Journal of Human Hypertension (2015) 29, 359–365 © 2015 Macmillan Publishers Limited All rights reserved 0950-9240/15 www.nature.com/jhh
ORIGINAL ARTICLE
Light-to-moderate alcohol intake reduces lipid accumulation product and attenuates its relation to hypertension I Wakabayashi Lipid accumulation product (LAP), an index calculated by using triglyceride level and waist circumference, has been shown to predict hypertension, diabetes and cardiovascular disease. Alcohol is known to influence blood pressure and blood lipids. The aim of this study was to clarify the relationships among alcohol intake, LAP and hypertension. The subjects, middle-aged Japanese men (n = 21 572), were divided into non-, light ( o22 g ethanol per day), moderate (⩾22 and o44 g ethanol per day) and heavy (⩾44 g ethanol per day) drinkers. The relationships between alcohol intake and LAP and between LAP and hypertension were investigated. There were U- and J-shaped relationships between alcohol intake and LAP in subjects with and without hypertension, respectively. The adjusted odds ratios with their 95% confidence intervals for hypertension in subjects with vs subjects without high LAP were 3.04 (2.69–3.43, P o 0.01), 2.32 (1.92–2.81, P o 0.01), 2.10 (1.89–2.33, Po 0.01) and 2.11 (1.87–2.38, P o0.01) in non-, light, moderate and heavy drinkers, respectively. Thus, the positive association between LAP and hypertension is weaker in drinkers than in nondrinkers. The results suggest that light-to-moderate alcohol drinking reduces LAP level in patients with hypertension and attenuates the relation of LAP to hypertension. Journal of Human Hypertension (2015) 29, 359–365; doi:10.1038/jhh.2014.97; published online 13 November 2014
INTRODUCTION The risk of cardiovascular disease is known to be lower in light-tomoderate alcohol drinkers than in nondrinkers.1,2 The preventive effect of alcohol is based on its antiatherosclerotic action, which is mainly explained by alteration in blood lipid concentrations, especially that of high-density lipoprotein (HDL) cholesterol.3,4 In addition, alcohol-induced inhibition of the blood coagulation system, including platelet aggregation and coagulation factors, is involved in the antiatherosclerotic action of alcohol.5 On the other hand, alcohol drinking is an important risk factor of hypertension.6,7 Moreover, excessive alcohol consumption is known to result in elevation of triglyceride (TG) level,8,9 which has been shown to be an independent cardiovascular risk factor.10,11 Thus, alcohol drinking shows both beneficial and detrimental effects on the progression of atherosclerosis depending on the amount of alcohol consumption. Obesity is also a major risk factor for cardiovascular disease as it deteriorates insulin sensitivity, blood lipid metabolism and blood pressure regulation.12 However, there is still debate regarding whether and how alcohol drinking influences the risk for obesity.13,14 Lipid accumulation product (LAP), calculated by using TG level and waist circumference (WC), has been shown to be associated with the risk of cardiovascular events15,16 and to predict all-cause mortality in nondiabetic patients at high risk for cardiovascular diseases.17 LAP has been reported to be better than body mass index in discriminating diabetes.18,19 LAP has also been shown to predict blood pressure.15 LAP has been reported to be lower in light drinkers, higher in heavy drinkers and not different in moderate drinkers when compared with nondrinkers, and there is therefore a J-shaped relationship between alcohol intake and LAP in the general population20 and in patients with diabetes.21 However, it remains to be elucidated how alcohol intake
influences LAP in patients with hypertension. In addition, it is unknown whether the relationship between LAP and blood pressure is modified by alcohol drinking. The purpose of this study was therefore to clarify the relationships among alcohol consumption, LAP and hypertension. SUBJECTS AND METHODS Subjects The subjects were Japanese men aged 35–60 years (n = 21 572) who had received periodic health checkup examinations at workplaces in Yamagata Prefecture in Japan. The subjects were recruited from a list of people receiving a set of annual health checkup examinations from April 2008 to March 2009. Histories of alcohol consumption, cigarette smoking, regular exercise (almost every day for 30 min or longer per day), illness and therapy for illness were surveyed by questionnaires. The proportion of men receiving lipid-lowering drug therapy was 4.7% in the original database, and they were excluded from the subjects for analysis in this study because lipid-lowering drug therapy was expected to considerably influence LAP levels. A cross-sectional study was performed using a local population-based database for the above subjects. This study was approved by the Ethics Committee of Yamagata University School of Medicine.
Evaluation of alcohol consumption The average alcohol consumption of each subject per week was reported on questionnaires. Among the overall number of subjects having annual health checkups in the original database, nondrinkers, regular drinkers and occasional drinkers were 20.8%, 45.9% and 33.3%, respectively. Since it is difficult to know the correct average alcohol consumption of occasional drinkers, only regular drinkers who drink almost every day were used as drinkers for analysis in this study. Occasional drinkers were thus excluded from subjects for analysis. The usual daily alcohol consumption was calculated in terms of the equivalent number of ‘go’, a traditional Japanese
Department of Environmental and Preventive Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan. Correspondence: Dr I Wakabayashi, Department of Environmental and Preventive Medicine, Hyogo College of Medicine, Mukogawa-cho 1-1, Nishinomiya, Hyogo 663-8501, Japan. E-mail: [email protected] Received 28 April 2014; revised 6 August 2014; accepted 18 September 2014; published online 13 November 2014
Alcohol intake, LAP and hypertension I Wakabayashi
360 unit of the amount of sake (rice wine). The amounts of other alcoholic beverages, including beer, wine, whisky and shochu (traditional Japanese distilled spirit), were converted and expressed as units of ‘go’. One go approximately corresponds to 180 ml of sake, 500 ml of beer, 240 ml of wine, 60 ml of whisky and 80 ml of shochu. The amount of daily alcohol drinking was categorized as ‘null’, ‘less than 1 go per day’, ‘1 go or more and less than 2 go per day’, ‘2 go or more and less than 3 go per day’ and ‘3 go or more per day’. One ‘go’ contains about 22 g of ethanol, and this amount was used to separate moderate drinkers from light drinkers since it is generally accepted that alcohol intake should be reduced to o30 ml or 20–30 g per day from the viewpoint of prevention of hypertension.22–24 The subjects were divided into four groups according to ethanol consumption per day (nondrinkers; light drinkers: o22 g of ethanol per day; moderate drinkers: ⩾ 22 g buto44 g of ethanol per day; heavy drinkers: ⩾ 44 g ethanol per day).
Measurements WC was measured at the navel level according to its definition by the Japanese Committee for the Diagnostic Criteria of Metabolic Syndrome.25 Blood pressure was measured by trained nurses, who were part of the local health-checkup company, with a mercury sphygmomanometer once on the day of the health checkup after each subject had rested quietly in a sitting position. Korotkoff phase V was used to define diastolic pressure. Normal blood pressure was defined as a systolic blood pressure of o140 mm Hg and a diastolic blood pressure of o 90 mm Hg. Hypertension was defined as a systolic blood pressure of ⩾ 140 mm Hg and/or a diastolic blood pressure of ⩾ 90 mm Hg. Subjects receiving medication therapy for hypertension were also included in the hypertensive group. Fasted blood was sampled from each subject in the morning, and serum TG concentrations were measured by the enzymatic method using a commercial kit named Pureauto S TG-N (Sekisui Medical Co., Ltd, Tokyo, Japan). The coefficient of variation for reproducibility of measurement of TGs was ⩽ 3%. LAP was determined by using TGs and WC as follows:15 LAP = TGs (mmol l − 1) × (WC (cm) − 65). The cutoff value of high LAP was defined as 37.2.26 Serum HDL cholesterol and low-density lipoprotein (LDL) cholesterol were measured by the enzymatic methods using commercial kits named Cholestest N-HDL and Cholestest LDL (Sekisui Medical Co., Ltd), respectively. Hemoglobin A1c was measured by using the latex cohesion method and standardized as previously described.27 Coefficients of variation for reproducibility of HDL cholesterol, LDL cholesterol and hemoglobin A1c measurements were ⩽ 5%. Metabolic syndrome was defined according to the criteria by the National Cholesterol Education Program’s Adult Treatment Panel III (NCEP-ATP III)28 as described previously.27
Statistical analysis Statistical analyses were performed using a computer software program (SPSS version 16.0J for Windows, Chicago, IL, USA). Percentages of smokers, drinkers, subjects doing exercise regularly, subjects receiving medical therapy for hypertension and subjects showing high LAP were compared between the normotensive and hypertensive groups using the chi-square test for independence. In univariate analysis, means of each variable were compared between the normotensive and hypertensive groups by using the unpaired Student’s t test. Since TGs and LAP did not show normal distributions, they were compared between the groups nonparametrically by using the Mann–Whitney U-test. In multivariate analysis, mean levels of each variable were compared by using analysis of covariance followed by the Student’s t-test after the Bonferroni correction, and the data of TGs and LAP were used after logarithm transformation. In linear regression analysis, Pearson’s correlation coefficients and standardized partial regression coefficients were calculated. Pearson’s correlation coefficients were compared in two different variable pairs by using the Fisher z-transformation applied to the sample correlation coefficients. In logistic regression analysis, crude and adjusted odds ratios for high LAP or hypertension were estimated. Crude odds ratios were compared between the normotensive and hypertensive groups and between each drinker group and the nondrinker group by using the Breslow–Day test. Age and histories of smoking and regular exercise were used as other explanatory variables or covariables in multivariate analyses. In some analyses, a history of medication therapy for hypertension was also added to the explanatory variables or covariables. Probability (P) values o0.05 were defined as significant. Two-tailed P values were used to evaluate statistical significance. Journal of Human Hypertension (2015) 359 – 365
RESULTS Characteristics of subjects Profiles of the subject groups showing normal blood pressure and hypertension are presented in Table 1. The subjects with hypertension were significantly older than those with normal blood pressure. Moderate and heavy drinkers as well as total drinkers were significantly higher in proportion in the hypertensive group than in the normotensive group, while the proportions of subjects with smoking habit and regular exercise were lower in the hypertensive group than in the normotensive group. WC, TGs, LDL cholesterol, ratio of LDL cholesterol to HDL cholesterol (LDLC/HDL-C ratio) and LAP were significantly higher in the hypertensive group than in the normotensive group, while HDL cholesterol was slightly but significantly lower in the hypertensive group than in the normotensive group. The proportion of subjects showing high LAP levels was significantly higher in the hypertensive group than in the normotensive group. Comparison of systolic and diastolic blood pressure levels among the alcohol groups Means of systolic and diastolic blood pressure of non-, light, moderate and heavy drinkers in the overall subjects are shown in Figure 1. Both systolic and diastolic blood pressure levels tended to be higher with an increase in alcohol intake and were significantly higher in light, moderate and heavy drinkers than in nondrinkers. Comparison of LAP, TGs and WC among the alcohol groups Figure 2 shows the means of log-transformed LAP (Figure 2a), logtransformed TGs (Figure 2b) and WC (Figure 2c) of non-, light, moderate and heavy drinkers in the normotensive and Table 1.
Characteristics of the normotensive and hypertensive subject
groups
Number Age (years) Drinkers (%) Light Moderate Heavy Total
Normotensive
Hypertensive
14175 47.0 ± 7.5
7397 50.6 ± 7.0**
12.5 34.2 19.4 66.1
10.2** 39.1** 28.8** 78.1**
Smokers (%) 63.6 55.9** Regular exercise (%) 10.1 9.3# Medical therapy for 0 30.0** hypertension (%) Waist circumference (cm) 81.6 ± 8.1 86.5 ± 9.0** Systolic blood pressure 121.8 ± 10.8 145.9 ± 14.2** (mm Hg) Diastolic blood pressure 73.7 ± 8.4 88.7 ± 10.5** (mm Hg) 1.24 (0.82, 1.93) 1.55 (1.02, 2.39)** Triglycerides (mM) HDL cholesterol (mg/dl) 57.7 ± 15.4 57.1 ± 15.4** LDL cholesterol (mg/dl) 114.3 ± 31.1 116.0 ± 32.4** LDL-C/HDL-C ratio 2.147 ± 0.874 2.199 ± 0.888** LAP 19.86 (9.72, 37.61) 32.61 (17.72, 56.27)** High LAP (%) 25.4 43.5** Abbreviations: LDL-C/HDL-C ratio, ratio of LDL cholesterol to HDL cholesterol; LAP, lipid accumulation product. Numbers, percentages of subjects, means with standard deviations, and medians with 25th and 75th percentile values indicated in the parentheses are shown. Asterisks denote significant differences from the normotensive group (**Po 0.01). Marginally significant difference (#P = 0.055).
© 2015 Macmillan Publishers Limited
Alcohol intake, LAP and hypertension I Wakabayashi
361 Nondrinkers Light drinkers Moderate drinkers Heavy drinkers
134 132
** **
130
Nondrinkers Light drinkers Moderate drinkers Heavy drinkers
82
Diastolic blood pressure (mmHg)
Systolic blood pressure (mmHg)
136
**
128 126 124 122 120
80
** **
**
78 76 74 72 70
Figure 1. Comparison of systolic and diastolic blood pressure levels among non-, light, moderate and heavy drinkers in the overall subjects. Mean levels of systolic blood pressure (a) and diastolic blood pressure (b) calculated after adjustment for age and histories of smoking, regular exercise and medication therapy for hypertension are shown. Asterisks denote significant differences from nondrinkers (P o0.01).
**
**
1.4 **
1.3 *
1.2 1.1
0.2 **
0.15 0.1
**
**
0.05 0
1
Normotensive
Hypertensive
90
**
Waist circumference (cm)
1.5
Log(LAP)
Nondrinkers Light drinkers Moderate drinkers Heavy drinkers
0.25
Log(triglycerides [mM])
1.6
Nondrinkers Light drinkers Moderate drinkers Heavy drinkers
Nondrinkers Light drinkers Moderate drinkers Heavy drinkers
88 ** ** **
86 84 82
*
80 78 76
Normotensive
Hypertensive
Normotensive
Hypertensive
Figure 2. Comparison of LAP, triglycerides and waist circumference among non-, light, moderate and heavy drinkers in the normotensive or hypertensive group. Mean levels of log-transformed LAP (a), log-transformed triglycerides (b) and waist circumference (c) calculated after adjustment for age and histories of smoking and regular exercise are shown. In the hypertensive group, a history of medication therapy for hypertension was also added as an explanatory covariable. Asterisks denote significant differences from nondrinkers (*P o0.05; **Po 0.01).
hypertensive groups. In the normotensive group, log-transformed LAP was significantly lower in light drinkers, significantly higher in heavy drinkers and not different in moderate drinkers when compared with nondrinkers. In the hypertensive group, logtransformed LAP was significantly lower in light and moderate drinkers than in nondrinkers, and was not significantly different in heavy drinkers and nondrinkers. Both in the normotensive and hypertensive groups, log-transformed TG levels were significantly lower in light drinkers and higher in heavy drinkers and were not significantly different in moderate drinkers when compared with nondrinkers. In the normotensive group, WC was significantly smaller in light drinkers than in nondrinkers and was not significantly different in non-, moderate and heavy drinkers. In the hypertensive group, WC was significantly smaller in light, moderate and heavy drinkers than in nondrinkers. Comparison of LAP between the subject groups with and without metabolic syndrome Overall, the proportion of subjects with metabolic syndrome was 18.0%. In the subjects with metabolic syndrome, log-transformed LAP after adjustment for age and histories of alcohol drinking, smoking and regular exercise was significantly higher than that in the subjects without metabolic syndrome (1.256 ± 0.003 vs 1.785 ± 0.006, P o 0.01). This finding is reasonable because the © 2015 Macmillan Publishers Limited
components of LAP, including WC and level of TGs, are included in the criteria of metabolic syndrome.28 Odds ratio for high LAP in each drinker group vs the nondrinker group Table 2 shows the results of logistic regression analysis regarding the relationships between alcohol intake and high LAP. In the hypertensive group, crude and adjusted odds ratios vs nondrinkers for high LAP were significantly lower than the reference level of 1.00 in light and moderate drinkers. In the normotensive group, crude and adjusted odds ratios vs nondrinkers for high LAP were significantly lower and higher than the reference level in light and heavy drinkers, respectively, and were not significantly different from the reference level in moderate drinkers. The crude odds ratios for high LAP in moderate and heavy drinkers vs nondrinkers were significantly lower in the hypertensive group than in the normotensive group, and the odds ratio in light drinkers vs nondrinkers was marginally significantly lower (P = 0.052) in the hypertensive group than in the normotensive group. In order to determine whether the above associations of alcohol use with LAP were different in normotensive and hypertensive subjects, the odds ratio for high LAP of the interaction term consisting of drinker category (light, moderate or heavy drinkers vs nondrinkers) and blood pressure status (hypertensive vs Journal of Human Hypertension (2015) 359 – 365
Alcohol intake, LAP and hypertension I Wakabayashi
362 normotensive) was investigated. As shown in Table 2, odds ratios for high LAP of the interaction term were significantly lower than the reference level of 1.00 in moderate and heavy drinkers. Thus, significant interaction of alcohol drinking and blood pressure status was found for high LAP, and this implies that the degree of the association between alcohol drinking and LAP was different in subjects with and those without hypertension. Correlation coefficients between LAP and blood pressure in the different alcohol groups Table 3 shows the results of linear regression analysis regarding the relationships between LAP and blood pressure. Pearson’s correlation coefficients and standardized partial regression coefficients between LAP and systolic or diastolic blood pressure were Table 2.
significant in all of the alcohol groups. Thus, both in the univariate and multivariate analyses, there were significant positive correlations of LAP with systolic and diastolic blood pressures. Pearson’s correlation coefficients between LAP and systolic or diastolic blood pressure were significantly lower in light, moderate and heavy drinkers than in nondrinkers, except for a marginally significant difference (P = 0.053) between light drinkers and nondrinkers in the coefficient of LAP with diastolic blood pressure. The correlation coefficients tended to be lower with an increase in alcohol intake. Odds ratio for hypertension in subjects with vs subjects without high LAP in each alcohol group Table 4 shows the results of logistic regression analysis regarding the relationships between LAP and hypertension. Crude and
Odds ratios for high LAP of each drinker subgroup vs the nondrinker subgroup in the normotensive and hypertensive groups Nondrinkers (n = 6430)
Light drinkers (n = 2524)
Normotensive Crude OR Adjusted OR
1.00 1.00
0.78 (0.69–0.89)** 0.78 (0.68–0.89)**
0.97 (0.88–1.06) 0.96 (0.87–1.05)
1.21 (1.09–1.35)** 1.18 (1.06–1.31)**
Hypertensive Crude OR Adjusted OR
1.00 1.00
0.63 (0.53–0.75)**,# 0.66 (0.55–0.79)**
0.68 (0.60–0.77)**,†† 0.72 (0.63–0.81)**
0.87 (0.76–0.99)*,†† 0.93 (0.81–1.06)
0.81 (0.65–1.01)
0.71 (0.61–0.83)**
0.72 (0.61–0.85)**
Overall OR of interaction term
—
Moderate drinkers (n = 7741)
Heavy drinkers (n = 4877)
Abbreviations: LAP, lipid accumulation product; OR, odds ratio. Crude and adjusted ORs with their 95% confidence intervals indicated in the parentheses are shown. Adjusted odds ratios for high LAP of each drinker subgroup vs the nondrinker subgroup in the normotensive and hypertensive groups were estimated using age, smoking, regular exercise and a history of medication therapy for hypertension as other explanatory variables. Odds ratios for high LAP of the interaction term consisting of drinker category (each drinker subgroup vs the nondrinker subgroup) and hypertension (yes vs no) were estimated by using drinker category, hypertension, age, smoking and regular exercise as other explanatory variables. Symbols denote significantly lower odds ratios compared with the reference level of 1.00 (*Po0.05; **Po0.01) and significant differences from the normotensive group (††Po0.01). Marginally significant difference from the normotensive group (#P = 0.052).
Table 3.
Correlations between LAP and systolic or diastolic blood pressure in non-, light, moderate and heavy drinkers Nondrinkers (n = 6430)
Light drinkers (n = 2524)
Moderate drinkers (n = 7741)
Heavy drinkers (n = 4877)
Systolic blood pressure Pearson’s coefficient Standardized coefficient
0.346** 0.327**
0.271**,†† 0.245**
0.256**,†† 0.238**
0.215**,†† 0.203**
Diastolic blood pressure Pearson’s coefficient Standardized coefficient
0.350** 0.335**
0.296**,# 0.275**
0.255**,†† 0.240**
0.239**,†† 0.229**
Abbreviation: LAP, lipid accumulation product. Pearson’s correlation coefficients and standardized partial regression coefficient for relationships of logtransformed LAP with systolic or diastolic blood pressure were calculated. Age, smoking status, a habit of regular exercise and a history of medication therapy for hypertension were used as other explanatory variables in the multivariate regression analysis. Symbols denote significant correlations (**Po0.01) and significant differences from nondrinkers (††Po0.01). #Marginally significant difference from nondrinkers (P = 0.053).
Table 4.
Odds ratios for hypertension of subjects with vs those without high LAP in non-, light, moderate and heavy drinkers
Crude OR Adjusted OR OR of interaction term
Nondrinkers (n = 6430)
Light drinkers (n = 2524)
Moderate drinkers (n = 7741)
Heavy drinkers (n = 4877)
2.86 (2.55–3.22)** 3.04 (2.69–3.43)** 1.00
2.30 (1.91–2.77)**,# 2.32 (1.92–2.81)** 0.75 (0.60–0.94)*
2.01 (1.82–2.22)**,†† 2.10 (1.89–2.33)** 0.67 (0.57–0.79)**
2.05 (1.82–2.31)**,†† 2.11 (1.87–2.38)** 0.69 (0.58–0.81)**
Abbreviations: LAP, lipid accumulation product; OR, odds ratio. Crude and adjusted ORs with their 95% confidence intervals indicated in the parentheses are shown. Adjusted odds ratios for hypertension were estimated using age, smoking and regular exercise as other explanatory variables. Odds ratios of the interaction term consisting of drinker category (each drinker group vs nondrinkers) and LAP (high vs not high) were estimated by using drinker category, LAP, age, smoking and regular exercise as other explanatory variables. Symbols denote significantly higher odds ratios compared with the reference level of 1.00 (*Po0.05; **P o0.01) and significant differences from nondrinkers (††Po0.01). Marginally significant difference from nondrinkers (#P = 0.052).
Journal of Human Hypertension (2015) 359 – 365
© 2015 Macmillan Publishers Limited
Alcohol intake, LAP and hypertension I Wakabayashi
363 relationship between alcohol intake and LAP in normotensive men, which agrees with the finding of a previous study for a general population.20 The results of the present study suggest that light-to-moderate drinking reduces LAP level in hypertensive men and agree with the results of previous studies showing an inverted relationship between light-to-moderate drinking and risk of cardiovascular disease.1,2 In a general population, LAP has been shown to be lower in light drinkers, higher in heavy drinkers and not different in moderate drinkers when compared with nondrinkers, and thus a J-shaped relationship was found between alcohol intake and LAP.20 A similar J-shaped relationship between alcohol intake and LAP has been reported in patients with diabetes21 and was found in the subjects without hypertension in the present study. The present study is the first to show the relationship of LAP with alcohol use in patients with hypertension, and demonstrated that LAP was significantly lower in light and moderate drinkers than in nondrinkers and was not significantly different in heavy drinkers and nondrinkers. Thus, there was a U-shaped relationship between alcohol intake and LAP in patients with hypertension. In summary, between alcohol and LAP, there was a J-shaped relationship in the general population, in persons without hypertension and in patients with diabetes, while there was a U-shaped relationship in patients with hypertension. Thus, the alcohol–LAP relationship is thought to be modified in hypertensive patients but not in diabetic patients. While the association of alcohol drinking with LAP was different in subjects with and those without hypertension, the associations of alcohol drinking with HDL cholesterol, LDL cholesterol and LDL-C/HDL-C ratio were similar in normotensive and hypertensive subjects (Figure 3). Alcohol is known to be a major risk factor of hypertension.6,7 In fact, systolic and diastolic blood pressure levels were significantly higher in light, moderate and heavy drinkers than in nondrinkers and tended to be higher with an increase in alcohol intake (Figure 1). In addition, the proportions of total drinkers and moderate or heavy drinkers were higher in subjects with hypertension than in subjects without hypertension (Table 1). Thus, it is obvious that alcohol is positively associated with blood pressure. Accordingly, even light-to-moderate drinking should not be recommended to patients with hypertension. LAP is calculated by using TGs and WC. The relationship between alcohol and TGs was similar in subjects with and without hypertension: In both groups of subjects, there was a J-shaped relationship between alcohol intake and TGs. However, there was a difference in the relationship of alcohol with WC in these groups. In the hypertensive group WC, was significantly smaller in light, moderate and heavy drinkers than in nondrinkers, while in the normotensive group WC, was significantly smaller in light drinkers
adjusted odds ratios for hypertension in subjects with vs those without high LAP were significantly higher than the reference level of 1.00 in all of the alcohol groups. The crude odds ratio was significantly lower in moderate and heavy drinkers than in nondrinkers and was marginally significantly lower (P = 0.052) in light drinkers than in nondrinkers. Whether alcohol use influences the relationship of high LAP with hypertension was investigated using an interaction term consisting of drinker category (light, moderate or heavy drinkers vs nondrinkers) and LAP level (high LAP vs not high LAP). As shown in Table 4, odds ratios for hypertension of the interaction terms were significantly lower than the reference level of 1.00 in light, moderate and heavy drinkers. Thus, a significant interaction of alcohol drinking and LAP was found for hypertension, and this implies that the positive association between LAP and blood pressure was weakened by alcohol drinking. Comparison of HDL cholesterol, LDL cholesterol and LDL-C/HDL-C ratio among the alcohol groups In both the normotensive and hypertensive groups, LDL cholesterol and LDL-C/HDL-C ratio were significantly lower and HDL cholesterol was significantly higher in each drinker group when compared with nondrinkers (Figure 3). In both of the groups, LDL cholesterol and LDL-C/HDL-C ratio tended to be lower with an increase in alcohol intake, while HDL cholesterol tended to be higher with an increase in alcohol intake (Figure 3). DISCUSSION This study demonstrated for the first time that the relationship between alcohol intake and LAP is different in men with and those without hypertension. In subjects with hypertension, LAP was significantly lower in light and moderate drinkers than in nondrinkers and was not significantly different in nondrinkers and heavy drinkers (Figure 2a); odds ratio vs nondrinkers for high LAP was significantly lower than the reference level in light and moderate drinkers and was not significantly different from the reference level in heavy drinkers (Table 2). Thus, there was a U-shaped relationship between alcohol intake and LAP in subjects with hypertension. In subjects without hypertension, LAP was significantly lower and higher in light and heavy drinkers, respectively, and was not significantly different in moderate drinkers, when compared with nondrinkers (Figure 2a); odds ratio vs nondrinkers for high LAP was significantly lower and higher than the reference level in light and heavy drinkers, respectively, and was not significantly different from the reference level in moderate drinkers (Table 2). Thus, there was a J-shaped
65
135 130
** **
**
60
**
**
**
55 50 45
Nondrinkers Light drinkers Moderate drinkers Heavy drinkers
3 2.8
125 **
120 115 110
**
** ** **
**
LDL-C/HDL-C ratio
Nondrinkers Light drinkers Moderate drinkers Heavy drinkers
LDL cholesterol (mg/dl)
HDL cholesterol (mg/dl)
70
Nondrinkers Light drinkers Moderate drinkers Heavy drinkers
2.6 2.4 2.2 2 1.8
** **
** **
** **
105 1.6
40
Normotensive
Hypertensive
100
Normotensive
Hypertensive
Normotensive
Hypertensive
Figure 3. Comparison of HDL cholesterol, LDL cholesterol and ratio of LDL cholesterol to HDL cholesterol (LDL-C/HDL-C ratio) among non-, light, moderate and heavy drinkers in the normotensive or hypertensive group. Mean levels of HDL cholesterol (a), LDL cholesterol (b) and LDL-C/HDL-C ratio (c) calculated after adjustment for age and histories of smoking and regular exercise are shown. In the hypertensive group, a history of medication therapy for hypertension was also added as an explanatory covariable. Asterisks denote significant differences from nondrinkers (P o0.01). © 2015 Macmillan Publishers Limited
Journal of Human Hypertension (2015) 359 – 365
Alcohol intake, LAP and hypertension I Wakabayashi
364 but not in moderate and heavy drinkers when compared with nondrinkers. Therefore, the difference in the relationships between alcohol intake and LAP, namely, J-shaped and U-shaped relationships, in the normotensive and hypertensive groups, respectively, is attributed to the difference in the relationship between alcohol intake and WC. The LAP level was significantly higher in the hypertensive group than in the normotensive group (Table 1) and showed a significant positive correlation with blood pressure (Table 3); the odds ratio for hypertension in subjects with vs those without high LAP was significantly higher than the reference level of 1.00 (Table 4). Thus, there is a positive association between LAP level and blood pressure. This study is also the first to show that the positive association of LAP with blood pressure was weaker in drinkers than in nondrinkers: the correlation coefficient between LAP and blood pressure was lower in drinkers than in nondrinkers (Table 3), and odds ratio for hypertension in subjects with vs those without high LAP was also lower in drinkers than in nondrinkers (Table 4). Moreover, odds ratios for hypertension of the interaction term consisting of alcohol and high LAP were lower than the reference level in all of the drinker groups (Table 4). These findings suggest that alcohol drinking not only influences LAP level but also confounds the relationship between LAP and blood pressure and therefore should be taken into account when LAP is used as a predictor of cardiovascular disease. This study has limitations. First, blood pressure was measured only once at the health checkup for each subject. Thus, there is an informational bias regarding blood pressure levels. Although age, history of medication therapy for hypertension, smoking status and history of regular exercise were adjusted in the multivariate analyses, there are other factors, for example, diet, nutrition and socioeconomic status, which possibly confound the relationships among alcohol intake, LAP and blood pressure. In addition, detailed information on the kind of alcohol beverages consumed by each subject was not available in this study, and there is a possibility that difference in alcohol beverage influences the association between alcohol intake and LAP. Although drugs used for hypertension possibly affected LAP levels, the kinds of antihypertensive drugs were not identified in the questionnaire at health checkup. In the present study, the proportion of smokers was 61.0% in overall subjects and thus much higher than that of overall Japanese men in 2008 (when the health check-ups were mainly performed) by the national statistic, which was 36.8%.29 Thus, there is a possibility of confounding by smoking for the relationship between alcohol and LAP, although smoking history was added to the explanatory variables and covariables in multivariate analyses. In the univariate analysis using data of overall subjects, medians of LAP, with its 25th and 75th percentile values in parentheses, were 23.25 (11.06, 43.70), 21.05 (10.55, 38.14), 23.34 (12.01, 43.05) and 26.37 (13.62, 50.28) in non-, light, moderate and heavy drinkers, respectively. Thus, changes in LAP by alcohol drinking were small and might not be clinically applicable in an individual person. The subjects of this study were all Japanese men, and there is a possibility of gender- or ethnicityrelated difference in the above relationships. The ratio of TGs to HDL cholesterol (TG/HDL-C ratio) is another good predictor for cardiovascular disease, and ethnicity-related differences have been reported in the relationship between insulin resistance and TG/HDL-C ratio: TG/HDL-C ratio has been reported to be a marker of insulin resistance in the subjects, of whom 87% were white, but not in African Americans.30,31 Furthermore, there was a significant positive association between TG/HDL-C ratio and insulin resistance in White European women but not in South Asian women.32 The medians with 25th and 75th percentile values of LAP level in US adult men from the third National Health and Nutrition Examination Survey (NHANES III) were 35.5 (20.1, 63.2) in men at 25–49 years of age and 53.4 (33.3, 85.6) in men at 50 years of age or older,15 which were higher than the median levels of LAP in the Journal of Human Hypertension (2015) 359 – 365
Japanese male subjects at 35–60 years of age in the present study (Table 1). Thus, a considerable ethnicity-related difference must exist in LAP level. Therefore, future studies are needed to determine whether people with other ethnicities also show the J-shaped and U-shaped associations of LAP with alcohol use in normotensive and hypertensive persons, respectively, found in the present study. Finally, further prospective studies are needed to conclude the causality of the findings of this study, which is crosssectional in its design. In conclusion, there was a U-shaped relationship between alcohol intake and LAP in men with hypertension, and the positive association between LAP and hypertension was weaker in light, moderate and heavy drinkers than in nondrinkers. Thus, light-tomoderate drinking is thought to lower LAP and attenuate its relationship with hypertension. What is known about this topic ● Lipid accumulation product (LAP) is a predictor for hypertension, diabetes and cardiovascular disease. ● A J-shaped relationship has been reported between alcohol intake and LAP in a general population. ● It remains to be elucidated how alcohol intake influences LAP in patients with hypertension. ● It is unknown whether the relationship of LAP with blood pressure is modified by alcohol drinking. What this study adds ● This study shows for the first time that light-to-moderate alcohol drinking is inversely associated with LAP in patients with hypertension and that the relationship of LAP with hypertension is weaker in light-to-moderate drinkers than in nondrinkers.
CONFLICT OF INTEREST The author declares no conflict of interest.
REFERENCES 1 Corrao G, Rubbiati L, Bagnardim V, Zambon A, Poikolainen K. Alcohol and coronary heart disease: a meta-analysis. Addiction 2000; 95: 1505–1523. 2 Ronksley PE, Brien SE, Turner BJ, Mukamal KJ, Ghali WA. Association of alcohol consumption with selected cardiovascular disease outcomes: a systematic review and meta-analysis. BMJ 2011; 342: d671. 3 Savolainen MJ, Kesäniemi YA. Effects of alcohol on lipoproteins in relation to coronary heart disease. Curr Opin Lipidol 1995; 6: 243–250. 4 Ellison RC, Zhang Y, Qureshi MM, Knox S, Arnett DK, Province MA. Investigators of the NHLBI Family Heart Study. Lifestyle determinants of high-density lipoprotein cholesterol: the National Heart, Lung, and Blood Institute Family Heart Study. Am Heart J 2004; 147: 529–535. 5 Salem RO, Laposata M. Effects of alcohol on hemostasis. Am J Clin Pathol 2005; 123(Suppl): S96–S105. 6 Klatsky AL. Alcohol and cardiovascular disease--more than one paradox to consider. Alcohol and hypertension: does it matter? Yes. J Cardiovasc Risk 2003; 10: 21–24. 7 Taylor B, Irving HM, Baliunas D, Roerecke M, Patra J, Mohapatra S et al. Alcohol and hypertension: gender differences in dose-response relationships determined through systematic review and meta-analysis. Addiction 2009; 104: 1981–1990. 8 Van de Wiel A. The effect of alcohol on postprandial and fasting triglycerides. Int J Vasc Med 2012; 2012: 862504. 9 Klop B, do Rego AT, Cabezas MC. Alcohol and plasma triglycerides. Curr Opin Lipidol 2013; 24: 321–326. 10 Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk 1996; 3: 213–219. 11 Labreuche J, Touboul PJ, Amarenco P. Plasma triglyceride levels and risk of stroke and carotid atherosclerosis: a systematic review of the epidemiological studies. Atherosclerosis 2009; 203: 331–345. 12 Sowers JR. Obesity as a cardiovascular risk factor. Am J Med 2003; 115(Suppl 8A): 37S–41S. 13 Suter PM. Is alcohol consumption a risk factor for weight gain and obesity? Crit Rev Clin Lab Sci 2005; 42: 197–227.
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365 14 Yeomans MR. Alcohol, appetite and energy balance: is alcohol intake a risk factor for obesity? Physiol Behav 2010; 100: 82–89. 15 Kahn HS. The "lipid accumulation product" performs better than the body mass index for recognizing cardiovascular risk: a population-based comparison. BMC Cardiovasc Disord 2005; 5: 26. 16 Wehr E, Pilz S, Boehm BO, März W, Obermayer-Pietsch B. The lipid accumulation product is associated with increased mortality in normal weight postmenopausal women. Obesity (Silver Spring) 2011; 19: 1873–1880. 17 Ioachimescu AG, Brennan DM, Hoar BM, Hoogwerf BJ. The lipid accumulation product and all-cause mortality in patients at high cardiovascular risk: a PreCIS database study. Obesity (Silver Spring) 2010; 18: 1836–1844. 18 Kahn HS. The lipid accumulation product is better than BMI for identifying diabetes: a population-based comparison. Diabetes Care 2006; 29: 151–153. 19 Bozorgmanesh M, Hadaegh F, Azizi F. Diabetes prediction, lipid accumulation product, and adiposity measures; 6-year follow-up: Tehran lipid and glucose study. Lipids Health Dis 2010; 9: 45. 20 Wakabayashi I. Relationship between alcohol intake and lipid accumulation product in middle-aged men. Alcohol Alcohol 2013; 48: 535–542. 21 Shimomura T, Wakabayashi I. Inverse associations between light-to-moderate alcohol intake and lipid-related indices in patients with diabetes. Cardiovasc Diabetol 2013; 12: 104. 22 Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr et al. National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289: 2560–2572. 23 European Society of Hypertension-European Society of Cardiology Guidelines Committee. 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003; 21: 1011–1053.
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24 Ogihara T, Kikuchi K, Matsuoka H, Fujita T, Higaki J, Horiuchi M et al. Japanese Society of Hypertension Committee. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009). Hypertens Res 2009; 32: 3–107. 25 Anonymous. Metabolic syndrome-definition and diagnostic criteria in Japan. J Jpn Soc Int Med 2005; 94: 794–809 (in Japanese). 26 Wakabayashi I, Daimon T. A strong association between lipid accumulation product and diabetes mellitus in Japanese women and men. J Atheroscler Thromb 2014; 21: 282–288. 27 Wakabayashi I. Relationship between smoking and metabolic syndrome in men with diabetes mellitus. Metab Syndr Relat Disord 2014; 12: 70–78. 28 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486–2497. 29 Anonymous; Health, Labour and Welfare Statistics Association. Annual Statistical Report of National Health Conditions. J Health Welfare Stat 2013; 60: 101 (in Japanese). 30 McLaughlin T, Abbasi F, Cheal K, Chu J, Lamendola C, Reaven G. Use of metabolic markers to identify overweight individuals who are insulin resistant. Ann Intern Med 2003; 139: 802–809. 31 Sumner AE, Finley KB, Genovese DJ, Criqui MH, Boston RC. Fasting triglyceride and the triglyceride-HDL cholesterol ratio are not markers of insulin resistance in African Americans. Arch Intern Med 2005; 165: 1395–1400. 32 Mostafa SA, Davies MJ, Morris DH, Yates T, Srinivasan BT, Webb D et al. The association of the triglyceride-to-HDL cholesterol ratio with insulin resistance in White European and South Asian men and women. PLoS ONE 2012; 7: e50931.
Journal of Human Hypertension (2015) 359 – 365
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ORIGINAL ARTICLE
Light-to-moderate alcohol intake reduces lipid accumulation product and attenuates its relation to hypertension I Wakabayashi Lipid accumulation product (LAP), an index calculated by using triglyceride level and waist circumference, has been shown to predict hypertension, diabetes and cardiovascular disease. Alcohol is known to influence blood pressure and blood lipids. The aim of this study was to clarify the relationships among alcohol intake, LAP and hypertension. The subjects, middle-aged Japanese men (n = 21 572), were divided into non-, light ( o22 g ethanol per day), moderate (⩾22 and o44 g ethanol per day) and heavy (⩾44 g ethanol per day) drinkers. The relationships between alcohol intake and LAP and between LAP and hypertension were investigated. There were U- and J-shaped relationships between alcohol intake and LAP in subjects with and without hypertension, respectively. The adjusted odds ratios with their 95% confidence intervals for hypertension in subjects with vs subjects without high LAP were 3.04 (2.69–3.43, P o 0.01), 2.32 (1.92–2.81, P o 0.01), 2.10 (1.89–2.33, Po 0.01) and 2.11 (1.87–2.38, P o0.01) in non-, light, moderate and heavy drinkers, respectively. Thus, the positive association between LAP and hypertension is weaker in drinkers than in nondrinkers. The results suggest that light-to-moderate alcohol drinking reduces LAP level in patients with hypertension and attenuates the relation of LAP to hypertension. Journal of Human Hypertension (2015) 29, 359–365; doi:10.1038/jhh.2014.97; published online 13 November 2014
INTRODUCTION The risk of cardiovascular disease is known to be lower in light-tomoderate alcohol drinkers than in nondrinkers.1,2 The preventive effect of alcohol is based on its antiatherosclerotic action, which is mainly explained by alteration in blood lipid concentrations, especially that of high-density lipoprotein (HDL) cholesterol.3,4 In addition, alcohol-induced inhibition of the blood coagulation system, including platelet aggregation and coagulation factors, is involved in the antiatherosclerotic action of alcohol.5 On the other hand, alcohol drinking is an important risk factor of hypertension.6,7 Moreover, excessive alcohol consumption is known to result in elevation of triglyceride (TG) level,8,9 which has been shown to be an independent cardiovascular risk factor.10,11 Thus, alcohol drinking shows both beneficial and detrimental effects on the progression of atherosclerosis depending on the amount of alcohol consumption. Obesity is also a major risk factor for cardiovascular disease as it deteriorates insulin sensitivity, blood lipid metabolism and blood pressure regulation.12 However, there is still debate regarding whether and how alcohol drinking influences the risk for obesity.13,14 Lipid accumulation product (LAP), calculated by using TG level and waist circumference (WC), has been shown to be associated with the risk of cardiovascular events15,16 and to predict all-cause mortality in nondiabetic patients at high risk for cardiovascular diseases.17 LAP has been reported to be better than body mass index in discriminating diabetes.18,19 LAP has also been shown to predict blood pressure.15 LAP has been reported to be lower in light drinkers, higher in heavy drinkers and not different in moderate drinkers when compared with nondrinkers, and there is therefore a J-shaped relationship between alcohol intake and LAP in the general population20 and in patients with diabetes.21 However, it remains to be elucidated how alcohol intake
influences LAP in patients with hypertension. In addition, it is unknown whether the relationship between LAP and blood pressure is modified by alcohol drinking. The purpose of this study was therefore to clarify the relationships among alcohol consumption, LAP and hypertension. SUBJECTS AND METHODS Subjects The subjects were Japanese men aged 35–60 years (n = 21 572) who had received periodic health checkup examinations at workplaces in Yamagata Prefecture in Japan. The subjects were recruited from a list of people receiving a set of annual health checkup examinations from April 2008 to March 2009. Histories of alcohol consumption, cigarette smoking, regular exercise (almost every day for 30 min or longer per day), illness and therapy for illness were surveyed by questionnaires. The proportion of men receiving lipid-lowering drug therapy was 4.7% in the original database, and they were excluded from the subjects for analysis in this study because lipid-lowering drug therapy was expected to considerably influence LAP levels. A cross-sectional study was performed using a local population-based database for the above subjects. This study was approved by the Ethics Committee of Yamagata University School of Medicine.
Evaluation of alcohol consumption The average alcohol consumption of each subject per week was reported on questionnaires. Among the overall number of subjects having annual health checkups in the original database, nondrinkers, regular drinkers and occasional drinkers were 20.8%, 45.9% and 33.3%, respectively. Since it is difficult to know the correct average alcohol consumption of occasional drinkers, only regular drinkers who drink almost every day were used as drinkers for analysis in this study. Occasional drinkers were thus excluded from subjects for analysis. The usual daily alcohol consumption was calculated in terms of the equivalent number of ‘go’, a traditional Japanese
Department of Environmental and Preventive Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan. Correspondence: Dr I Wakabayashi, Department of Environmental and Preventive Medicine, Hyogo College of Medicine, Mukogawa-cho 1-1, Nishinomiya, Hyogo 663-8501, Japan. E-mail: [email protected] Received 28 April 2014; revised 6 August 2014; accepted 18 September 2014; published online 13 November 2014
Alcohol intake, LAP and hypertension I Wakabayashi
360 unit of the amount of sake (rice wine). The amounts of other alcoholic beverages, including beer, wine, whisky and shochu (traditional Japanese distilled spirit), were converted and expressed as units of ‘go’. One go approximately corresponds to 180 ml of sake, 500 ml of beer, 240 ml of wine, 60 ml of whisky and 80 ml of shochu. The amount of daily alcohol drinking was categorized as ‘null’, ‘less than 1 go per day’, ‘1 go or more and less than 2 go per day’, ‘2 go or more and less than 3 go per day’ and ‘3 go or more per day’. One ‘go’ contains about 22 g of ethanol, and this amount was used to separate moderate drinkers from light drinkers since it is generally accepted that alcohol intake should be reduced to o30 ml or 20–30 g per day from the viewpoint of prevention of hypertension.22–24 The subjects were divided into four groups according to ethanol consumption per day (nondrinkers; light drinkers: o22 g of ethanol per day; moderate drinkers: ⩾ 22 g buto44 g of ethanol per day; heavy drinkers: ⩾ 44 g ethanol per day).
Measurements WC was measured at the navel level according to its definition by the Japanese Committee for the Diagnostic Criteria of Metabolic Syndrome.25 Blood pressure was measured by trained nurses, who were part of the local health-checkup company, with a mercury sphygmomanometer once on the day of the health checkup after each subject had rested quietly in a sitting position. Korotkoff phase V was used to define diastolic pressure. Normal blood pressure was defined as a systolic blood pressure of o140 mm Hg and a diastolic blood pressure of o 90 mm Hg. Hypertension was defined as a systolic blood pressure of ⩾ 140 mm Hg and/or a diastolic blood pressure of ⩾ 90 mm Hg. Subjects receiving medication therapy for hypertension were also included in the hypertensive group. Fasted blood was sampled from each subject in the morning, and serum TG concentrations were measured by the enzymatic method using a commercial kit named Pureauto S TG-N (Sekisui Medical Co., Ltd, Tokyo, Japan). The coefficient of variation for reproducibility of measurement of TGs was ⩽ 3%. LAP was determined by using TGs and WC as follows:15 LAP = TGs (mmol l − 1) × (WC (cm) − 65). The cutoff value of high LAP was defined as 37.2.26 Serum HDL cholesterol and low-density lipoprotein (LDL) cholesterol were measured by the enzymatic methods using commercial kits named Cholestest N-HDL and Cholestest LDL (Sekisui Medical Co., Ltd), respectively. Hemoglobin A1c was measured by using the latex cohesion method and standardized as previously described.27 Coefficients of variation for reproducibility of HDL cholesterol, LDL cholesterol and hemoglobin A1c measurements were ⩽ 5%. Metabolic syndrome was defined according to the criteria by the National Cholesterol Education Program’s Adult Treatment Panel III (NCEP-ATP III)28 as described previously.27
Statistical analysis Statistical analyses were performed using a computer software program (SPSS version 16.0J for Windows, Chicago, IL, USA). Percentages of smokers, drinkers, subjects doing exercise regularly, subjects receiving medical therapy for hypertension and subjects showing high LAP were compared between the normotensive and hypertensive groups using the chi-square test for independence. In univariate analysis, means of each variable were compared between the normotensive and hypertensive groups by using the unpaired Student’s t test. Since TGs and LAP did not show normal distributions, they were compared between the groups nonparametrically by using the Mann–Whitney U-test. In multivariate analysis, mean levels of each variable were compared by using analysis of covariance followed by the Student’s t-test after the Bonferroni correction, and the data of TGs and LAP were used after logarithm transformation. In linear regression analysis, Pearson’s correlation coefficients and standardized partial regression coefficients were calculated. Pearson’s correlation coefficients were compared in two different variable pairs by using the Fisher z-transformation applied to the sample correlation coefficients. In logistic regression analysis, crude and adjusted odds ratios for high LAP or hypertension were estimated. Crude odds ratios were compared between the normotensive and hypertensive groups and between each drinker group and the nondrinker group by using the Breslow–Day test. Age and histories of smoking and regular exercise were used as other explanatory variables or covariables in multivariate analyses. In some analyses, a history of medication therapy for hypertension was also added to the explanatory variables or covariables. Probability (P) values o0.05 were defined as significant. Two-tailed P values were used to evaluate statistical significance. Journal of Human Hypertension (2015) 359 – 365
RESULTS Characteristics of subjects Profiles of the subject groups showing normal blood pressure and hypertension are presented in Table 1. The subjects with hypertension were significantly older than those with normal blood pressure. Moderate and heavy drinkers as well as total drinkers were significantly higher in proportion in the hypertensive group than in the normotensive group, while the proportions of subjects with smoking habit and regular exercise were lower in the hypertensive group than in the normotensive group. WC, TGs, LDL cholesterol, ratio of LDL cholesterol to HDL cholesterol (LDLC/HDL-C ratio) and LAP were significantly higher in the hypertensive group than in the normotensive group, while HDL cholesterol was slightly but significantly lower in the hypertensive group than in the normotensive group. The proportion of subjects showing high LAP levels was significantly higher in the hypertensive group than in the normotensive group. Comparison of systolic and diastolic blood pressure levels among the alcohol groups Means of systolic and diastolic blood pressure of non-, light, moderate and heavy drinkers in the overall subjects are shown in Figure 1. Both systolic and diastolic blood pressure levels tended to be higher with an increase in alcohol intake and were significantly higher in light, moderate and heavy drinkers than in nondrinkers. Comparison of LAP, TGs and WC among the alcohol groups Figure 2 shows the means of log-transformed LAP (Figure 2a), logtransformed TGs (Figure 2b) and WC (Figure 2c) of non-, light, moderate and heavy drinkers in the normotensive and Table 1.
Characteristics of the normotensive and hypertensive subject
groups
Number Age (years) Drinkers (%) Light Moderate Heavy Total
Normotensive
Hypertensive
14175 47.0 ± 7.5
7397 50.6 ± 7.0**
12.5 34.2 19.4 66.1
10.2** 39.1** 28.8** 78.1**
Smokers (%) 63.6 55.9** Regular exercise (%) 10.1 9.3# Medical therapy for 0 30.0** hypertension (%) Waist circumference (cm) 81.6 ± 8.1 86.5 ± 9.0** Systolic blood pressure 121.8 ± 10.8 145.9 ± 14.2** (mm Hg) Diastolic blood pressure 73.7 ± 8.4 88.7 ± 10.5** (mm Hg) 1.24 (0.82, 1.93) 1.55 (1.02, 2.39)** Triglycerides (mM) HDL cholesterol (mg/dl) 57.7 ± 15.4 57.1 ± 15.4** LDL cholesterol (mg/dl) 114.3 ± 31.1 116.0 ± 32.4** LDL-C/HDL-C ratio 2.147 ± 0.874 2.199 ± 0.888** LAP 19.86 (9.72, 37.61) 32.61 (17.72, 56.27)** High LAP (%) 25.4 43.5** Abbreviations: LDL-C/HDL-C ratio, ratio of LDL cholesterol to HDL cholesterol; LAP, lipid accumulation product. Numbers, percentages of subjects, means with standard deviations, and medians with 25th and 75th percentile values indicated in the parentheses are shown. Asterisks denote significant differences from the normotensive group (**Po 0.01). Marginally significant difference (#P = 0.055).
© 2015 Macmillan Publishers Limited
Alcohol intake, LAP and hypertension I Wakabayashi
361 Nondrinkers Light drinkers Moderate drinkers Heavy drinkers
134 132
** **
130
Nondrinkers Light drinkers Moderate drinkers Heavy drinkers
82
Diastolic blood pressure (mmHg)
Systolic blood pressure (mmHg)
136
**
128 126 124 122 120
80
** **
**
78 76 74 72 70
Figure 1. Comparison of systolic and diastolic blood pressure levels among non-, light, moderate and heavy drinkers in the overall subjects. Mean levels of systolic blood pressure (a) and diastolic blood pressure (b) calculated after adjustment for age and histories of smoking, regular exercise and medication therapy for hypertension are shown. Asterisks denote significant differences from nondrinkers (P o0.01).
**
**
1.4 **
1.3 *
1.2 1.1
0.2 **
0.15 0.1
**
**
0.05 0
1
Normotensive
Hypertensive
90
**
Waist circumference (cm)
1.5
Log(LAP)
Nondrinkers Light drinkers Moderate drinkers Heavy drinkers
0.25
Log(triglycerides [mM])
1.6
Nondrinkers Light drinkers Moderate drinkers Heavy drinkers
Nondrinkers Light drinkers Moderate drinkers Heavy drinkers
88 ** ** **
86 84 82
*
80 78 76
Normotensive
Hypertensive
Normotensive
Hypertensive
Figure 2. Comparison of LAP, triglycerides and waist circumference among non-, light, moderate and heavy drinkers in the normotensive or hypertensive group. Mean levels of log-transformed LAP (a), log-transformed triglycerides (b) and waist circumference (c) calculated after adjustment for age and histories of smoking and regular exercise are shown. In the hypertensive group, a history of medication therapy for hypertension was also added as an explanatory covariable. Asterisks denote significant differences from nondrinkers (*P o0.05; **Po 0.01).
hypertensive groups. In the normotensive group, log-transformed LAP was significantly lower in light drinkers, significantly higher in heavy drinkers and not different in moderate drinkers when compared with nondrinkers. In the hypertensive group, logtransformed LAP was significantly lower in light and moderate drinkers than in nondrinkers, and was not significantly different in heavy drinkers and nondrinkers. Both in the normotensive and hypertensive groups, log-transformed TG levels were significantly lower in light drinkers and higher in heavy drinkers and were not significantly different in moderate drinkers when compared with nondrinkers. In the normotensive group, WC was significantly smaller in light drinkers than in nondrinkers and was not significantly different in non-, moderate and heavy drinkers. In the hypertensive group, WC was significantly smaller in light, moderate and heavy drinkers than in nondrinkers. Comparison of LAP between the subject groups with and without metabolic syndrome Overall, the proportion of subjects with metabolic syndrome was 18.0%. In the subjects with metabolic syndrome, log-transformed LAP after adjustment for age and histories of alcohol drinking, smoking and regular exercise was significantly higher than that in the subjects without metabolic syndrome (1.256 ± 0.003 vs 1.785 ± 0.006, P o 0.01). This finding is reasonable because the © 2015 Macmillan Publishers Limited
components of LAP, including WC and level of TGs, are included in the criteria of metabolic syndrome.28 Odds ratio for high LAP in each drinker group vs the nondrinker group Table 2 shows the results of logistic regression analysis regarding the relationships between alcohol intake and high LAP. In the hypertensive group, crude and adjusted odds ratios vs nondrinkers for high LAP were significantly lower than the reference level of 1.00 in light and moderate drinkers. In the normotensive group, crude and adjusted odds ratios vs nondrinkers for high LAP were significantly lower and higher than the reference level in light and heavy drinkers, respectively, and were not significantly different from the reference level in moderate drinkers. The crude odds ratios for high LAP in moderate and heavy drinkers vs nondrinkers were significantly lower in the hypertensive group than in the normotensive group, and the odds ratio in light drinkers vs nondrinkers was marginally significantly lower (P = 0.052) in the hypertensive group than in the normotensive group. In order to determine whether the above associations of alcohol use with LAP were different in normotensive and hypertensive subjects, the odds ratio for high LAP of the interaction term consisting of drinker category (light, moderate or heavy drinkers vs nondrinkers) and blood pressure status (hypertensive vs Journal of Human Hypertension (2015) 359 – 365
Alcohol intake, LAP and hypertension I Wakabayashi
362 normotensive) was investigated. As shown in Table 2, odds ratios for high LAP of the interaction term were significantly lower than the reference level of 1.00 in moderate and heavy drinkers. Thus, significant interaction of alcohol drinking and blood pressure status was found for high LAP, and this implies that the degree of the association between alcohol drinking and LAP was different in subjects with and those without hypertension. Correlation coefficients between LAP and blood pressure in the different alcohol groups Table 3 shows the results of linear regression analysis regarding the relationships between LAP and blood pressure. Pearson’s correlation coefficients and standardized partial regression coefficients between LAP and systolic or diastolic blood pressure were Table 2.
significant in all of the alcohol groups. Thus, both in the univariate and multivariate analyses, there were significant positive correlations of LAP with systolic and diastolic blood pressures. Pearson’s correlation coefficients between LAP and systolic or diastolic blood pressure were significantly lower in light, moderate and heavy drinkers than in nondrinkers, except for a marginally significant difference (P = 0.053) between light drinkers and nondrinkers in the coefficient of LAP with diastolic blood pressure. The correlation coefficients tended to be lower with an increase in alcohol intake. Odds ratio for hypertension in subjects with vs subjects without high LAP in each alcohol group Table 4 shows the results of logistic regression analysis regarding the relationships between LAP and hypertension. Crude and
Odds ratios for high LAP of each drinker subgroup vs the nondrinker subgroup in the normotensive and hypertensive groups Nondrinkers (n = 6430)
Light drinkers (n = 2524)
Normotensive Crude OR Adjusted OR
1.00 1.00
0.78 (0.69–0.89)** 0.78 (0.68–0.89)**
0.97 (0.88–1.06) 0.96 (0.87–1.05)
1.21 (1.09–1.35)** 1.18 (1.06–1.31)**
Hypertensive Crude OR Adjusted OR
1.00 1.00
0.63 (0.53–0.75)**,# 0.66 (0.55–0.79)**
0.68 (0.60–0.77)**,†† 0.72 (0.63–0.81)**
0.87 (0.76–0.99)*,†† 0.93 (0.81–1.06)
0.81 (0.65–1.01)
0.71 (0.61–0.83)**
0.72 (0.61–0.85)**
Overall OR of interaction term
—
Moderate drinkers (n = 7741)
Heavy drinkers (n = 4877)
Abbreviations: LAP, lipid accumulation product; OR, odds ratio. Crude and adjusted ORs with their 95% confidence intervals indicated in the parentheses are shown. Adjusted odds ratios for high LAP of each drinker subgroup vs the nondrinker subgroup in the normotensive and hypertensive groups were estimated using age, smoking, regular exercise and a history of medication therapy for hypertension as other explanatory variables. Odds ratios for high LAP of the interaction term consisting of drinker category (each drinker subgroup vs the nondrinker subgroup) and hypertension (yes vs no) were estimated by using drinker category, hypertension, age, smoking and regular exercise as other explanatory variables. Symbols denote significantly lower odds ratios compared with the reference level of 1.00 (*Po0.05; **Po0.01) and significant differences from the normotensive group (††Po0.01). Marginally significant difference from the normotensive group (#P = 0.052).
Table 3.
Correlations between LAP and systolic or diastolic blood pressure in non-, light, moderate and heavy drinkers Nondrinkers (n = 6430)
Light drinkers (n = 2524)
Moderate drinkers (n = 7741)
Heavy drinkers (n = 4877)
Systolic blood pressure Pearson’s coefficient Standardized coefficient
0.346** 0.327**
0.271**,†† 0.245**
0.256**,†† 0.238**
0.215**,†† 0.203**
Diastolic blood pressure Pearson’s coefficient Standardized coefficient
0.350** 0.335**
0.296**,# 0.275**
0.255**,†† 0.240**
0.239**,†† 0.229**
Abbreviation: LAP, lipid accumulation product. Pearson’s correlation coefficients and standardized partial regression coefficient for relationships of logtransformed LAP with systolic or diastolic blood pressure were calculated. Age, smoking status, a habit of regular exercise and a history of medication therapy for hypertension were used as other explanatory variables in the multivariate regression analysis. Symbols denote significant correlations (**Po0.01) and significant differences from nondrinkers (††Po0.01). #Marginally significant difference from nondrinkers (P = 0.053).
Table 4.
Odds ratios for hypertension of subjects with vs those without high LAP in non-, light, moderate and heavy drinkers
Crude OR Adjusted OR OR of interaction term
Nondrinkers (n = 6430)
Light drinkers (n = 2524)
Moderate drinkers (n = 7741)
Heavy drinkers (n = 4877)
2.86 (2.55–3.22)** 3.04 (2.69–3.43)** 1.00
2.30 (1.91–2.77)**,# 2.32 (1.92–2.81)** 0.75 (0.60–0.94)*
2.01 (1.82–2.22)**,†† 2.10 (1.89–2.33)** 0.67 (0.57–0.79)**
2.05 (1.82–2.31)**,†† 2.11 (1.87–2.38)** 0.69 (0.58–0.81)**
Abbreviations: LAP, lipid accumulation product; OR, odds ratio. Crude and adjusted ORs with their 95% confidence intervals indicated in the parentheses are shown. Adjusted odds ratios for hypertension were estimated using age, smoking and regular exercise as other explanatory variables. Odds ratios of the interaction term consisting of drinker category (each drinker group vs nondrinkers) and LAP (high vs not high) were estimated by using drinker category, LAP, age, smoking and regular exercise as other explanatory variables. Symbols denote significantly higher odds ratios compared with the reference level of 1.00 (*Po0.05; **P o0.01) and significant differences from nondrinkers (††Po0.01). Marginally significant difference from nondrinkers (#P = 0.052).
Journal of Human Hypertension (2015) 359 – 365
© 2015 Macmillan Publishers Limited
Alcohol intake, LAP and hypertension I Wakabayashi
363 relationship between alcohol intake and LAP in normotensive men, which agrees with the finding of a previous study for a general population.20 The results of the present study suggest that light-to-moderate drinking reduces LAP level in hypertensive men and agree with the results of previous studies showing an inverted relationship between light-to-moderate drinking and risk of cardiovascular disease.1,2 In a general population, LAP has been shown to be lower in light drinkers, higher in heavy drinkers and not different in moderate drinkers when compared with nondrinkers, and thus a J-shaped relationship was found between alcohol intake and LAP.20 A similar J-shaped relationship between alcohol intake and LAP has been reported in patients with diabetes21 and was found in the subjects without hypertension in the present study. The present study is the first to show the relationship of LAP with alcohol use in patients with hypertension, and demonstrated that LAP was significantly lower in light and moderate drinkers than in nondrinkers and was not significantly different in heavy drinkers and nondrinkers. Thus, there was a U-shaped relationship between alcohol intake and LAP in patients with hypertension. In summary, between alcohol and LAP, there was a J-shaped relationship in the general population, in persons without hypertension and in patients with diabetes, while there was a U-shaped relationship in patients with hypertension. Thus, the alcohol–LAP relationship is thought to be modified in hypertensive patients but not in diabetic patients. While the association of alcohol drinking with LAP was different in subjects with and those without hypertension, the associations of alcohol drinking with HDL cholesterol, LDL cholesterol and LDL-C/HDL-C ratio were similar in normotensive and hypertensive subjects (Figure 3). Alcohol is known to be a major risk factor of hypertension.6,7 In fact, systolic and diastolic blood pressure levels were significantly higher in light, moderate and heavy drinkers than in nondrinkers and tended to be higher with an increase in alcohol intake (Figure 1). In addition, the proportions of total drinkers and moderate or heavy drinkers were higher in subjects with hypertension than in subjects without hypertension (Table 1). Thus, it is obvious that alcohol is positively associated with blood pressure. Accordingly, even light-to-moderate drinking should not be recommended to patients with hypertension. LAP is calculated by using TGs and WC. The relationship between alcohol and TGs was similar in subjects with and without hypertension: In both groups of subjects, there was a J-shaped relationship between alcohol intake and TGs. However, there was a difference in the relationship of alcohol with WC in these groups. In the hypertensive group WC, was significantly smaller in light, moderate and heavy drinkers than in nondrinkers, while in the normotensive group WC, was significantly smaller in light drinkers
adjusted odds ratios for hypertension in subjects with vs those without high LAP were significantly higher than the reference level of 1.00 in all of the alcohol groups. The crude odds ratio was significantly lower in moderate and heavy drinkers than in nondrinkers and was marginally significantly lower (P = 0.052) in light drinkers than in nondrinkers. Whether alcohol use influences the relationship of high LAP with hypertension was investigated using an interaction term consisting of drinker category (light, moderate or heavy drinkers vs nondrinkers) and LAP level (high LAP vs not high LAP). As shown in Table 4, odds ratios for hypertension of the interaction terms were significantly lower than the reference level of 1.00 in light, moderate and heavy drinkers. Thus, a significant interaction of alcohol drinking and LAP was found for hypertension, and this implies that the positive association between LAP and blood pressure was weakened by alcohol drinking. Comparison of HDL cholesterol, LDL cholesterol and LDL-C/HDL-C ratio among the alcohol groups In both the normotensive and hypertensive groups, LDL cholesterol and LDL-C/HDL-C ratio were significantly lower and HDL cholesterol was significantly higher in each drinker group when compared with nondrinkers (Figure 3). In both of the groups, LDL cholesterol and LDL-C/HDL-C ratio tended to be lower with an increase in alcohol intake, while HDL cholesterol tended to be higher with an increase in alcohol intake (Figure 3). DISCUSSION This study demonstrated for the first time that the relationship between alcohol intake and LAP is different in men with and those without hypertension. In subjects with hypertension, LAP was significantly lower in light and moderate drinkers than in nondrinkers and was not significantly different in nondrinkers and heavy drinkers (Figure 2a); odds ratio vs nondrinkers for high LAP was significantly lower than the reference level in light and moderate drinkers and was not significantly different from the reference level in heavy drinkers (Table 2). Thus, there was a U-shaped relationship between alcohol intake and LAP in subjects with hypertension. In subjects without hypertension, LAP was significantly lower and higher in light and heavy drinkers, respectively, and was not significantly different in moderate drinkers, when compared with nondrinkers (Figure 2a); odds ratio vs nondrinkers for high LAP was significantly lower and higher than the reference level in light and heavy drinkers, respectively, and was not significantly different from the reference level in moderate drinkers (Table 2). Thus, there was a J-shaped
65
135 130
** **
**
60
**
**
**
55 50 45
Nondrinkers Light drinkers Moderate drinkers Heavy drinkers
3 2.8
125 **
120 115 110
**
** ** **
**
LDL-C/HDL-C ratio
Nondrinkers Light drinkers Moderate drinkers Heavy drinkers
LDL cholesterol (mg/dl)
HDL cholesterol (mg/dl)
70
Nondrinkers Light drinkers Moderate drinkers Heavy drinkers
2.6 2.4 2.2 2 1.8
** **
** **
** **
105 1.6
40
Normotensive
Hypertensive
100
Normotensive
Hypertensive
Normotensive
Hypertensive
Figure 3. Comparison of HDL cholesterol, LDL cholesterol and ratio of LDL cholesterol to HDL cholesterol (LDL-C/HDL-C ratio) among non-, light, moderate and heavy drinkers in the normotensive or hypertensive group. Mean levels of HDL cholesterol (a), LDL cholesterol (b) and LDL-C/HDL-C ratio (c) calculated after adjustment for age and histories of smoking and regular exercise are shown. In the hypertensive group, a history of medication therapy for hypertension was also added as an explanatory covariable. Asterisks denote significant differences from nondrinkers (P o0.01). © 2015 Macmillan Publishers Limited
Journal of Human Hypertension (2015) 359 – 365
Alcohol intake, LAP and hypertension I Wakabayashi
364 but not in moderate and heavy drinkers when compared with nondrinkers. Therefore, the difference in the relationships between alcohol intake and LAP, namely, J-shaped and U-shaped relationships, in the normotensive and hypertensive groups, respectively, is attributed to the difference in the relationship between alcohol intake and WC. The LAP level was significantly higher in the hypertensive group than in the normotensive group (Table 1) and showed a significant positive correlation with blood pressure (Table 3); the odds ratio for hypertension in subjects with vs those without high LAP was significantly higher than the reference level of 1.00 (Table 4). Thus, there is a positive association between LAP level and blood pressure. This study is also the first to show that the positive association of LAP with blood pressure was weaker in drinkers than in nondrinkers: the correlation coefficient between LAP and blood pressure was lower in drinkers than in nondrinkers (Table 3), and odds ratio for hypertension in subjects with vs those without high LAP was also lower in drinkers than in nondrinkers (Table 4). Moreover, odds ratios for hypertension of the interaction term consisting of alcohol and high LAP were lower than the reference level in all of the drinker groups (Table 4). These findings suggest that alcohol drinking not only influences LAP level but also confounds the relationship between LAP and blood pressure and therefore should be taken into account when LAP is used as a predictor of cardiovascular disease. This study has limitations. First, blood pressure was measured only once at the health checkup for each subject. Thus, there is an informational bias regarding blood pressure levels. Although age, history of medication therapy for hypertension, smoking status and history of regular exercise were adjusted in the multivariate analyses, there are other factors, for example, diet, nutrition and socioeconomic status, which possibly confound the relationships among alcohol intake, LAP and blood pressure. In addition, detailed information on the kind of alcohol beverages consumed by each subject was not available in this study, and there is a possibility that difference in alcohol beverage influences the association between alcohol intake and LAP. Although drugs used for hypertension possibly affected LAP levels, the kinds of antihypertensive drugs were not identified in the questionnaire at health checkup. In the present study, the proportion of smokers was 61.0% in overall subjects and thus much higher than that of overall Japanese men in 2008 (when the health check-ups were mainly performed) by the national statistic, which was 36.8%.29 Thus, there is a possibility of confounding by smoking for the relationship between alcohol and LAP, although smoking history was added to the explanatory variables and covariables in multivariate analyses. In the univariate analysis using data of overall subjects, medians of LAP, with its 25th and 75th percentile values in parentheses, were 23.25 (11.06, 43.70), 21.05 (10.55, 38.14), 23.34 (12.01, 43.05) and 26.37 (13.62, 50.28) in non-, light, moderate and heavy drinkers, respectively. Thus, changes in LAP by alcohol drinking were small and might not be clinically applicable in an individual person. The subjects of this study were all Japanese men, and there is a possibility of gender- or ethnicityrelated difference in the above relationships. The ratio of TGs to HDL cholesterol (TG/HDL-C ratio) is another good predictor for cardiovascular disease, and ethnicity-related differences have been reported in the relationship between insulin resistance and TG/HDL-C ratio: TG/HDL-C ratio has been reported to be a marker of insulin resistance in the subjects, of whom 87% were white, but not in African Americans.30,31 Furthermore, there was a significant positive association between TG/HDL-C ratio and insulin resistance in White European women but not in South Asian women.32 The medians with 25th and 75th percentile values of LAP level in US adult men from the third National Health and Nutrition Examination Survey (NHANES III) were 35.5 (20.1, 63.2) in men at 25–49 years of age and 53.4 (33.3, 85.6) in men at 50 years of age or older,15 which were higher than the median levels of LAP in the Journal of Human Hypertension (2015) 359 – 365
Japanese male subjects at 35–60 years of age in the present study (Table 1). Thus, a considerable ethnicity-related difference must exist in LAP level. Therefore, future studies are needed to determine whether people with other ethnicities also show the J-shaped and U-shaped associations of LAP with alcohol use in normotensive and hypertensive persons, respectively, found in the present study. Finally, further prospective studies are needed to conclude the causality of the findings of this study, which is crosssectional in its design. In conclusion, there was a U-shaped relationship between alcohol intake and LAP in men with hypertension, and the positive association between LAP and hypertension was weaker in light, moderate and heavy drinkers than in nondrinkers. Thus, light-tomoderate drinking is thought to lower LAP and attenuate its relationship with hypertension. What is known about this topic ● Lipid accumulation product (LAP) is a predictor for hypertension, diabetes and cardiovascular disease. ● A J-shaped relationship has been reported between alcohol intake and LAP in a general population. ● It remains to be elucidated how alcohol intake influences LAP in patients with hypertension. ● It is unknown whether the relationship of LAP with blood pressure is modified by alcohol drinking. What this study adds ● This study shows for the first time that light-to-moderate alcohol drinking is inversely associated with LAP in patients with hypertension and that the relationship of LAP with hypertension is weaker in light-to-moderate drinkers than in nondrinkers.
CONFLICT OF INTEREST The author declares no conflict of interest.
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