Chronic alcohol ingestion leads to the development of alcoholic cardiomyopathy, which is manifested by left ventricular dilation, impaired left ventricular contractility, reduced ejection fraction and cardiac output, cardiac hypertrophy and enhanced risk of stroke and hypertension. The occurrence of the cardiomyopathy under chronic alcoholism has been well documented, although the pathogenesis of the myopathy is still unclear. Several mechanisms have been postulated including oxidative stress, accumulation of triglycerides, altered fatty acid extraction, decreased myofilament responsiveness to Ca2+ and catecholamines, and impaired cardiac protein synthesis, however, neither the mechanism nor the ultimate toxin has been established. Principle candidates for the specific toxins are ethanol, the first product of the ethanol metabolism - acetaldehyde and fatty acid ethyl esters. Compelling evidence from our laboratories and others has suggested that acetaldehyde directly impairs cardiac excitation-contraction coupling, promotes oxidative damage, and exacerbates the severity of alcoholic cardiomyopathy. Our central hypothesis is that (1) elevated exposure of heart to acetaldehyde due to overexpression of alcohol dehydrogenase exacerbates ventricular dysfunction following alcohol ingestion via enhanced oxidative damage and lipid peroxidation; (2) development of alcoholic cardiomyopathy can be protected by increased acetaldehyde breakdown with non-specific over-expression of aldehyde dehydrogenase; (3) acetaldehyde-induced alcoholic cardiomyopathy is mediated in part through CYP2E1-mediated oxidative damage and may be protected by overexpression of free radical scavengers such as superoxide dismutase and metallothionein. State-of-the-arts cell biology, physiology and transgenic techniques will be used to evaluate cardiac excitation-contraction coupling at cellular, whole heart and in vivo levels in transgenic mice models. These studies will provide useful insights into the role of acetaldehyde in the development of alcoholic cardiomyopathy in the pathogenesis and therapeutics of alcoholic cardiomyopathy. Our long-term goal is to establish the toxic mechanism of acetaldehyde in the development of alcoholic cardiomyopathy so that prevention and treatment can be optimized ? ?
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