Insights into length-dependent regulation of cardiac cross-bridge cycling kinetics in human myocardium

Cross-bridge cycling kinetics play an essential role in the heart's ability to contract and relax. The rate of tension redevelopment (k_tr) slows down as a muscle length is increased in intact human myocardium. We set out to determine the effect of rapid length step changes and protein kinase A (PKA) and protein kinase C-βII (PKC-βII) inhibitors on the k_tr in ultra-thin non-failing and failing human right ventricular trabeculae. After stabilizing the muscle either at L₉₀ (90% of optimal length) or at L_opt (optimal length), we rapidly changed the length to either L_opt or L₉₀ and measured k_tr. We report that length-dependent changes in k_tr occur very rapidly (in the order of seconds or faster) in both non-failing and failing muscles and that the length at which a muscle had been stabilized prior to the length change does not significantly affect k_tr. In addition, at L₉₀ and at L_opt, PKA and PKC-βII inhibitors did not significantly change k_tr. Our results reveal that length-dependent regulation of cross-bridge cycling kinetics predominantly occurs rapidly and involves the intrinsic properties of the myofilament rather than post-translational modifications that are known to occur in the cardiac muscle as a result of a change in muscle/sarcomere length.