1 Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA.
2 Division of General Internal Medicine, University of California, San Francisco, San Francisco, CA.
3 Division of Cardiology, University of California, San Francisco, San Francisco, CA.
4 Division of Preventive Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL.
5 Veterans Affairs Medical Center, Birmingham, AL.
6 Division of Research, Kaiser Permanente, Oakland, CA.
Received for publication July 16, 2004; accepted for publication September 20, 2004.
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ABSTRACT |
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alcohol drinking; calcification, physiologic; calcium; coronary arteriosclerosis; coronary disease; ethanol; heart diseases
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INTRODUCTION |
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Alcohol may affect coronary heart disease through a variety of mechanisms. Moderate consumption of alcohol, for example, has favorable effects on levels of lipids (particularly high density lipoprotein cholesterol) (15), clotting and platelet aggregation (15), systemic inflammation (16), endothelial function (17, 18), and resistance of myocytes to ischemic injury (19), and it has mixed effects on glucose tolerance (2022); heavier alcohol consumption also has detrimental effects on blood pressure (23, 24). Several basic questions remain unanswered, however: Does some combination of these mechanisms explain the J-shaped relation between regular alcohol consumption and clinical coronary heart disease, or are unidentified mechanisms or noncausal associations in play? Why should moderate drinkers who occasionally binge on alcohol not also show lower rates of coronary heart disease than abstainers? If the observed associations are causal, at what stage in the development of clinical coronary heart diseaseatherogenesis, plaque destabilization, platelet aggregation and clot formation, or ischemic injury and cell deathdo moderate alcohol consumption and bingeing exert their effects?
To address these questions, we sought to isolate the relation between alcohol and the development of coronary atherosclerosis. This early pathophysiologic event in the process leading to clinical coronary heart disease may be detected by measuring coronary calcium, a common component of atherosclerotic plaques that occurs only in the context of atherosclerosis (25) and strongly predicts future coronary heart disease events (26). Therefore, we analyzed the relation between usual alcohol consumption, binge drinking, and coronary calcification among 33- to 45-year-old Black and White women and men participating in the Coronary Artery Risk Development in Young Adults (CARDIA) Study.
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MATERIALS AND METHODS |
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Measurement of alcohol consumption
Alcohol consumption was measured during each of the six CARDIA examinations. Participants were asked, "Did you drink any alcoholic beverages in the past year?" and three follow-up questions regarding how many drinks of wine, beer, and liquor they usually consumed per week. Assuming that one drink of beer, wine, or liquor contains 16.7 ml, 17.0 ml, or 19.1 ml of ethanol, respectively (per CARDIA protocol), we estimated total ethanol consumption per week in milliliters of ethanol and divided it by 17.24 ml of ethanol per average drink to estimate the usual number of drinks per week that each participant reported at year 15. Information on binge drinking was elicited separately by asking participants how many times during the past 30 days they had consumed five or more drinks on any one occasion.
Using data from past CARDIA examinations, we identified lifetime abstainers, past drinkers, and occasional drinkers (persons reporting some consumption in the past year but zero drinks in a typical week) and measured usual consumption at the baseline CARDIA examination. We also estimated lifetime alcohol consumption in "drink-years," defining 1 drink-year as the amount of alcohol consumed in 1 year by a person consuming 1 drink/day (365 days/year x 17.24 ml of alcohol/day = 6,293 ml of alcohol). Finally, we categorized current alcohol drinkers by beverage preference. Participants who reported more drinks of wine each week than beer and liquor combined were classified as preferring wine; participants preferring beer and preferring liquor were similarly identified; and participants not meeting these criteria were labeled as having no preference.
Measurement of coronary calcification
Consenting CARDIA participants reporting for their year 15 examination underwent computed tomography scanning with either an Imatron C-150 electron beam scanner (GE Imatron, San Francisco, California), a GE Lightspeed multidetector scanner (General Electric Company, Fairfield, Connecticut), or a Siemens VZ multidetector scanner (Siemens AG, Munich, Germany). A committee composed of cardiologists, radiologists, and a physicist developed a scanning protocol for standardizing scan acquisition across these slightly different technologies; the protocol included two electrocardiogram-gated scans 2.53 mm thick that were completed within 100520 ms on each participant, using a hydroxyapatite phantom to allow standardization of image brightness. With the help of specialized image processing software, cardiovascular radiologists blinded as to participant characteristics identified the presence of coronary calcification in each scan. An expert investigator reviewed and adjudicated all discordant scan pairs. A total coronary calcium score was calculated for each scan by multiplying the area of the focus by a coefficient ranging between 1 and 4 based on the peak density in the focus (1 = 131200 Hounsfield units (HU), 2 = 201300 HU, 3 = 301400 HU, and 4 = 401 HU), according to the method described by Agatston et al. (29). All readers were blinded to participant characteristics, as well as to image data from the other paired scan. Both between- and within-reader reproducibility were high (30).
Measurement of other covariates
Gender, ethnicity, and date of birth were recorded at baseline. A positive family history of coronary artery disease was defined as a heart attack before age 60 years in either of the subjects parents. Educational grade attained, family income, and level of physical activity were measured by self-report at the year 15 examination. Lifetime exposure to tobacco in pack-years was estimated on the basis of self-reported number of cigarettes smoked per day at each CARDIA examination. Glucose intolerance was defined as the use of diabetes mellitus medication or a fasting blood glucose level greater than 110 mg/dl. Body mass index (weight (kg)/height (m)2), systolic and diastolic blood pressure, and plasma levels of low density lipoprotein cholesterol, high density lipoprotein cholesterol, and triglycerides were measured during the year 15 examination according to CARDIA protocol (31). Plasma C-reactive protein levels were measured during the year 15 examination using the high-sensitivity assay manufactured by Calbiochem (EMD Biosciences, Inc., Darmstadt, Germany). Plasma fibrinogen levels were measured during the year 5 examination by Medlantic Laboratories (Hyattsville, Maryland). Duplicate serum analyses were carried out on 10 percent of participants for quality control.
Statistical analysis
We categorized participants by their usual alcohol consumption (0, 16, 713, or 14 drinks/week) in order not to obscure a nonlinear (J- or U-shaped) relation. Only 127 participants usually consumed 21 or more drinks per week, so we did not analyze them separately. We compared the prevalence of alcohol consumption and the prevalence of binge drinking according to category of participant characteristics using
2 tests, testing for trend where appropriate. We used nonparametric tests (Kruskal-Wallis test, or Cuzicks extension to the Wilcoxon rank-sum test to test for trend where appropriate) to compare median alcohol consumption by participant characteristics among drinkers. To assess the association between alcohol consumption and potential mediators of coronary heart disease, we used linear regression (and logistic regression for proportion with glucose intolerance), log-transforming data on triglycerides and C-reactive protein; we tested for trend with a linear contrast. When assessing the age-adjusted relation between different measures of alcohol consumption and the prevalence of coronary calcification, we used logistic regression, testing for trend where appropriate with a linear contrast. We tested interactions between usual alcohol consumption and ethnicity, beverage preference, and binge drinking by simultaneously testing interaction terms between alcohol indicator variables and the characteristic of interest.
We used logistic regression to model the association of alcohol consumption with coronary calcification. We examined this association in stages: first without adjustment, then adjusting for age and other potential confounders, and then additionally adjusting for potential mediators of coronary disease. We considered age, gender, ethnicity, income, education, self-reported physical activity, body mass index, family history of coronary artery disease, and smoking to be potential confounders of the relation between alcohol consumption and coronary calcification, thinking them unlikely to mediate etiologic pathways of interest. We considered lipids, blood pressure, C-reactive protein, fibrinogen, and the presence of glucose intolerance to be potential intermediary factors. For all multivariable regression analyses, we used a backwards stepwise variable selection process, eliminating the variable with the highest p value until all variables in the model were associated with the outcome at p < 0.1. Participants missing any covariate data were excluded from all multivariable analyses.
We performed several sensitivity analyses to assess the impact of four alternate modeling decisions: 1) excluding past drinkers, 2) keeping all variables in the model (instead of using a backwards stepwise elimination process), 3) lim-iting the analysis to nonsmokers, and 4) further categorizing nonzero coronary calcium scores (instead of dichotomizing as any vs. none) and using ordinal logistic regression. All analyses were performed using Stata 7.0 (Stata Corporation, College Station, Texas) and verified by the CARDIA Data Coordinating Center. All p values are two-sided.
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RESULTS |
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Among the half of participants who consumed alcohol on a regular basis at year 15, the median level of consumption was 5 drinks/week (interquartile range: 2, 10). Nearly one fourth of participants (23 percent) reported having engaged in binge drinking on at least one occasion during the past 30 days. Consumption patterns were strongly related to many participant characteristics (table 1), and frequency of binge drinking was highly correlated with usual alcohol consumption (figure 1; Spearmans rank correlation coefficient = 0.57, p < 0.001).
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The association between alcohol consumption and coronary calcification did not differ by alcoholic beverage preference (figure 2).
Multivariable analysis
Usual alcohol consumption and binge drinking remained strong predictors of coronary calcification in multivariable analyses (table 4). While many potentially strong confounders were included in the final logistic modelsincluding age, gender/ethnicity, tobacco exposure, body mass index, family history of coronary heart disease, and incomethe association between alcohol variables and coronary calcification persisted (table 4). Higher systolic blood pressure, higher low density lipoprotein cholesterol, and lower high density lipoprotein cholesterol were also strong independent predictors of coronary calcification; inclusion of these potential mediators had no apparent effect on associations between alcohol and coronary calcification (table 4). Simultaneous adjustment for both usual consumption and binge drinking weakened each individual alcohol-calcification association, but the overall contribution of alcohol variables to the model remained significant (table 4, second section). Categorization of all participants according to both binge frequency and usual consumption suggested that increases in either binge frequency or usual alcohol consumption were sufficient to induce an association with coronary calcification (table 4, third section).
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DISCUSSION |
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To our knowledge, our study is the first to demonstrate an association between binge drinking and atherosclerosis of the coronary arteries (as measured by coronary artery calcification). This association is consistent with previous studies of binge drinking and coronary heart disease events, most of which have found higher rates of events among persons who binge (9, 10). Our findings also support previous research suggesting that binge drinking is associated with coronary heart disease at least partly through its association with atherosclerosis (32) (demonstrated by ultrasonography of carotid arteries) rather than merely through its association with sudden death from arrhythmia or other nonatherosclerotic mechanisms. Dysregulation of inflammatory cytokines associated with the "hangover" after a binge (33) is a potential explanation for this relation.
In contrast with much previous research on alcohol and clinical coronary heart disease (5), we did not find evidence of protection against atherosclerosis from light-to-moderate regular alcohol consumption. At higher levels of alcohol consumption (14 drinks/week), the risk of coronary calcification was elevated; among Black men, even moderate drinking was associated with increased risk. While binge drinking among otherwise-moderate drinkers offers a partial explanation, we detected no beneficial association with alcohol consumption even after excluding binge drinkers.
There are several potential explanations for these findings. One possibility is that the beneficial associations between alcohol and clinical coronary heart disease events seen in previous studies are not generally mediated through an atherosclerotic pathway, and therefore would not be detected by measuring coronary calcification. This explanation is consistent with previous research showing beneficial effects of alcohol on platelet aggregation (15), endothelial function (17, 18), inflammation (16), and myocyte resistance to ischemic injury (19). It is also consistent with three previous studies that failed to show a protective association between moderate alcohol consumption and carotid atherosclerosis (3436), although two other studies did show such an association (37, 38). Investigators in one prior study who commented only briefly on alcohol use and coronary calcification in their much older population also found no beneficial association with alcohol consumption (39).
Perhaps more likely is that the increase in high density lipoprotein cholesterol caused by alcohol, which accounts for approximately 50 percent of alcohol-mediated coronary heart disease protection (40), and other potential benefits derived from alcohol in terms of atherosclerosis protection are counterbalanced by other harmful effects from alcohol in young persons. Even among older adults, the benefits of alcohol appear to be outweighed by harmful effects at high levels of consumption (the upswing of the J-shaped curve (5)). These harmful effects may be more important in young adults as atherosclerosis develops and perhaps most important among Black men, in whom the dose-response association between alcohol and coronary calcification appeared to be strongest. The mechanisms by which alcohol may induce atherosclerosis are unclear, but they may involve inflammation, low density lipoprotein cholesterol oxidation, acetaldehyde produced as a metabolic byproduct, or increased shear stress and flow turbulence associated with higher blood pressure or adrenergic stress (32).
Finally, it is possible that the coronary calcium we found in atherosclerotic plaques among these young adults may in fact represent plaque stabilization. Such a possibility might imply that lower coronary heart disease rates among moderate drinkers seen in other studies could be caused by a plaque-stabilizing effect of alcohol. However, while a given calcified plaque may be more stable on average than a noncalcified plaque, the presence of calcified plaques generally indicates a larger overall atherosclerotic plaque burden (41) and is associated with higher, not lower, rates of coronary heart disease events (26).
Our finding that the linear trend of increasing coronary calcification with increasing alcohol consumption was strongest among Black men is notable. Blacks have historically been underrepresented in large studies of cardiovascular disease, including those examining the link between alcohol and coronary heart disease. One previous analysis using data from the First National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study did focus on Blacks and found higher rates of all-cause mortality with higher alcohol intake (13) and no apparent beneficial association with moderate consumption. The authors hypothesized that the lack of benefit might be due to the binge pattern of alcohol consumption noted previously (but not in their study) to be more common among Blacks (42). In our study, there were no ethnic differences in binge drinking, and the strong dose-response relation between alcohol consumption and coronary calcification among Black men appeared to persist even after exclusion of binge drinkers.
The associations we observed persisted despite adjustment for many correlates of alcohol consumption and binge drinking. While this does not exclude confounding as an explanation for our findings, the extensive data on potential confounders are a strength of our analysis in comparison with many other studies of alcohol and coronary heart disease. Limitations of our study include uncertainty about the degree to which findings in our young-to-middle-aged population will apply to older men and women and the suboptimal sample size for subgroup and interaction analysis. We also lacked detailed data on drinking frequency, a potentially important factor in characterizing alcohol intake (12). A strength of our study is the longitudinal assessment of alcohol consumption patterns available in CARDIA. The consistency with which different assessments of exposure over 15 years are associated with coronary calcification strengthens our inferences, and the estimate of lifetime alcohol exposure in "drink-years" (a new measure analogous to "pack-years" in the smoking literature) may prove useful for examining other cumulative effects of alcohol exposure.
In conclusion, our findings add to the emerging evidence that binge drinking is associated with higher rates of cardiovascular disease and strengthen the rationale for recommending that those who drink alcohol do so in moderation. Surprisingly, our findings also raise the possibility that even moderate alcohol consumption could have proatherogenic effects among young adults. This result appears to be driven by the strong dose-response association between alcohol consumption and coronary calcification that we observed among Black men. The recent NHANES I Epidemiologic Follow-up Study report (13) showing higher mortality for Blacks at all levels of alcohol consumption in comparison with abstinence supports this potentially important finding and emphasizes the importance of studying the effects of alcohol in a variety of ethnic and cultural groups.
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ACKNOWLEDGMENTS |
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The authors acknowledge Dr. Mark Pereira, Dr. David Jacobs, Feng Lin, and Heather McCreath for their generous assistance.
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NOTES |
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REFERENCES |
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