<p>3038</p><p>A GENERAL PARADIGM OF PROGRESS OF HEART FAILURE WITH THE CLEAVAGE AND TRANSLOCATION OF MYOCARDIAL DYSTROPHIN T Toyo-oka 1 , H Kumagai2, T Kawada3, F Masui1, A Tezuka1, T Ebisawa1, S Kostin4, M Nakazawa3, J Schaper4, K Ozawa5 1University of Tokyo, Tokyo, Japan, 2Tohoku University, Sendai, Japan, 3Niigata University, Niigata, Japan, 4Max-Planck Institute, Bad Nauheim, Germany, 5Jichi Medical Scool, Tochigi, Japan</p><p>Precise mechanism on the progression of advanced heart failure (HF) should be clarified to establish the prevention and/or therapy. We assessed a new scheme in 3 HF models: (I) congenital DCM hamsters of which gene mutation we have identified in delta- sarcoglycan (Sakamoto et al., PNAS 1997), (II) administration of a toxic dose of isoproterenol as an acute HF in rats and (III) human HF sampled after the cardiac transplantation . In DCM hamsters, we followed time course of the histological, physiological and metabolic progressions of HF up to the end stage. In the first 2 animal models, double fluoroscopy of dystrophin (Dys) and Evans blue entry to MP revealed the time-dependent translocation of Dys from sub-sarcolemma (SL) to myoplasm (MP) and increased SL fragility detected in situ in the same cardiomyocytes as the Dys shift. Western blotting of all 3 models including human DCM revealed a limited cleavage of Dys at the rod domain, strongly suggesting the hydrolysis by endogenous protease(s). In vivo supplementation of normal delta-SG gene in DCM hearts employing long-lasting and non-cytotoxic rAAV vector improved the pathological features and rescued the DCM animals (Kawada et al., PNAS, 2002). These results of HF irrespective of the origins suggest a vicious cycle formed by the increased SL permeability, cleavage and translocation of Dys would commonly lead to advanced HF, in human DCM as well (Toyo-oka et al., PNAS, 2004). If time is available, we present data of an involvement of endogenous calpain-1 and -2.</p>