Abstract 13327: Mechanistic Basis of Sinoatrial Node Pacemaker Failure in Atrial Cardiomyopathy

Abstract

Introduction: Sinoatrial node (SAN) dysfunction commonly occurs in atrial cardiomyopathy (ACM: “tachy-brady syndrome”), often requiring pacemaker implantation, but mechanisms are unknown. Atrial-selective myosin light chain-4 (MYL-4) mutations cause familial ACM with a high rate of early SAN dysfunction and pacemaker requirement. We studied rats engineered with a knock-in MYL-4 clinical E11K mutation and addressed mechanisms of SAN dysfunction. Methods: Atrial electrical properties were assessed with in vivo electrophysiology (EPS), ex vivo optical mapping, SAN single-cell voltage and current clamp, Ca 2+ -handling with Ca 2+ -sensitive dye microscopy. Gene expression was assessed by qPCR and fibrosis with Masson-Trichrome stain. Results: E11K rats showed progressive SAN recovery-time increases (Fig. A) and conduction-slowing (Fig. B). SAN cells showed slowed phase-4 depolarization (Fig. C) and reduced pacemaker “funny” current (I f ) (Fig. D). Ca 2+ homeostasis was also affected, showing decreased Ca 2+ -transients (Fig. E). SAN also displayed remodeling with increased collagen deposition (Fig. F). Conclusions: ACM resulting from E11K mutation induces multimodal electrical and structural remodeling of the SAN region, worsening with age. These observations provide new insights into mechanisms of the clinically important tachy-brady syndrome associated with ACM.