The relationship between alcohol consumption and cardiovascular disease (CVD) may be more nuanced than previously thought, with evidence emerging that alcohol use may both increase and decrease the risk for CVD.
The answer may depend on the presence of circulating metabolites of alcohol, some of which may be beneficial while others may be harmful, new research suggests.
"We adopted an association analysis, looking at 60 metabolites produced during or after alcohol has been metabolized, to see whether those metabolites can link alcohol consumption with CVD," senior author Jiantao Ma, PhD, MBBS, assistant professor, Division of Nutrition Epidemiology and Data Science, Friedman School, Tufts University, Boston, Massachusetts, told theheart.org | Medscape Cardiology.
"We found that the relationship is quite complex, with some metabolites showing protective effects against CVD and others showing harmful effects," said Ma. "This opens the door for future research because we think that these molecules can help [us] understand the mechanism of the relationship between alcohol and CVD."
The study was published online on November 16 in BMC Medicine.
J-Shaped Relationship?
Previous research has painted a confusing picture of the relationship between alcohol consumption and CVD. For example, some studies have suggested that moderate levels of drinking ma y be hazardous to cardiac health, while others have pointed to potential cardioprotective effects.
Nevertheless, "according to the latest ACC/AHA guidelines regarding alcohol consumption and its relationship to CVD, there is no level of alcohol use that is deemed safe and considered acceptable," Saurabh Sharma, MD, program director, Internal Medicine Residency Program, and clinical assistant professor of cardiology, Geisinger Commonwealth School of Medicine, Scranton, Pennsylvania, told theheart.org | Medscape Cardiology.
Older observational data suggested a "J-shaped" relationship between alcohol consumption and cardiovascular risk, such that a low to moderate amount might reduce risk, while higher amounts increase it, said Sharma, a member of the American College of Cardiology (ACC) Prevention of Cardiovascular Diseases Council.
"But it's essential to note that these findings were based on observational studies. No randomized controlled trials have provided conclusive evidence supporting the idea that moderate alcohol consumption actively reduces cardiovascular risk," he said.
The current study is also observational, but it shines a somewhat different spotlight on the subject by examining alcohol consumption–related metabolites, said Ma — that is, small molecules that are the intermediates or end-products of metabolism in many cellular processes.
Some recent research "shows that alcohol may be harmful or at least has no beneficial effect in CVD prevention," he said. "Our motivation was to analyze the association using metabolites, genetics, and epigenetics, because we think that these molecules may help us understand some of the mechanisms that underlie the relationship between alcohol consumption and CVD, and partially answer the question of whether alcohol may be harmful or helpful."
Caution Warranted
Although some previous studies have looked at metabolites, most analyzed alcohol consumption measured at a single time point, "which may not represent habitual or long-term alcohol consumption," the researchers note.
The team used data derived from 2458 Framingham Heart Study Offspring participants (mean age, 56 ± 9.3 years at the fifth examination; 52% female), calculating the cumulative average alcohol consumption from total intake of beer, wine, and liquor over an average 20-year period. Most participants were overweight, close to one fifth were current smokers, and 636 developed CVD over the study period.
Participants were assessed every 4-8 years, with metabolites measured during the fifth examination.
Linear models were used to investigate the association of alcohol consumption with 211 plasma metabolites, adjusting for a variety of potential confounders, including age, sex, batch, smoking, diet, physical activity, body mass index, and familial relationship.
Sixty metabolites associated with cumulative average alcohol consumption were identified (P < .00024), after adjusting for confounders. Of these, 40 displayed positive associations with the cumulative average alcohol consumption, with the most significant metabolite being cholesteryl palmitoleate (CE16:1), a plasma cholesteryl ester involved with cholesterol metabolism.
One gram per day of higher alcohol consumption was associated with a higher-level CE16:1 in the blood (b = .023). Several other phosphatidylcholine metabolites were also positively associated with alcohol consumption.
On the other hand, 20 metabolites were negatively associated with alcohol consumption, with triacylglycerol 54:4 (TAG 54:4) displaying the most significant association (b = -.017).
The alcoholic beverages were not equal when it came to association with metabolites: 19 metabolites were significantly associated with the cumulative average consumption of beer, 30 with wine, and 32 with liquor. Seven were significantly associated with the cumulative consumption of all three types of drinks.
The researchers conducted survival analysis that identified 10 alcohol-associated metabolites associated with differential CVD risks, after adjusting for confounders. They also built two alcohol consumption–weighted metabolite scores using these 10 metabolites. After adjusting for confounders including CVD risk factors, the two scores had "comparable but opposite" associations with incident CVD, HR 1.11 (95% CI, 1.02-1.21) vs 0.88 (0.78-0.98; both P values = .02).
"We found that seven metabolites were harmful, while three were beneficial, " Ma reported.
Ma cautioned that association "doesn't represent causation." On the basis of the findings, however, "we can hypothesize that if you drink a moderate amount of alcohol, you can either increase or decrease your risk of CVD."
For people with cardiac conditions, "it would be [wise to be] cautious in recommending alcohol consumption," he said. "For people without cardiac conditions, I would follow the recommendations of the AHA. If people don't already drink alcohol, we don't recommend that you start drinking it; and if you already drink, we'd recommend keeping it minimal."
He cautioned that this is "only one study and we need more research if we are to generate a clearer message to the patient." At present, perhaps the best message to patients is "to be cautious and warn them that there are potentially harmful effects," he said.
Mendelian Randomization?
Sharma, who was not involved in the study, emphasized that it's "crucial" to recognize that the study "does not alter the established understanding that any level of alcohol consumption poses harm to the heart," and that "any amount of alcohol consumption has the potential to elevate triglyceride levels, thereby contributing to the increased risk of cardiovascular complications."
Previously reported cardioprotective benefits "are likely influenced by confounding factors, such as lifestyle and sociodemographic elements," he speculated.
He noted that observational studies "encounter challenges in disentangling the influence of factors like obesity, lack of exercise, and tobacco use" as well as reverse causality.
"To overcome these limitations, Mendelian randomization emerges as a robust method," he suggested. "This approach utilizes measured genetic variations with known functions to investigate the causal effect of a modifiable exposure on disease within the framework of observational studies."
Notably, certain studies using this approach, including one by Larsson and colleagues, and another by Biddinger and associates, "have provided valuable insights by establishing a clear and causal relationship between alcohol consumption and CVD," he said.
The study was funded by the National Institute of Health's National Institute on Alcohol Abuse and Alcoholism. Data collection in the Framingham Heart Study was supported by the National Heart, Lung, and Blood Institute. Ma and co-authors and Sharma disclosed no relevant financial relationships.
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