Author + information
- Mariann R. Piano, PhD∗ ()
- Center for Research Development and Scholarship, Vanderbilt University School of Nursing, Nashville, Tennessee
- ↵∗Address for correspondence:
Dr. Mariann R. Piano, Center for Research Development and Scholarship, Vanderbilt University School of Nursing, 415 Godchaux Hall, 21st Avenue South, Nashville, Tennessee 37240.
Much has been learned about the genetic basis of cardiomyopathies (CM). Consequently, contemporary CM classification schemas are based upon molecular genetics (1). Absent from existing genetic classifications, however, is alcoholic cardiomyopathy (ACM), a specific heart muscle disease found in individuals with a long-term history of heavy alcohol consumption (2). There are no specific histological, immunological, or biomarkers for the diagnosis of ACM. A key factor in ruling in ACM is a long-term history of heavy alcohol consumption in the absence of coronary artery disease. A number of pathophysiologic mechanisms have been linked to the development of ACM; however, one of the most important unresolved questions has been related to how certain genetic mutations may influence susceptibility to ACM.
There are reports of the relationships among alcohol consumption, occurrence of cardiovascular conditions, such as myocardial infarction, and genetic polymorphisms in enzymes related to ethanol metabolism (e.g., alcohol dehydrogenase [ADH] and aldehyde dehydrogenase [ALDH]) (3,4). However, prior to the study by Ware et al. (5) in this issue of the Journal, there were few reports that examined a genetic origin of ACM. In individuals with a history of heavy alcohol consumption and upon autopsy, Kajander et al. (6) examined polymorphisms in genes that encoded components of the renin-angiotensin-aldosterone system (RAAS) in relationship to changes in myocardial weight and dimensions. Myocardial biopsies from male victims of sudden cardiac death were evaluated for RAAS gene variants (e.g., insertion or deletion polymorphisms of angiotensin-converting enzyme and the cytosine allele of −344 cytosine/thymidine polymorphism of aldosterone synthase) also examined were ADH and ALDH polymorphisms (6). Even though daily lifetime alcohol dose was associated with increased myocardial weight and right ventricular size, there were no significant associations with the above RAAS genetic polymorphisms (6). In Japanese men (n = 10) with a history of heavy drinking and with the diagnosis of dilated cardiomyopathy (DCM), Teragaki et al. (7) examined the occurrence of mitochondrial deoxyribonucleic acid (mtDNA) point mutations from myocardial biopsies. Several mtDNA point mutations were found in subjects; however, because point mutations in mtDNA can arise during the repair of mtDNA in response to oxidative stress, it is difficult to ascertain whether such changes were a cause or consequence of heavy alcohol consumption (7,8).
In this issue of the Journal, Ware et al. (5) provide evidence that there may be a genetic predisposition to ACM. The authors examined mutations in 9 genes known to be associated with DCM in a well-characterized cohort of ACM (n = 141) and DCM (n = 716) cases and healthy controls (n = 445). Several of the genes examined were those encoding sarcomeric proteins, such as the truncated variants in the titin (TTNtv) gene. It is estimated that mutations in TTNtv genes may account for 20% to 25% of familial DCM cases (9). Even though other genetic mutations may give rise to DCM, focusing on TTNtv and the other sarcomeric genes was an excellent starting point.
The authors found 20 distinct variants in 19 ACM cases involving 4 genes (TTNtv, BCL2-associated athanogene 3 protein, lamin A/C, and myosin heavy chain). The prevalence of variants in ACM subjects was significantly higher than in healthy controls (13.5% vs. 2.9%, respectively) but similar to that in the DCM cohort (19.4%). The TTNtv genes accounted for the majority of variants in ACM cases (9.9%) and were significantly greater than in healthy controls (0.7%) but similar to the frequency found in DCM cases (12.0%). Except for a family history of CM, there were no differences in demographic or myocardial parameters (e.g., left ventricular ejection fraction [LVEF]) between ACM cases with the TNNtv variant and those without the TNNtv variant. There were no differences between groups in event-free survival and with reductions in alcohol intake and pharmacologic treatment of heart failure, ACM cases showed improvement in LVEF regardless of TTNtv status.
In subjects with the DCM and the TTNtv variant, the effects of drinking above the limits for “sensible drinking” on myocardial function recommended in the United Kingdom were also examined. Drinking above the U.K. “sensible limits” was defined as consuming >14 U/week for women and 21 U/week for men (approximately 9 to 13 standard U.S. drinks); however, none of the DCM cases had a history of prolonged alcohol consumption for a diagnosis of ACM. Among DCM cases (n = 716), 111 participants (15.5%) drank above the sensible limits and had a lower LVEF (median: −37.0% vs. 41.0%; p = 0.02, respectively) compared to DCM cases without a history of drinking above the sensible limits. When accounting for the TTNtv variant, the authors found additional significant reductions in LVEF. As the authors acknowledge, these findings suggest alcohol consumption exceeding sensible limits may also account for a substantial proportion of DCM risk.
Do the Above Results Suggest it Is Time for Genetic Testing in ACM?
The presence of the TTNtv gene may represent a genetic predisposition and increased vulnerability to ACM. In this study, ACM subjects had a self-reported history of alcohol intake >80 g/day (∼6 U.S. standard drinks/day) over a period of ≤5 years. This level of drinking could represent an environmental trigger in the background of a genetic susceptibly to a CM. Therefore, in individuals presenting with ACM, it seems appropriate to obtain familial evaluation and a 3-generation pedigree analysis, to determine whether there is a family history of ACM for ≥3 generations, and to consider genetic testing. Not all individuals who consume high levels of alcohol develop ACM. To this end, the authors acknowledge an important control group is missing from this study, that is, a cohort consuming high levels of alcohol but without ACM and determination of the presence of gene variants in this ACM-free cohort. Future studies should consider detailed information related to duration of alcohol consumption and patterns. Finally, with regard to ACM, 97.9% of the cohort was male, and among all the groups, 100% of the subjects were Caucasian.
Findings from this study also revealed some important messages about alcohol consumption and the need for patient counseling. Among DCM cases, 15.5% of participants consumed alcoholic beverages above the sensible limit, suggesting the need to council DCM patients about alcohol use. To place this into context, a U.S. population-based study found 12.6% of individuals consumed alcoholic beverages at high-risk levels (i.e., drinking ≥4 to 5 standard drinks on any day for women or men at least weekly) (10). A U.K. study found that among patients (N = 1,937,360) admitted to a hospital for cardiovascular disease, 8.4% reported drinking over the sensible limits (11). Ware et al. (5) reported heart failure therapy and reduction in alcohol consumption was associated with an improvement in cardiac function. At least in ACM patients, abstinence from alcohol is recommended, as continued drinking despite optimal heart failure therapies is associated with increased cardiovascular mortality (12,13). Therefore, in subjects with ACM, abstaining from alcohol consumption is probably the best advice. Those with DCM and drinking over the sensible limits need to reduce their alcohol intake.
Currently, in the United Kingdom, the sensible drinking limits are the same for men and women: no more than 14 units per week (14). In the United States, “low-risk” drinking levels are defined as no more than 3 to 4 drinks on any given day for women and men and no more than 7 to 14 drinks per week for women or men (15). When discussing the risks associated with alcohol consumption, clinicians need to consider an individual’s risk factors and reinforce the importance of physical activity, maintenance of normal body weight, avoidance of tobacco products, and consumption of a diet rich in fruits, vegetables, whole grains, and unsaturated fat.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Piano has reported that she has no relationships relevant to the contents of this paper to disclose.
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- ↵National Institute on Alcohol Abuse and Alcoholism. Rethinking drinking: alcohol and your health. National Institutes of Health. U.S. Department of Health and Human Services Available at: https://www.rethinkingdrinking.niaaa.nih.gov/How-much-is-too-much/Whats-the-harm/What-Are-The-Risks.aspx. Accessed March 18, 2018.