Background: Although it seems that reactive oxygen species contribute to chronic myocardial remodeling, questions remain about (1) the specific types of reactive oxygen species involved, (2) the role of reactive oxygen species in mediating specific cellular events, and (3) the cause-and-effect relationship between myocardial reactive oxygen species and the progression to heart failure. Transgenic mice with myocyte-specific overexpression of G(alpha)q develop a dilated cardiomyopathy that progresses to heart failure. We used this model to examine the role of H(2)O(2) in mediating myocardial remodeling and the progression to failure.
Methods and results: In G(alpha)q myocardium, markers of oxidative stress were increased at 4 weeks and increased further at 20 weeks. G(alpha)q mice were crossbred with transgenic mice having myocyte-specific overexpression of catalase. At 4 weeks of age, left ventricular end-diastolic dimension was increased and left ventricular fractional shortening decreased in G(alpha)q mice and deteriorated further through 20 weeks. In G(alpha)q mice, myocardial catalase overexpression had no effect on left ventricular end-diastolic dimension or fractional shortening at 4 weeks but prevented the subsequent deterioration in both. In G(alpha)q mice, myocyte hypertrophy; myocyte apoptosis; interstitial fibrosis; and the progression to overt heart failure, as reflected by lung congestion and exercise intolerance, were prevented by catalase overexpression.
Conclusions: In G(alpha)q mice, myocyte-specific overexpression of catalase had no effect on the initial phenotype of left ventricular dilation and contractile dysfunction but prevented the subsequent progressive remodeling phase leading to heart failure. Catalase prevented the cellular hallmarks of adverse remodeling (myocyte hypertrophy, myocyte apoptosis, and interstitial fibrosis) and the progression to overt heart failure. Thus, H(2)O(2), associated oxidant pathways, or both play a critical role in adverse myocardial remodeling and the progression to failure.