Activation sequence as a key factor in spatio-temporal optimization of myocardial function.
Using one-dimensional models of myocardial tissue, implemented as chains of virtual ventricular muscle segments that are kinematically connected in series, we studied the role of the excitation sequence in spatio-temporal organization of cardiac function. Each model element was represented by a well-verified mathematical model of cardiac electro-mechanical activity. We found that homogeneous chains, consisting of identical elements, respond to non-simultaneous stimulation by generation of complex spatio-temporal heterogeneities in element deformation. These are accompanied by the establishment of marked gradients in local electro-mechanical properties of the elements (heterogeneity in action potential duration, Ca2+ transient characteristics and sarcoplasmic reticulum Ca2+ loading). In heterogeneous chains, composed of elements simulating fast and slow contracting cardiomyocytes from different transmural layers, we found that only activation sequences where stimulation of the slower elements preceded that of faster ones gave rise to optimization of the system's electro-mechanical function, which was confirmed experimentally. Based on the results obtained, we hypothesize that the sequence of activation of cardiomyocytes in different ventricular layers is one of the key factors of spatio-temporal organization of myocardium. Moreover, activation sequence and regional differences in intrinsic electro-mechanical properties of cardiac muscle must be matched in order to optimize myocardial function.