Modulation of cardiac electrophysiology by tissue alignment

Most cardiac arrhythmias are associated with pathology-triggered ion channel remodeling. However, multicellular effects, e.g. exaggerated anisotropy and altered cell-to-cell coupling, can also indirectly affect action potential morphology and electrical stability via changed electrotonus. Recent computational studies showed that electrotonus affects stability by altering dynamic properties (restitution). Here, we address the question of how cell alignment and connectivity alter function and whether these effects depend on wave propagation direction. We show that cardiac cell arrangement alters electrical stability in an in vitro cardiac tissue model by mechanisms both dependent and independent of wave propagation direction, and local structural remodeling is felt beyond a space constant. Notably, restitution of action potential duration (APD) and conduction velocity were significantly steepened in the direction of cell alignment. Furthermore, prolongation of APD and calcium transient duration was found in highly anisotropic cell networks, in both longitudinal and transverse propagation. This is in contrast to expected correlation between wave propagation direction and APD based on electrotonic effects only, but is consistent with our findings of increased secretion of atrial natriuretic peptide, a hypertrophy marker, in the aligned structures. Our results indicate anisotropic structure is a potent modulator of electrical stability via electrotonus and molecular signaling.