Effects of growth hormone on cardiac dysfunction and gene expression in genetic murine dilated cardiomyopathy

Beneficial cardiac effects of growth hormone (GH) have been shown in heart failure in several settings, but studies are lacking on this and other form s of treatment in the cardiomyopathic (CM) mouse heart. In mice with dilate d cardiomyopathy due to disruption of the muscle LIM protein (MLP) gene [ML P null mice (MLP-/-)],natural history was first assessed by an initial echo cardiogram at 8 weeks and a later follow-up study (n = 31). In most mice, l eft ventricular (LV) dilation increased and/or function decreased by 5 mont hs, and 3 of 12 mice followed for 9 months died. At the end of follow-up. 2 2 MLP-/- mice (average age 10.2 months) had both LV dilation and reduced LV function and were selected for studies of GH effects on cardiac function a nd gene expression; mice were randomized to vehicle (controls) or recombina nt human (rh) GH and restudied after 2 weeks. In the GH-treated group compa red to the control group, LV % fractional shortening and LV wall thickness (echocardiography) were increased, the LV dP/dt(max) (catheter-tip microman ometry) was enhanced, and LV relaxation (tau) improved; however, the LV wei ght was not significantly increased. The LV expression of many genes was al tered in MLP-/- mice,and several were influenced by GH. Thus, short-term Rh GH treatment improved LV function in a setting of chronic cardiac deteriora tion and significantly reduced elevated LV mRNA expression of some (ANP, BN P) but not other members of the embryonic gene program. The MLP null cardio myopathic mouse can be useful for exploring altered signaling and therapeut ic interventions in heart failure.