Mutations in KCNE1 Promote Cardiac Alternans in Long QT Syndrome Type 5 Rabbits

Abstract

Long QT syndrome type 5 (LQT5) is caused by mutations in KCNE1, an accessory subunit of slowly activating delayed rectifier K+ channel (IKs), and is associated with polymorphic ventricular tachycardia (pVT). We hypothesized that mutations in KCNE1 alter multiple K+ channels causing APD instability such as alternans thereby increasing vulnerability to pVT. We investigated APD dynamics in transgenic LQT5 rabbits using optical mapping, microelectrode recording, and voltage clamp techniques. APD alternans occurred at relatively slower heart rates in LQT5 than littermate control (LMC) hearts (the onset of alternans cycle length of 207.0 ms vs. 176.3 ms respectively, p < 0.05). Onset of alternans occurred without steep APD restitution curves (slope < 1), suggesting that a simple APD restitution kinetics cannot explain this alternans. Microelectrode recordings of alternans from intact heart showed that the short APD beat was associated with higher plateau Vm while the long APD beat was associated with lower plateau Vm, suggesting that the ionic currents responsible for plateau Vm underlie alternans. Single myocyte voltage clamp studies showed that the transient outward K+ current (Ito) in LQT5 myocytes had slower inactivation (τ=14 and 99 ms for double exponential curve fit), and slower recovery kinetics from inactivation (τ=217 and 3100 ms for Ito,f and Ito,s, respectively). Partial blockage of Ito with 4-AP (0.5 mM) eliminated the alternans, while treatment of Ito enhancer (NS5806, 2 μM) aggravated the alternans with same plateau Vm pattern associated with long-short APDs in LMC. These data support the notion that Ito modification by KCNE1 mutation contributes to APD alternans in LQT5 rabbits. Thus, KCNE1 mutation alters multiple K+ channels including Ito, leading to Ito-mediated alternans that is unrelated to the steep APD restitution hypothesis.