Slow force response and auto-regulation of contractility in heterogeneous myocardium

Abstract

Classically, the slow force response (SFR) of myocardium refers to slowly developing changes in cardiac muscle contractility induced by external mechanical stimuli, e.g. sustained stretch. We present evidence for an intra-myocardial SFR (SFRIM), caused by the internal mechanical interactions of muscle segments in heterogeneous myocardium. Here we study isometric contractions of a pair of end-to-end connected functionally heterogeneous cardiac muscles (an in-series muscle duplex). Duplex elements can be either biological muscles (BM), virtual muscles (VM), or a hybrid combination of BM and VM. The VM implements an Ekaterinburg–Oxford mathematical model accounting for the ionic and myofilament mechanisms of excitation–contraction coupling in cardiomyocytes. SFRIM is expressed in gradual changes in the overall duplex force and in the individual contractility of each muscle, induced by cyclic auxotonic deformations of coupled muscles. The muscle that undergoes predominant cyclic shortening shows force enhancement upon return to its isometric state in isolation, whereas average cyclic lengthening may decrease the individual muscle contractility. The mechanical responses are accompanied with slow and opposite changes in the shape and duration of both the action potential and Ca2+ transient in the cardiomyocytes of interacting muscles. Using the mathematical model we found that the contractility changes in interacting muscles follow the alterations in the sarcoplasmic reticulum loading in cardiomyocytes which result from the length-dependent Ca2+ activation of myofilaments and intracellular mechano-electrical feedback. The SFRIM phenomena unravel an important mechanism of cardiac functional auto-regulation applicable to the heart in norm and pathology, especially to hearts with severe electrical and/or mechanical dyssynchrony.