Min Luo, Xiaoqun Guan, Elizabeth D. Luczak, Di Lang, William Kutschke, Zhan Gao, Jinying Yang, Patric Glynn, Samuel Sossalla, Paari D. Swaminathan, Robert M. Weiss, Baoli Yang, Adam G. Rokita, Lars S. Maier, Igor R. Efimov, Thomas J. Hund, Mark E. Anderson
SAN cell death and fibrosis lead to decreased conduction velocity and spontaneous beating.
(A) Cell loss data from vehicle- and STZ-treated WT mice were incorporated into a 2-dimensional histologically reconstructed mathematical model of the intact sinoatrial node (action potentials from central [Cen] and peripheral [Per] SAN and right atrium are shown). The STZ model with 19% cell loss in the SAN predicts a shift of lead pacemaker site (red asterisks on action potential traces), slowing of conduction time and block (double red lines on action potential traces), and decreased heart rate similar to experimental measurements. Red arrows denote direction of action potential propagation. (B) Mouse atria prepared for optical measurements (left). Original magnification, ×20. Representative pseudocolored isochrones from optical mapping (middle and right). SVC, superior vena cava; AVN, atrioventricular node; IVC, inferior vena cava; LA, left atrium; RA, right atrium; LV, left ventricle; RV, right ventricle; CT, crista terminalis. White asterisks denote the earliest activation in the SAN. (C) Conduction velocity during pacing in STZ- and vehicle-treated mice in the absence (**P = 0.004; n = 5 per group) and presence of isoproterenol (3 nM, *P = 0.01; n = 5 per group). (D) Heart rate in isolated atria in the absence (*P = 0.03; n = 4–5 per group) or presence of isoproterenol (ISO; 3 nM, **P = 0.0056; n = 4–5 per group).