RAS-DEPENDENT PATHWAYS INDUCE OBSTRUCTIVE HYPERTROPHY IN ECHO-SELECTED TRANSGENIC MICE

To overcome the genetic and interindividual variability frequently not ed in complex phenotypes, me used echocardiographic selection to devel op a substrain of myosin light chain (MLC)-Ras (RAS) transgenic mice w ith an enhanced ventricular hypertrophic phenotype. These echo-selecte d mice mere then compared with wild-type (WT) animals and a pressure o verload hypertrophy model (transverse aortic constriction; TAG), Echoc ardiography demonstrated increased wall thickness in RAS compared with the other groups, We developed novel miniaturized physiological techn ology to quantitatively identify in vivo intraventricular gradients; i ncreased systolic Doppler velocity was seen in the left ventricle (LV) in 69% of RAS vs, none of WT or TAG. Intracavitary pressure gradients were present in 3 of 10 RAS vs, none of TAC or WT, Passive diastolic LV stiffness was not different among the three groups. Myofibrillar di sarray was present in all RAS animals and,vas significantly more exten sive (21.7% area fraction) than in TAC (1.5%) or WT (0.0%). RAS mice h ad selective induction of natriuretic peptide genes in the LV, a patte rn distinct from that induced by pressure overload. Juvenile mortality was significantly increased in the offspring of echo-selected RAS par ents, We conclude that adaptation of echocardiography to the mouse per mits selection for cardiac phenotypes, and that selectively inbred MLC -Ras transgenic mice faithfully reproduce the molecular, physiological , and pathological features of human hypertrophic cardiomyopathy (HCM) , Because previous studies support the concept that hypertrophy in hum an HCM is secondary to dysfunction created by sarcomeric protein mutat ions, the current studies suggest that Pas-dependent pathways might pl ay a similar role in forms of human HCM.