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Vol. 291, Issue 2, 766-772, November 1999
Departments of Pharmacology and Toxicology (Q.L., P.N.E.), Anatomy
and Cell Biology (E.C.C.), and Chemistry (A.J.B.), University of North
Dakota, Grand Forks, North Dakota
Chronic alcohol consumption produces alcoholic heart muscle disease
(AHMD), a prevalent form of congestive heart failure. Several
hypotheses have been proposed to explain the damaging effects of
alcohol on the heart, but neither the mechanism nor the ultimate toxin
has been established. In this study, we use transgenic overexpression
of alcohol dehydrogenase to elevate cardiac exposure to acetaldehyde,
the major and most reactive metabolite of alcohol. Overexpression of
alcohol dehydrogenase by 40-fold produced no detectable deleterious
effects to the heart in the absence of alcohol. In the presence of
alcohol, transgenic hearts contained 4-fold higher acetaldehyde than
control hearts. Chronic alcohol exposure produced many changes similar
to AHMD in transgenic hearts. Compared with control hearts, these
pathological changes occurred more rapidly and to a greater extent:
alcohol-exposed transgenic hearts were almost twice as large as control
hearts. They demonstrated ultrastructural damage consistent with AHMD and had much lower contractility than alcohol-exposed control hearts.
In addition, the transgenic hearts showed greater changes in mRNA
expression for 
-skeletal actin and atrial natriuretic factor than
alcohol-exposed control hearts. Alterations in NAD+/NADH
levels were insufficient to account for such severe damage in
cardiomyopathic hearts. The increased damage produced in transgenic hearts suggests an important role for acetaldehyde in AHMD.
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