Date of Award

6-19-2000

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Paul N. Epstein

Abstract

Alcohol abuse is a major health problem in the United States with 14 million people affected. Long term alcohol abuse leads to alcoholic heart muscle disease (AHMD) in one third of alcoholics. Several hypotheses have been proposed to explain alcohol's damaging effects on the heart but neither the mechanism nor the ultimate toxin has been established. The principal candidates for the specific toxin are alcohol, acetaldehyde and fatty acid ethyl esters. In order to test the hypothesis that acetaldehyde, the major oxidative metabolite of ethanol by alcohol dehydrogenase (ADH), is the specific toxin responsible for AHMD, seven lines of transgenic mice were produced in which ADH activity was increased specifically in the heart. Overexpression of ADH by fifty-fold produced no detectable deleterious effects to the heart in the absence of alcohol. In the presence of alcohol, transgenic hearts contained four-fold higher acetaldehyde than control hearts. Compared to control hearts, the pathological changes in alcohol-exposed transgenic hearts occurred more rapidly and to a greater extent. Following chronic alcohol intake, transgenic hearts were extremely enlarged and dilated, atrial thrombi were common, contractility was greatly reduced, mitochondria and myofilaments were disrupted and fibrosis was present. All of these changes were far more severe in the transgenic hearts than in the control hearts. In addition, the transgenic hearts showed greater changes in mRNA expression than alcohol exposed control hearts. The damage observed in these transgenic mice resembled that seen in human AHMD. Alcohol was essential for the induction of damage in the transgenic mice. In the absence of alcohol, the transgene was completely benign. Thus, it is unlikely that the cardiac damage resulted from insertional mutation by the transgene. Alterations in NAD/NADH levels were also insufficient to account for such severe damage in cardiomyopathic hearts. In addition, organs outside of the heart were unaffected by the transgene. Therefore, the most reasonable explanation for more severe cardiac damage in the transgenic hearts was the direct exposure to acetaldehyde. The increased damage seen in transgenic hearts indicated an important role of acetaldehyde in the pathogenesis of AHMD. Another transgenic model is being constructed overexpressing skeletal muscle aldehyde dehydrogenase in order to reduce cardiac exposure to acetaldehyde during chronic alcohol intake. Studies with this transgenic model will attempt to confirm our current findings supporting an etiological role of acetaldehyde in AHMD.

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