The Fast Cardiac Relaxation is Explained by the Transported Cross-bridge Cluster Theory; Implications on Diastolic Dysfunction

Background: Diastolic dysfunction causes heart failure in more than half of the heart failure patients. Current theories fail to explain how the relaxation rate is as fast the contraction rate, when cross-bridges (XB) detachment rate is significantly slower than XB attachment rate.

Methods: To precisely quantify the relaxation rate, a novel system for sarcomere length (SL) measurement was developed, with: spatial resolution of <2nm, temporal resolution of 150, and recording of SL distribution (inhomogeneity). Trabeculae were isolated from the rat right ventricles. The relaxation rate was studied at different initial preloads.

Results & Discussions: Empirically: relaxation was characterized by 3 phenomena: 1) Prolongation of contraction at higher loading conditions. 2) Parallel increase in the contraction and relaxation rates with the increase in the preload. 3) The point of maximum force relaxation rate appears simultaneously with the time point of maximum sarcomere lengthening rate, although sarcomere lengthening is generally associated with force enhancement.

Theoretically: Force generation was simulated by coupling calcium handling with XB dynamics. The recruited XBs have various energy levels. They are recruited at the highest energy level and the whole XB cluster is shifted/transported in time according to the rate of energy consumption. The energy depletion rate (transport rate) is a linear function of the velocity. Thus, a faster recruitment rate (contraction) is associated with a faster dissipation (relaxation) rate. The simulation successfully describes the above three characteristics of relaxation.

Conclusions: The novel theory, denoted as the “transported XB cluster theory”, provides explanations to the basic features of cardiac relaxation. The study provides better understanding of the sarcomeric control of relaxation, and how changes in calcium kinetics and XB cycling that determine cardiac contraction interact and affect the relaxation rate.