risk factor for ischemic and hemorrhagic strokes in Western populations.⁴² However, in epidemiological surveys in Japan including our study, smoking was not related to CI or CH.^{5 7} This discrepancy might be due to differences in the topographic distribution of cerebral atherosclerosis between Japanese and whites. Thus, excessive smoking in men could not be directly related to the male preponderance of stroke in our country.

Stroke incidence and mortality among Japanese have been decreasing during the past two decades, and the decrease in the risk of CH for men has been remarkable, resulting in a decrease in the sex difference.¹⁴ This is presumably due to decreased blood pressure by antihypertensive therapy and restriction of salt intake in the Japanese population.¹³ Since alcohol consumption has not been reduced,⁴³ it is possible that hypertension management may diminish the potentiating effect of drinking and hypertension on CH. The impact of hypertension and alcohol intake on stroke should thus be reexamined in a Japanese population in which antihypertensive therapy has become widespread.

	Acknowledgments

 
This study was supported in part by a grant from the Ministry of Education, Japan (No. 04670539).

Received September 27, 1994; revision received November 29, 1994; accepted November 29, 1994.

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