Abstract 236: Myocardial Relaxation is Modified by Fast Stretch but not Titin Isoform Size

Abstract

Fast myocardial relaxation is important in vivo to reduce left ventricular pressure and promote efficient filling after cardiac contraction and ejection. Afterload is theorized to be a modifier of relaxation, but afterload reduction does not appear to help patients with diastolic dysfunction or Heart Failure with preserved Ejection Fraction. We hypothesized that a fast stretch, not afterload, modifies the relaxation rate, and that this relationship is modified by the giant elastic protein titin. A rat model carrying a spontaneous mutation in the RNA binding motif-20 (RBM20) results in long titin isoforms. Cardiac trabeculae from wild-type and RBM20 rats were dissected, paced at 0.5 Hz, and stretched to Lo, the length at which maximum isometric twitch force was developed. Isotonic load clamps maintained a specified afterload in experimental twitches by shortening and (if needed) relengthening the muscles using feedback control. Identical protocols were performed at reduced preload and two temperature conditions (37°C and 25°C). We determined that myocardial relaxation rate (1/tau) was modified by fast stretch (strain rate) just prior to relaxation; preventing stretch eliminated the inverse relationship between afterload and relaxation rate. Computational modeling indicates that fast stretch enhances crossbridge detachment and that passive tension compensates for some of the active force reduction during stretch. Stretch of 1 length•s -1 causes a 240% increase in relaxation rate (54.6 s -1 vs 22.5 s -1 ) at 37°C. Relaxation rate was preload independent and was slower but more responsive to stretch at 25°C. Trabeculae from long-titin mutant rats were not statistically different than control animals, but trend (p<0.1) towards faster relaxation and may require faster stretch to maintain a load clamp at 50% peak developed force. The faster stretch may compensate for a reduced passive tension in the long-titin mutant rats that made it harder to maintain the load-clamp during stretch. In all, these data suggest that fast myocardial stretch (strain rate) at end systole is a preload independent mechanism to modify the relaxation rate. The fast stretch appears to enhance crossbridge detachment to accelerate relaxation independently of titin based stiffness.