Mechano-electric feedback reduces the occurrence of delayed-afterdepolarization-driven focal activity

Delayed afterdepolarizations (DADs), which occur during the diastolic phase of a cardiomyocyte action potential (AP), are frequently observed under specific pathophysiological conditions. The synchronization of DAD-capable myocytes can effectively overcome the inherent source-sink mismatch with adjacent normal myocytes, so it is an important mechanism for the genesis of premature ventricular contractions (PVCs). Our study elucidates the role of mechano-electrical feedback in modulating this critical source-sink requirement and its interplay with diffusional anisotropy in cardiac tissue. We combine the ten Tusscher-Panfilov 06 (TP06) electrophysiological model for human ventricular myocytes with cardiac-tissue-mechanics models and account for spontaneous calcium releases (SCRs) and the randomness associated with these and with the disordered arrangement of DAD myocytes in a clump. Our work leads to a quantification of the time dependence of the intracellular cytosolic calcium transient Ca_i and the active-contraction ratio λ_o, without and with SCRs and shows explicitly how the parameter g_spon, which controls the strength of the SCRs, affects DADs and λ_o. We then illustrate the spatiotemporal evolution of the PVCs in the presence of domain deformation and a clump of DAD-capable myocytes. In a cable-type domain we demonstrate how contraction and elongation of the domain, the coupling interval of the DADs with the previous AP, and the width of the probability distribution function (PDF) of the coupling interval influence the source-size requirement for the formation of PVCs. We then extend our cable results to two dimensions (2D) by calculating the effect of the mechano-electric feedback on the origin and evolution of DAD-induced PVCs in 2D tissue. Our work leads to the following insights on the interplay of mechanical deformation and electrophysiology in DAD-induced PVCs: (1): mechano-electrical feedback markedly reduces the source requirement, which we quantify by the size of a clump of DAD-myocytes; (2): an extended coupling interval of DADs, relative to the preceding AP, reduces the source requirement; (3): sparse distribution of DAD-myocytes in a clump and the distribution in their coupling intervals, along with mechano-electric feedback, reduces the chances of the DAD-induced PVCs; (4): this suppression of PVCs is more pronounced in 2D than in 1D domains.