Abstract 3857: Structural Heterogeneities are a Substrate for Re-excitation, Reflection, and Arrhythmogenesis in Cardiac Muscle

Abstract

Background: Heart diseases predispose to arrhythmias and sudden cardiac death by mechanisms that are poorly understood. We tested the hypothesis that in fully excitable tissue abrupt geometrical expansions resulting from varying wall thickness, replacement fibrosis, ischemia, or accessory pathways, set the stage for to-and-fro propagation (reflection) of electrical impulses over the same pathway, leading to premature excitation and reentry initiation. Methods: We used patterned monolayers of cultured neonatal rat ventricular myocytes consisting of two wide regions connected by a fully excitable, thin isthmus (0.1, 0.5, 1, & 2 mm wide, 6 mm long). We compared control monolayers with those overexpressing Na channels (NaCh, Ad-hSCN5a). Impulse propagation was optically imaged (Di-8-ANEPPS) at high resolution. Results: Impulses initiated proximally in a wide region propagated 1:1 through relatively broad isthmuses (2 mm) and then into the distal expansion at higher frequencies than through narrower isthmuses (0.1 mm). In control monolayers, with relatively low excitability, the prevalence of reflection was small (15%, n=61). NaCh overexpression increased excitability. It also increased the incidence of reflection (38%, n=26). In homogeneous monolayers, NaCh overexpression increased the conduction velocity (15–17%) and prolonged the action potential duration (APD, 21–26%) at the frequencies (2– 4 Hz) at which reflection occurred. During reflection, the APD at the distal expansion was prolonged, compared to APDs within the isthmus or distally when there was no reflection. APD prolongation provided a substrate for local phase-3 re-excitation at the isthmus, and thus reflection. In some cases, reflection was sustained over several consecutive beats. Reflection also triggered the initiation of reentry; as the beat reflected back, a small distal region was re-excited, resulting in unidirectional propagation and the initiation of reentry. Reflection was never observed in structurally homogeneous monolayers, whether with or without the presence of NaCh overexpression. Conclusion: Source-to-sink mismatch in areas of cardiac muscle expansion creates APD heterogeneities, which may serve as a substrate for reflection and arrhythmogenesis.