Models of Dilated Cardiomyopathy in Small Animals and Novel Positive Inotropic Therapies

Several randomized clinical trials of vesnarinone and milrinone in patients with heart failure left disappointing results in the 1990s. Thereafter, use of positive inotropic agents has been avoided. Exceptions are the use of digitalis glycosides to treat mild-moderate heart failure and the intravenous administration of catecholamines and phosphodiesterase inhibitors in patients with acute and/or refractory heart failure. It is not, however, exactly known whether chronic enhancement of cardiac contractility indeed has harmful effects, besides increased risk of arrhythmia and mortality. We investigated the potential chronic benefit of positive inotropic modification to treat progressive cardiomyopathy and associated heart failure using a genetic complementation strategy of muscle lim-protein and phospholamban (PLN) double mutagenesis in the mouse and found clear evidence of positive effects. Subsequent somatic modification of PLN function via gene transfer with recombinant adeno-associated virus vectors in small animal models of dilated cardiomyopathy further supported the chronic benefit of enhanced cardiac function achieved in an beta-adrenergic stimulus-independent manner. This study examines current small animal models of dilated cardiomyopathy and recent multiple attempts to use these models as novel gene-based inotropic therapies.