Alcohol abuse is a major public health problem leading to premature death, impaired hospital recovery, and the dysfunction of multiple organ systems. Alcoholic heart muscle disease (AHMD.) is a hallmark of sustained alcohol abuse and the associated cardiomyopathy is diagnosed in nearly a third of those individuals who chronically abuse alcohol. The mechanisms leading to AHMD are undoubtedly multifactorial, involving both cardiac myocytes and fibroblasts. Whereas the preponderance of research to date on AHMD has involved changes in cardiac muscle per se, over time the accumulation of collagen and extracellular matrix (ECM) in the heart may represent a central mechanism contributing to pathogenesis. As such, elucidation of the cellular and molecular mechanisms regulating cardiac myofibroblast conversion and activation in response to prolonged alcohol intake is of clinical significance. Our long-term goal is to elucidate the etiology and pathogenesi of AHMD.. Our preliminary data indicate that chronic (24 wk) alcohol consumption in mice produces definitive evidence for the transdifferentiation of cardiac fibroblasts to myofibroblasts (myoFBs), a cellular transition associated with increased collagen deposition (e.g., fibrosis) and cardiac contractile dysfunction. Hearts from alcohol-fed mice also show a decrease in sirtuin (SIRT)-3, a protein deacetylase which has emerged as an important member of a protein family regulating cell transformation and metabolism. Finally, we have discovered chronic alcohol consumption increases the ?- to ?-myosin heavy chain (MHC) ratio in cardiomyocytes. Therefore, based on these preliminary data and information present in the literature, we hypothesize that AHMD is caused by a decrease in SIRT3. We posit this change subsequently stimulates the transformation of cardiac fibroblasts to myoFBs, thereby enhancing collagen deposition and interstitial fibrosis, which ultimately impairs cardiac function. To address the questions implicit in this hypothesis, the proposed research has the following specific aims: (1) To delineate whether the alcohol-induced decrease in cardiac SIRT3 is causally related to ECM turnover and a mediator of AHMD.;and (2) To determine whether in vivo activation of SIRT3 prevents the development of AHMD.. Our application exploits the availability of a murine model of cardiac-specific SIRT3 over-expression and is supported by exciting preliminary data. Our focus on state-of-the-art in vivo approaches permits us to definitively assign physiological importance to our observations. To maintain the focus of the current application, in vitro studies are not specifically proposed. However, preliminary data are available indicating that alcohol also decreases SIRT3 and increases ECM production in cultured human cardiac fibroblasts, suggesting a direct effect of alcohol on this cell type. The expected research outcomes will contribute fundamental knowledge pertaining to the metabolic effects of SIRT3 and provide seminal mechanistic insights into the clinically significant pathology of AHMD., thereby providing a broad translational basis for our research focus and the potential for therapeutic development.

Public Health Relevance

Consumption of excessive alcohol for a prolonged duration impairs heart function and thereby increases morbidity and mortality in this patient population. The underlying pathology and mechanism for this so called alcoholic heart muscle disease (AHMD.) is poorly understood. While others have focused on muscle cells within the heart as the cause of organ dysfunction, our work is unique because it principally focuses on cardiac fibroblasts. Based on strong preliminary data, the present study proposes that excessive alcohol consumption decreases SIRT3 which produces a maladaptive fibrotic response in the heart. Our work will elucidate whether such changes are causally related to the development of AHMD and whether this cardiac disease can be prevented or reversed by substances known to increase SIRT3 activity.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Exploratory/Developmental Grants (R21)
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Health Services Research Review Subcommittee (AA)
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Orosz, Andras
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Pennsylvania State University
Schools of Medicine
United States
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