FINDING A THERAPEUTIC FOR DIASTOLIC DYSFUNCTION BY EXPERIMENTALLY INCREASING TITIN’S COMPLIANCE

Abstract

Heart Failure is the leading cause of death in the United States. Stiffening of the Left Ventricle (LV) leads to Heart Failure with Preserved Ejection Fraction (HFpEF). This is a condition that has no current treatment available. It was hypothesized that increasing titin’s compliance by inhibiting RBM20 expression allows for reduced stiffness of the LV chamber and alleviates diastolic dysfunction in the heart. A MCM;cRbm20ΔRRM +/- mouse model in which inhibition of RBM20 could be regulated in a time and tissue specific manner was used in this current study. The animals underwent transverse aortic constriction surgery with deoxycorticosterone acetate (DOCA) pellet implantation which created cardiac pathology that mimic HFpEF condition in human patients. Two weeks post-surgery, all the mice developed LV hypertrophy and diastolic dysfunction. At the end of week 4, subgroup HFpEF mince in which RBM20 was inhibited demonstrated recovery of diastolic function. Through titin gel analysis showed an expression of super compliant N2BA titin isoform in the heart of HFpEF mice after RBM20 inhibition. It was also confirmed through Western Blot analysis that only myofilament changes and not changes in CaMKIIδ, LDB3, or the Ca2+ handling proteins contributed to alleviating diastolic dysfunction.