Modeling and Experiment to Determine the Role of Passive Stiffness on Mechanical (Strain Rate) Control of Relaxation

Abstract

Diastolic dysfunction is increasingly linked to exercise intolerance and heart failure-like symptoms. The serendipitous discovery of a rat with a spontaneous mutation in the RNA Binding Motif-20 (RBM20) has led to new studies showing the effects of reduced titin-based passive tension. Decreased passive stiffness in the heart is associated with increased exercise tolerance, but also slowed crossbridge attachment and detachment rates. The influence on relaxation, and specifically mechanical control of relaxation by fast end systolic stretch, is not yet known. We utilized MyoSim, a computational modeling environment, and experiments using intact trabeculae to investigate the relationship between titin-based passive stiffness and mechanical control of relaxation. We have previously obtained physiological myofilament parameters by fitting a 2-state crossbridge model to experimental data using MyoSim. These model parameters were held fixed except for passive stiffness, which was reduced by 50 and 75% to match passive stiffness in heterozygous and homozygous RBM20 mutant tissues. Isometric relaxation was slowed by 4 and 5%, respectively, but relaxation rate became 19 and 23% more sensitive to mechanical control of relaxation (slope of relationship between relaxation rate and end systolic strain rate). These data predict that titin based stiffness may modify relaxation rate. Trabeculae experiments using wild-type, heterozygous, and homozygous RBM20 mutant rats, show no significant change in the mechanical control of relaxation. However, reduced titin stiffness was associated with a later time to peak contraction (shortening). Reducing crossbridge attachment and detachment rates in the computational model parameters replicates the experimental results. These data suggest that passive stiffness may play a role on mechanical control of relaxation and confirm that crossbridge properties significantly contribute to early diastolic relaxation.