A transgenic model of acetaldehyde overproduction accelerates alcohol cardiomyopathy

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 neit her the mechanism nor the ultimate toxin has been established. In this stud y, we use transgenic overexpression of alcohol dehydrogenase to elevate car diac exposure to acetaldehyde, the major and most reactive metabolite of al cohol. Overexpression of alcohol dehydrogenase by 40-fold produced no detec table deleterious effects to the heart in the absence of alcohol. In the pr esence of alcohol, transgenic hearts contained 4-fold higher acetaldehyde t han control hearts. Chronic alcohol exposure produced many changes similar to AHMD in transgenic hearts. Compared with control hearts, these pathologi cal changes occurred more rapidly and to a greater extent: alcohol-exposed transgenic hearts were almost twice as large as control hearts. They demons trated ultrastructural damage consistent with AHMD and had much lower contr actility than alcohol-exposed control hearts. In addition, the transgenic h earts showed greater changes in mRNA expression for alpha-skeletal actin an d atrial natriuretic factor than alcohol-exposed control hearts. Alteration s in NAD(+)/NADH levels were insufficient to account for such severe damage in cardiomyopathic hearts. The increased damage produced in transgenic hea rts suggests an important role for acetaldehyde in AHMD.