Effects of Habitual Alcohol Intake on Ambulatory Blood Pressure, Heart Rate, and Its Variability Among Japanese Men

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1 Effects of Habitual Alcohol Intake on Ambulatory Blood Pressure, Heart Rate, and Its Variability Among Japanese Men Tetsuya Ohira, Takeshi Tanigawa, Minako Tabata, Hironori Imano, Akihiko Kitamura, Masahiko Kiyama, Shinichi Sato, Tomonori Okamura, Renzhe Cui, Kazuko A. Koike, Takashi Shimamoto, Hiroyasu Iso Abstract We sought to examine effects of habitual alcohol intake on ambulatory blood pressure (BP), heart rate (HR), and HR variability among Japanese men. Subjects were 539 men aged 35 to 65 years from rural and urban communities. Ambulatory BP and HR were monitored with an automated, portable, noninvasive multibiomedical recorder. Power spectral analysis of the RR intervals on the ECG was performed every 5 minutes. Compared with nondrinkers, moderate drinkers (alcohol intake 23 to 45 g/d) and heavy drinkers (alcohol intake 46 g/d) showed higher age- and field-adjusted mean values of systolic and diastolic BPs during the morning and while awake, but there were no differences in BPs over 24-hour periods and while asleep among the alcohol intake categories. Alcohol intake was positively associated with mean values of sleep-morning differences and daytime variability in BPs, HRs while awake and asleep, and low frequency:high frequency ratio while asleep. The results were virtually unchanged after adjustment for body mass index, smoking, and diabetes mellitus. Compared with the nondrinkers, age- and field-adjusted odds ratios of the morning BP surge (excess elevation of BP in the morning: morning systolic BP minus sleep systolic BP 37 mm Hg) for light (alcohol intake 0 to 22 g/d), moderate, and heavy drinkers were 0.96 (95% CI: 0.34 to 2.78), 1.68 (95% CI: 0.64 to 4.38), and 2.73 (95% CI: 1.12 to 6.67), respectively. Habitual alcohol intake was associated with increased BP in the morning, HR while awake and asleep, and sympathetic activity while asleep, which may explain some of the mechanisms of the relationship between heavy alcohol intake and risk of cardiovascular diseases. (Hypertension. 2009;53:13-19.) Key Words: alcohol intake ambulatory blood pressure monitoring autonomic nerve function heart rate variability population-based. Several prospective studies have reported that heavy alcohol intake increases the risk of stroke, 1 5 especially hemorrhagic stroke. 1 3 Because daily alcohol intake is positively associated with blood pressure (BP) levels, high BP is thought to be an important mediator between alcohol intake and the risk of stroke. However, although the associations of daily alcohol intake with casual BP are well documented, 6,7 the associations with 24-hour ambulatory BP are not, 7 because the effect of daily alcohol intake on BP depends on the time elapsed after alcohol intake. 8,9 Recent studies have indicated that morning BP surge, the excessive elevation of BP in the morning, could be associated with risk of stroke. 10,11 Kario et al showed that, in 519 Japanese older hypertensives, a higher morning BP surge was associated with a higher incidence of stroke independent of mean values of 24-hour systolic BP. 10 Another prospective study of 1430 Japanese men and women aged 40 years also found a positive association of morning BP surge with the incidence of hemorrhagic stroke after adjustment for 24-hour systolic BP and antihypertensive medication use but no association between morning BP surge and risk of ischemic stroke. 11 Because BP levels decrease soon ( 4 hours) after alcohol intake and increase later ( 10 hours later), 7 alcohol intake may be associated with morning BP surge. Few studies, however, have reported any associations of habitual alcohol intake with morning BP surge in a population-based sample. 7 Moreover, the effect of heavy drinking on morning BP surge has not been determined because of the limited number of heavy drinkers in previous studies. 7 The aim of this study was to examine the associations of habitual alcohol intake with ambulatory BP, including morning BP surge, in a population-based sample free from stroke Continuing medical education (CME) credit is available for this article. Go to to take the quiz. Received April 24, 2008; first decision May 7, 2008; revision accepted October 26, From the Department of Social and Environmental Medicine (T.O., R.C., H.I.), Osaka University, Osaka; Department of Public Health (T.T.), Ehime University, Ehime; Institute of Community Medicine (T.T., M.T.), University of Tsukuba, Ibaraki; Osaka Medical Center for Health Science and Promotion (T.O., H.I., A.K., M.K., S.S.), Osaka; Department of Preventive Cardiology (T.O.), National Cardiovascular Center, Osaka; and Ibaraki Prefectural University of Health Sciences (K.A.K.), Ibaraki, Japan. Correspondence to Tetsuya Ohira, Department of Social and Environmental Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka fwge1119@mb.infoweb.ne.jp 2008 American Heart Association, Inc. Hypertension is available at DOI: /HYPERTENSIONAHA

2 14 Hypertension January 2009 and coronary heart disease. We also investigated the associations of habitual alcohol intake with heart rate (HR), HR variability, serum insulin levels, and salivary cortisol levels, which may mediate the associations between alcohol intake and ambulatory BP. Subjects and Methods Populations The subjects were population-based samples of Japanese men who lived in a northeastern rural community, Ikawa; a southwestern rural community, Noichi; a central rural community, Kyowa; and a southwestern urban suburb, Yao. Annual cardiovascular risk surveys have been conducted since 1963 in the district of Yao City, Ikawa, and Noichi and since 1981 in Kyowa by a research team of the Osaka Medical Center for Health Science and Promotion, the University of Tsukuba, and Osaka University This study is an ancillary study to these population-based surveys, and the main aim of this study was to examine associations of psychosocial factors and lifestyles with ambulatory BP and HR variability in middle-aged men not taking antihypertensive medication. The participation rates between 1997 and 2003 for the census population within the target age group were 74% for Ikawa, 29% for Kyowa, 28% for Yao, and 28% for Noichi. The lower rates for Kyowa, Yao, and Noichi were probably attributable to the residents in these populations having more opportunities to undergo medical checkups other than our risk factor surveys. The initial exclusion criteria were persons with a history of stroke, coronary heart disease, or taking antihypertensive medication. We recruited 925 men aged 35 to 65 years who participated in the surveys between 1997 and 2003, and 601 men (65%) gave their informed consent and participated in the study. This study was approved by the ethics committee of the Osaka Medical Center for Health Science and Promotion. Measurements of 24-Hour BP and HR Variability Ambulatory BP and HR were monitored with an automated, portable, noninvasive multibiomedical recorder (TM2425M, A&D Co, Inc). 15 We used a modified version of TM2425 that can record a beat-to-beat ECG for an entire 24-hour period. An appropriately sized cuff was placed on the subject s left arm, and BP was recorded automatically every 30 minutes from 6 AM to 12 AM and every 60 minutes from 12 AM to 6 AM. Although the systolic and diastolic BPs were measured with both the cuff-oscillometric method and the Riva-Rocci/Korotkoff method, we used only data obtained with the cuff-oscillometric method for analysis. Participants were asked to continue their daily activities as usual and to keep a diary in which they recorded their daily activities, including the time at which they went to bed and arose. We excluded participants if the monitoring period of ambulatory BP was 8 hours while awake (daytime) or 3 hours while in bed (nighttime). Sleep BP was defined as the average of BPs from the time when the participants went to bed until the time they got out of bed, and awake BP was defined as the average of BPs recorded during the rest of the day. Morning BP was defined as the average of BPs during the first 2 hours after waking up, and the morning BP surge group was defined with the following criteria: morning systolic BP minus sleep systolic BP 37 mm Hg ( 90th percentile). In a previous study, 10 morning BP surge was defined as the morning systolic BP (average BP during the first 2 hours after waking up) minus the lowest systolic BP (average BP of 3 readings centered on the lowest nighttime reading), and the top decile of morning BP surge was used. To identify the morning BP surge group in our study, we used the same criteria for the cutoff point of morning BP surge (the top decile), although sleep systolic BP was used instead of the lowest systolic BP while asleep, because we made fewer measurements of BP while asleep in our study than in the other study, which could lead to misclassification of the morning BP surge group because of wide variations. Power spectral analysis for RR intervals of ECG was performed every 5 minutes to yield the low-frequency (LF) component (0.05 to 0.15 Hz) and the high-frequency (HF) component (0.15 to 0.40 Hz) and their ratio (LF:HF). LF was analyzed as an index of sympathetic and parasympathetic nervous system activity, HF as an index of parasympathetic nervous system activity, and LF:HF as an index of sympathetic nervous system activity. Sleep LF, HF, and LF:HF were defined as the average of these values from the time when the participants went to bed until the time they got out of bed, and those of awake were defined as the average of those values recorded during the rest of the day. Twenty-four hour BP, LF, HF, and LF:HF were calculated as [(asleep average of the values asleep hours) (awake average of the values awake hours)]/24. Measurements of Alcohol Intake and Confounding Variables Detailed methods of risk factor surveys were described elsewhere Briefly, an interviewer assessed the smoking status and the number of cigarettes smoked per day, as well as the habitual weekly intake of alcohol in units of go (a Japanese traditional unit of volume corresponding with 23 g of ethanol), which was converted to grams of ethanol per day. One go is 180 ml of sake, and it corresponds with 1 bottle (633 ml) of beer, 2 single shots (75 ml) of whiskey, or 2 glasses (180 ml) of wine. Persons who reported consuming 0.3 go per week were regarded as current drinkers. Former drinkers were defined as abstainers for the previous 3 months or more. Persons who smoked 1 cigarette per day were defined as current smokers. Height in stocking feet and weight in light clothing were measured, and body mass index (BMI) was calculated as weight (kilograms)/height (meters squared). Casual systolic and diastolic BPs were measured by trained technicians using a standard mercury sphygmomanometer on the right arm of seated participants after at least a 5-minute rest. Readings were made to the nearest 2 mm Hg, and diastolic BP was taken as the phase V Korotkoff sound. Serum total cholesterol and high-density lipoprotein cholesterol after heparin-manganese precipitation were measured with the enzymatic method using the Autoanalyzer Hitachi 7250 (Hitachi) or AU2700 (Olympus) at the Osaka Medical Center for Health Science and Promotion. This laboratory has been standardized by Centers for Disease Control and Prevention-National Heart, Lung, and Blood Institute Lipid Standardization Program and has successfully met the criteria for precision and accuracy of triglycerides and total and high-density lipoprotein cholesterol measurements as an international member of the US National Cholesterol Reference Method Laboratory Network. 16 Serum levels of insulin were measured by a commercial radioimmunoassay. The homeostasis model of insulin resistance was calculated as follows: {[fasting glucose (mmol/l)] [fasting insulin ( U/mL)]}/22.5. Salivary samples obtained in the morning (first 2 hours after waking up) and evening (5 PM to 7 PM before the evening meal) were collected with the Salivette (Sarstedt), and salivary cortisol concentrations were assayed with the competitive ELISA. 17 Diabetes mellitus was defined as a fasting glucose level of 126 mg/dl (7.0 mmol/l), a nonfasting glucose level of 200 mg/dl (11.1 mmol/l), and/or use of medication for diabetes mellitus. Statistical Analyses Three participants stopped measurement of their ambulatory BP during the night because the measurement device disturbed the continuity of their sleep. We excluded participants who started taking antihypertensive medication before the measurement period (n 27) and those whose ambulatory BP data were incomplete or of poor quality (n 32). The remaining data of 539 men (mean age: 50.0 years) were used for the analyses. The participants were divided into 4 categories according to their current alcohol intake: nondrinker (0 g of alcohol per day), light drinker (0 to 22 g/d), moderate drinker (23 to 45 g/d), and heavy drinker ( 46 g/d). Age- and field-adjusted mean values or prevalence of potential confounding factors were calculated according to the category of alcohol intake by using ANCOVA or logistic regression models, 18 and trends were tested by using linear regression for continuous variables and logistic regression for dichotomous

3 Ohira et al Alcohol and Ambulatory Blood Pressure 15 Table 1. Characteristics of 539 Men Aged 35 to 65 Years Variables Mean SD Age, y Casual systolic BP, mm Hg Casual diastolic BP, mm Hg Hypertension, %* 41 NA BMI, kg/m Current smoking, % 50 NA Ethanol intake, g/d Excess ethanol intake, 46 g/d, % 29 NA Diabetes mellitus, % 11 NA Total cholesterol, mmol/l HDL cholesterol, mmol/l Fasting insulin, U/ ml HOMA-IR Morning salivary cortisol, ng/ml Evening salivary cortisol, ng/ml NA indicates not applicable; HOMA-IR, homeostasis model of insulin resistance. *Systolic BP 140 mm Hg and/or diastolic BP 90 mm Hg. Values are prevalence (%). Sample sizes vary somewhat among characteristics examined because of nonfasting or missing data, n 332 for fasting insulin and HOMA-IR, n 460 for morning salivary cortisol, and n 505 for evening salivary cortisol. variables. Although there is a circadian rhythm for salivary cortisol, there were no significant differences (P 0.30) among alcohol intake categories in terms of the times that the participants collected saliva in the morning and evening. Therefore, no adjustments were made in the analysis of salivary cortisol for the time of saliva collection. Differences among the categories of alcohol intake in age- and Table 2. Age- and Field-Adjusted Characteristics According to Habitual Alcohol Intake field-adjusted and multivariate-adjusted mean values of ambulatory BP, HR, and HR variability were also calculated using ANCOVA. Adjustment was made for those factors associated previously with hypertension in this study, including age (year), BMI (kilograms per meters squared), smoking status (never/former or current smokers), and diabetes mellitus status (yes or no). Odds ratios (ORs) and 95% CIs of the morning surge in relation to nondrinkers versus light and heavy drinkers were calculated by using logistic regression models. SAS 9.1 software (SAS Institute, Inc) was used for all of the statistical analyses. All of the P values for statistical tests were 2-tailed, and values of P 0.05 were regarded as statistically significant. Results Characteristics of the participants are shown in Table 1. Their mean age was 50 years, and mean alcohol intake was 29 g/d. As shown in Table 2, the mean values of casual systolic and diastolic BPs, high-density lipoprotein cholesterol, and salivary morning cortisol, as well as the prevalence of hypertension and current smoking, were positively associated with alcohol intake, whereas serum insulin level and homeostasis model of insulin resistance were inversely associated with alcohol intake. The Figure shows the time trend of BP levels during a 24-hour period according to alcohol intake category, and Table 3 shows age- and field-adjusted mean values of ambulatory BP, HR, LF, HF, and LF:HF ratio according to alcohol intake category. Compared with nondrinkers, moderate drinkers (alcohol intake 23 to 45 g/d) and heavy drinkers (alcohol intake 46 g/d) showed higher age- and fieldadjusted mean values of systolic and diastolic BP during the morning and while awake, whereas there were no differences in systolic and diastolic BPs during the 24-hour periods and while asleep among the alcohol intake category groups. Characteristics Nondrinker Light Drinker Moderate Drinker Heavy Drinker P for Difference n NA Ethanol intake range, g/d 0 1 to to NA Age, y * 49.2* Casual SB, mm Hg * Casual diastolic BP, mm Hg 81 83* Hypertension, % 27 39* BMI, kg/m Current smoking, % Diabetes mellitus, % Total cholesterol, mmol/l HDL cholesterol, mmol/l Fasting insulin, U/ ml # * 7.8* HOMA-IR Morning salivary cortisol, ng/ml Evening salivary cortisol, ng/ml HDL indicates high-density lipoprotein; HOMA-IR, homeostasis model of insulin resistance; NA, not applicable. Significantly different from 0 group, *P 0.05, P Significantly different from 1 to 22 group, P 0.05, P Significantly different from group, P Sample sizes vary somewhat among characteristics examined because of nonfasting or missing data, n 332 for fasting insulin and HOMA-IR, n 460 for morning salivary cortisol, and n 505 for evening salivary cortisol. #Fasting insulin indicates the geometric mean.

4 16 Hypertension January Systolic blood pressure (mmhg) Figure. Time-trend of systolic BP levels during 24 hours according to alcohol intake category Before waking After waking (h) Non-drinker Light drinker Moderate drinker Heavy drinker Alcohol intake was positively associated with mean values of sleep-morning differences and daytime variability in BPs, HR while awake and asleep, and LF:HF ratio while asleep. When we further adjusted for BMI, smoking status, and diabetes mellitus, the results were virtually unchanged (Table S1, please see the online data supplement available at hyper.ahajournals.org). In addition, similar positive associations of alcohol intake with systolic and diastolic BPs during the morning and while awake were observed in each community, and there was no statistical evidence that associations of alcohol intake with systolic and diastolic BPs varied by community (P 0.15). Age-adjusted mean values of systolic and diastolic BPs during the morning for nondrinkers, light drinkers, moderate drinkers, and heavy drinkers were 129/82, 133/85, 132/89, and 135/88 mm Hg for Ikawa (n 204); 127/83, 133/86, 134/89, and 132/91 mm Hg for Kyowa (n 95); 128/78, 130/81, 131/83, and 135/83 mm Hg for Yao (n 163); and 127/83, 130/84, 143/90, and 137/88 mm Hg for Noichi (n 77). Moreover, similar and positive associations of alcohol intake with HR and LF:HF ratio were observed in the communities (data not shown). There was also no statistical evidence that associations of alcohol intake with BPs, HR, and HR variability varied according to smoking status or diabetes mellitus (P 0.15). As shown in Table 4, compared with the nondrinkers, ageand field-adjusted ORs and 95% CIs of the morning surge for the light, moderate, and heavy drinkers were 0.96 (95% CI: 0.34 to 2.78), 1.68 (95% CI: 0.64 to 4.38), and 2.73 (95% CI: 1.12 to 6.67), respectively. The associations of alcohol intake with the morning surge were slightly attenuated after adjustment for BMI, smoking status, diabetes mellitus, morning salivary cortisol, sleep HR, and sleep LF:HF ratio but remained statistically significant. We further divided the heavy drinkers into 2 groups (alcohol intake 46 to 68 g/d and 69 g/d), and the latter group (n 62) had a higher multivariate-adjusted OR of the morning BP surge than the former (n 94), at 4.15 (95% CI: 1.43 to 12.1) and 2.11 (95% CI: 0.77 to 5.76), respectively. Discussion The main findings of the present cross-sectional study were that habitual alcohol intake was positively associated with BP levels in the morning, HR while awake and asleep, and sympathetic activities while asleep, and that, compared with nondrinkers, heavy drinkers had a 2.7-times higher risk of morning BP surge. Although the association of heavy drinking with risk of stroke is well established, 1 5 the mechanisms underlying this association remain unclear. However, our findings are consistent with the hypothesis that heavy drinking raises the risk of stroke in part through morning BP surge and increased sympathetic activities. Recent prospective studies have reported that morning BP surge could be associated with risk of all types of stroke or hemorrhagic stroke independent of mean 24-hour systolic BP, 10,11 but the effects of alcohol intake on this association were not clarified, because these studies did not include alcohol intake in their analyses. On the other hand, several experimental studies have indicated the time-dependent biphasic effect of alcohol intake on 24-hour BP levels, ie, a decrease in BP levels several hours after ingestion and an increase later on. 8,19,20 Because, in general, most drinkers consume alcohol in the evening, alcohol intake could be associated with morning BP surge. However, few studies to date have investigated the association between habitual alcohol intake and morning BP surge in population-based samples. 7,21 Our findings confirmed that alcohol intake was positively associated with morning BP surge, and the association was dose dependent and independent of confounding factors. Additional research is needed to confirm the associations among alcohol intake, morning surge, and incidence of stroke. Although the mechanisms by which alcohol intake leads to an increase in BP levels have not been fully elucidated, the

5 Ohira et al Alcohol and Ambulatory Blood Pressure 17 Table 3. Age- and Field-Adjusted BPs, HR, and HR Variability According to Habitual Alcohol Intake Characteristics Nondrinker Light Drinker Moderate Drinker Heavy Drinker P for Difference n NA Ethanol intake range, g/d 0 1 to to NA Systolic blood pressure, mm Hg 24-h Awake * 134.8* 0.04 Asleep * 0.13 Morning Sleep-morning difference * SD of awake value SD of asleep value Diastolic blood pressure, mm Hg 24-h Awake Asleep Morning Sleep-morning difference SD of awake value SD of asleep value * 8.8* 0.11 Heart rate, bpm 24-h * Awake * Asleep LF, ms/sqr Hz 24-h Awake Asleep HF, ms/sqr Hz 24-h Awake Asleep LF/HF 24-h * 0.03 Awake * Asleep NA indicates not applicable. Significantly different from 0 group, *P 0.05, P Significantly different from 1 to 22 group, P 0.05, P Significantly different from 23 to 45 group, P following potential mechanisms have been identified: (1) stimulation of the renin-angiotensin-aldosterone axis; (2) abnormal sympathetic stimulation; (3) increased cortisol secretion; (4) reduction of insulin sensitivity with impairment of glucose tolerance; (5) HR variability; (6) effects on peripheral muscle tone via changes in calcium or sodium transport into smooth muscle cells; and (7) endothelial dysfunction because of release of endothelin or inhibition of endothelium-dependent NO production. 22 Our findings that alcohol intake is positively associated with HR, sympathetic activity evaluated by HR variability, and morning salivary cortisol levels seem to partly support the validity of these mechanisms. Furthermore, we showed previously that habitual alcohol intake was associated with severity of sleep-disordered breathing among middle-aged Japanese men, independent of age, BMI, and smoking. 23 Because sleep-disordered breathing was found to be positively associated with morning BP surge in children who had never consumed alcohol, 24 heavy drinking may increase morning BP levels via the combined effect of sleepdisordered breathing and the above-mentioned pharmacodynamic action of alcohol. Although evidence for an association between alcohol intake and activity of the hypothalamic-pituitary-adrenal axis remains inconclusive, the present results supported the previous hypothesis that chronic heavy alcohol drinking could be

6 18 Hypertension January 2009 Table 4. ORs and 95% CIs of Morning Surge for Drinkers Compared With Nondrinkers Characteristics Nondrinker Light Drinker Moderate Drinker Heavy Drinker P for Trend n Morning surge, n (%)* 7 (6.6) 8 (6.1) 14 (9.6) 26 (16.7) Age- and field-adjusted OR (95% CI) (0.34 to 2.78) 1.68 (0.64 to 4.38) 2.73 (1.12 to 6.67) Multivariate-adjusted OR (95% CI) (0.34 to 2.88) 1.69 (0.65 to 4.43) 2.79 (1.14 to 6.84) Multivariate-adjusted OR (95% CI) (0.35 to 2.94) 1.61 (0.60 to 4.35) 2.72 (1.08 to 6.89) 0.01 *Morning surge indicates morning systolic BP minus sleep systolic BP 37 mm Hg (90th percentile). Data shows adjustment for age, field, BMI, smoking status, and diabetes mellitus. Further adjustment was made for morning salivary cortisol, sleep HR, and sleep LF:HF ratio. associated with increased salivary cortisol levels in the morning, which is a marker of activation of the hypothalamicpituitary-adrenal axis. 25 In our study, on the other hand, habitual alcohol intake was inversely associated with fasting insulin levels and homeostasis model of insulin resistance, which are markers of insulin resistance, whereas insulin resistance or compensatory hyperinsulinemia could be associated with hypertension. However, these findings are in line with those of previous epidemiological studies that insulin levels and insulin resistance index decreased with an elevation of alcohol intake and that elevated insulin levels were associated with incidence of hypertension for nondrinkers but not for drinkers. 26 Our study also demonstrated that, compared with nondrinkers and/or light drinkers, heavy drinkers showed higher mean values of SD of daytime BPs, a marker of BP variability, which seems to support the notion that increased alcohol intake raises the risk of cardiovascular disease incidence and mortality through increased BP variability. 27,28 The strength of the present study is that we were able to use population-based data from a large number of participants whose mean alcohol intake is greater than that of Western populations for analysis of the associations of habitual alcohol intake with 24-hour BP, HR, and HR variability. In addition, all of the participants were free from stroke and coronary heart disease and were not taking any antihypertensive medication, which could have a modifying effect on these associations. Potential limitations of this study warrant consideration. First, the temporal relationship of habitual alcohol intake with elevated morning and daytime BPs cannot be inferred because of the cross-sectional design. Nevertheless, a recent meta-analysis of 15 randomized, controlled trials (a total of 2234 participants) reported that reduction of alcohol intake was associated with a significant reduction in mean systolic and diastolic BPs of 3.3 mm Hg and 2.0 mm Hg, respectively 6 ; this may support a causal relationship between habitual alcohol intake and elevated BP. Secondly, we analyzed the associations of habitual alcohol intake with BP, HR, and HR variability using a single 24-hour assessment, which may lead to misclassification of the habitual alcohol intake levels of some individuals. However, most heavy drinkers (97.5%) in this study consumed 46 g of alcohol every day, and 85.3% of heavy drinkers consumed the same amount of alcohol throughout the entire week. We, therefore, believe that the effects of the single assessment on the observed associations of alcohol intake with BP, HR, and HR variability might be modest, especially in a comparison between the nondrinkers and the heavy drinkers. Thirdly, because the participation rates were comparatively low for the populations of Kyowa, Yao, and Noichi, there is some doubt as to whether the participants in our study are representative of the community populations, although similar and positive associations of alcohol intake with systolic and diastolic BPs during the morning were observed in each community. Although we analyzed the associations between alcohol intake and BPs, HR, and HR variability using the multivariable-adjusted model, lifestyle factors other than the selected covariates may have an effect on these associations. For instance, consumption of 1 cigarette and/or cup of coffee during the morning surge period could lead to elevations in BPs and HR. Unfortunately, we did not assess smoking status or coffee consumption on the measurement day. However, our findings showed no statistical evidence that associations of alcohol intake with BPs, HR, and HR variability varied according to smoking status. Moreover, between 1995 and 2000, we investigated coffee consumption in the morning using the 24-hour recall method for 1282 men aged 40 to 69 years in the 4 communities. The results showed that 14% of the subjects drank coffee in the morning, but there was no significant association between alcohol intake and coffee consumption in the morning. We, therefore, believe that the effect of smoking and coffee consumption during the morning surge period on the association of alcohol intake with morning BP surge is probably minor. Finally, we did not examine the effect of type of alcoholic beverages on the associations between alcohol intake and BP. However, a previous study conducted with 4335 Japanese men reported that there were no differences in BP among types of alcoholic beverages after adjustment for other lifestyle factors. 29 In conclusion, habitual alcohol intake was found to be associated with increased BPs in the morning, HR while awake and asleep, and sympathetic activity while asleep, which may explain some of the mechanisms for the association of heavy alcohol intake with risk of cardiovascular diseases. Additional research is needed to examine the effect of habitual alcohol intake on the associations of morning BP surge with incidence of cardiovascular diseases. Perspectives The findings of the present study have both clinical and methodologic implications. From a clinical viewpoint, for treatment of morning BP surge, avoidance of excessive alcohol intake should be recommended as one nonpharmaco-

7 Ohira et al Alcohol and Ambulatory Blood Pressure 19 logical treatment. From a methodologic viewpoint, when researchers examine a relationship between morning BP surge and incidence of cardiovascular disease, it is necessary to consider effects of alcohol intake on the association between morning BP surge and incidence of cardiovascular disease. Sources of Funding This study was supported in part by research grants from the Japan Small- and Medium-Sized Enterprise Welfare Foundation (FULLHAP) and the Health and Labor Sciences Research Grant (Clinical Research for Evidence Based Medicine) from the Ministry of Health, Welfare and Labor of Japan. None. Disclosures References 1. Iso H, Kitamura A, Shimamoto T, Sankai T, Naito Y, Sato S, Kiyama M, Iida M, Komachi Y. Alcohol intake and the risk of cardiovascular disease in middle-aged Japanese men. Stroke. 1995;26: Kiyohara Y, Kato I, Iwamoto H, Nakayama K, Fujishima M. 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