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Influence of the Flushing Response in the Relationship between Alcohol Consumption and Cardiovascular Disease Risk

Background The purpose of this study was to examine the relationship between cardiovascular disease risk and alcohol consumption according to facial flushing after drinking among Korean men. Methods The subjects were 1,817 Korean men (non-drinker group, 283 men; drinking-related facial flushing group, 662 men; non-flushing group, 872 men) >30 years who had undergone comprehensive health examinations at the health promotion center of a Chungnam National University Hospital between 2007 and 2009. Alcohol consumption and alcohol-related facial flushing were assessed through a questionnaire. Cardiovascular disease risk was investigated based on the 2008 Framingham Heart Study. With the non-drinker group as reference, logistic regression was used to analyze the relationship between weekly alcohol intake and cardiovascular disease risk within 10 years for the flushing and non-flushing groups, with adjustment for confounding factors such as body mass index, diastolic blood pressure, low density lipoprotein cholesterol, triglycerides, and exercise patterns. Results Individuals in the non-flushing group with alcohol consumption of ≤4 standard drinks (1 standard drink = 14 g of alcohol) per week had significantly lower moderate or high cardiovascular disease risk than individuals in the nondrinker group (adjusted odds ratio, 0.51; 95% confidence interval, 0.37 to 0.71). However, no significant relationship between the drinking amount and cardiovascular disease risk was observed in the flushing group. Conclusion Cardiovascular disease risk is likely lowered by alcohol consumption among non-flushers, and the relationship between the drinking amount and cardiovascular disease risk may differ according to facial flushing after drinking, representing an individual's vulnerability.


INTRODUCTION
Deaths caused by cardiovascular disease are gradually increasing worldwide, including in Korea. 1) The increase in the elderly population has been suggested as a fundamental cause.
Further, the westernized life style attributable to the improved economy in developing countries is also a factor. In other words, cardiovascular disease risk increases with a decrease in Korean J Fam Med physical activity and an increase in obesity risk resulting from the conveniences of life such as changes in dietary habits, and automobile use. Thus, cardiovascular disease is emerging as an increasingly important public health problem.
The underlying diseases that could lead to cardiovascular disease include diabetes, hypertension, and dyslipidemia. The major factors causing cardiovascular diseases in adults are those related to lifestyle such as drinking, smoking, lack of exercise, stress, and eating habits. 2,3) Among these factors, drinking is popular among the Korean people, and hence, examining its influence on the development of cardiovascular disease may be important in promoting public health.
A small amount of 1 to 2 drinks of alcohol per day is known to reduce the risk of cardiovascular disease. Several studies have identified a J-or U-shaped relationship between alcohol consumption and cardiovascular disease risk. Corrao et al. 4) reported that individuals who drink ≤ 20 g of alcohol a day have a significantly lower relative risk (0.8) of coronary heart disease than those who do not drink at all, and even up to 72 g of alcohol a day may have a protective effect on the risk of coronary heart disease. Furthermore, Muntwyler et al. 5) also showed that alcohol consumption lowers the risk of cardiovascular disease. On observing individuals in a cohort of the Physicians' Health Study with a history of myocardial infarction for 5 years, they found that consumption of 1 to 4 drinks a month had a 0.85 relative risk of death; 2 to 4 drinks a week, a 0.79 relative risk of death; and 2 to 4 drinks a day, a 0.84 relative risk of death compared to not drinking at all. In that study, 1 cup of liquor or 1 glass of wine was considered as 1 drink (14 g alcohol). These results indicate a protective effect of alcohol consumption on cardiovascular disease as alcohol increases high density lipoprotein (HDL) cholesterol and inhibits blood coagulation and platelet aggregation. In contrast, Shaper and Wannamethee 6) reported that the relative risk of death increases to 1.05 when people with myocardial infarction drink > 3 drinks a day compared to 'occasional drinkers' who drink 1 to 2 drinks a month, with 8 to 10 g of alcohol being considered as 1 drink.
With regard to alcohol-related flushing symptoms, for individuals who do not flush after drinking, consuming ≤ 4 drinks (1 drink = 14 g alcohol) per week has been reported to improve insulin resistance and health, but for individuals who do flush, alcohol consumption in even small amounts, does not reduce the risk of insulin resistance and rather can increase it. 7) Alcohol is metabolized to acetaldehyde by a number of enzymes. Acetaldehyde is known to interfere with the DNA synthesis and repair mechanism and increases the risk of cancer by generating free radicals. 8) Mutations in the gene encoding aldehyde dehydrogenase 2 (ALDH2), the most important among ALDH isoenzymes that break down acetaldehyde, result in inactive ALDH2. Alcohol consumption in individuals with this inactive form of ALDH2 could result in symptoms such as facial flushing, headache, tachycardia, sweating, and nausea. Inactive ALDH2 is much more common in Asian races, including Korean individuals, than in Westerners. 9) However, currently, there is no research on whether alcoholrelated flushing, which has been suggested to be related to insulin resistance, affects cardiovascular disease risk. Since diabetes occurs in a large proportion of those with cardiovascular disease and many Korean adults have inactive ALDH2, studies regarding alcohol-related flushing are needed. Thus, the present study was performed to investigate whether alcohol-related flushing affects the relationship between alcohol consumption and cardiovascular disease risk in Korean men.

Subjects
We studied 1,817 men over the age of 30 years (non-drinker

Data Collection
Through retrospective reviews of the research subjects' medical records, information was obtained on body measurements, blood tests, and self-administered questionnaires conducted on the day of health screening. The waist circumference was measured at 0.1 cm increments between the iliac crests and the lowest rib while the subject was in an erect position, as recommended by the World Health Organization. 10 Flushing after drinking was surveyed by response options of 'always,' 'sometimes,' and 'not always.' Subjects who responded with 'always' and 'sometimes' were assigned to the flushing group, and those who responded with 'not always' were assigned to the non-flushing group, based on the study by Yokoyama et al. 12) who reported a sensitivity and specificity of 96.1% and 79.0%, respectively, for the identification of inactive ALDH2 when identifying flushing using this method.
Cardiovascular disease risk was evaluated using the Framingham risk score. 13) The Framingham risk score predicts the risk for cardiovascular disease events, i.e., coronary heart disease, cerebrovascular disease, peripheral vascular disease, and heart failure, of each patient within 10 years. This measure is converted into cardiovascular disease risk (%) within 10 years by considering gender, age, total cholesterol, HDL cholesterol, systolic blood pressure, smoking, and presence of diabetes. In the present study, cardiovascular disease risk within 10 years was classified into three groups: <10% (low risk); 10%≤ and <20% (moderate risk); and 20%≤ (high risk).

Statistical Analysis
General characteristics, anthropometric measurements, and blood test results of the facial flushing and non-flushing groups were compared with the non-drinker group. Categorical variables such as smoking status, exercise status, and cardiovascular disease risk classification were compared using the chi-square test.
Continuous variables such as age, BMI, waist circumference, systolic blood pressure, diastolic blood pressure, total cholesterol,

General Characteristics of the Research Subjects
When comparing the general characteristics of the nonflushing and flushing groups with those of the non-drinker group, the mean ± SD age (years) in the flushing group (50.4 ± 9.4) and the non-flushing group (49.7 ± 9.6) was significantly lower than that in the non-drinker group (53.8 ± 9.5). BMI (mean ± SD) in the flushing group (25.1 ± 2.8) was significantly higher than that in the non-drinker group (24.4 ± 3.1). Waist circumference (mean ± SD) in the flushing group was 86.6 ± 7.8 cm, which was significantly higher than that in the non-drinker group (84.6 ± 8.6 cm). With regard to smoking behavior, there were significantly more smokers in the flushing (39.7%) and non-flushing (40.8%) groups than in the non-drinker group (21.9%). With regard to exercise behavior, the non-flushing group had significantly fewer people who did not exercise at all than the non-drinker group.

Korean J Fam Med
Systolic blood pressure in the flushing group was significantly higher than that in the non-drinker group. Diastolic blood pressure in both the flushing and non-flushing groups was significantly higher than that in the non-drinker group. The flushing and non-flushing groups showed significantly higher levels of HDL cholesterol and triglycerides than the non-drinker group. The fasting blood glucose level in the flushing group was significantly higher than that in the non-drinker group. GGT in the non-flushing group was significantly higher than that in the non-drinker group. The Framingham risk score of the nonflushing group was 10.1 ± 4.4 points, which was significantly lower than that in the non-drinker group (10.9 ± 4.4 points).
Total cholesterol, LDL cholesterol, AST, and ALT levels were not significantly different in the flushing and non-flushing groups compared to the non-drinker group (Table 1).  In this study, alcohol consumption was related to a significant reduction in moderate or high cardiovascular disease risk in the subjects in the non-flushing group who consumed ≤4 drinks per week. These results are consistent with those of Gaziano et al., 14) who found that alcohol consumption of 5 to 6 drinks (1 drink = 14 g alcohol) or less per week can lower the death rate and reduce the mortality caused by cardiovascular disease. Our results also appear to coincide with those of Di Castelnuovo et al. 15) in that alcohol consumption of <4 drinks (1 drink = 10 g alcohol) per day in men is associated with a reduction in death   16) and Djousse et al. 17) indicated improved lipid profiles and insulin resistance as the mediating factors in the drinking-related decrease in the mortality caused by cardiovascular disease in women. Arriola et al. 18) reported that blood pressure, cholesterol, and diabetes do not affect the relationship between alcohol consumption and the reduction in cardiovascular mortality. Femia et al. 19) also reported that these factors are irrelevant for the mortality caused by atherosclerosis and heart disease. Therefore, more studies on the potential mechanism underlying alcohol intake-related decrease in the mortality caused by cardiovascular disease will be needed. were targeted in the current study. The drinking behaviors of women have changed because of changes in their social life, and the Framingham risk score for women differs from that for men.
Further research will be needed to target women. Furthermore, a causal relationship cannot be established with certainty because of the cross-sectional study design, and this will have to be investigated further through a cohort study.
In conclusion, the present study suggests that drinking does not reduce the cardiovascular disease risk for men with facial flushing, while alcohol consumption of ≤4 drinks (56 g alcohol) per week is associated with a significant reduction in cardiovascular disease risk for Korean men with no alcoholrelated facial flushing. In addition, the current study suggests that the presence of alcohol-related facial flushing must be considered together with alcohol consumption during health promotion consultation for drinkers.

CONFLICT OF INTEREST
No potential conflict of interest relevant to this article was reported.