Real-Time Closed-Loop Suppression of Repolarization Alternans Reduces Arrhythmia Susceptibility In Vivo

Abstract

Background: Repolarization alternans (RA) has been implicated in the pathogenesis of ventricular arrhythmias and sudden cardiac death. Methods: We have developed a real-time, closed-loop system to record and analyze RA from multiple intracardiac leads, and deliver dynamically R-wave triggered pacing stimuli during the absolute refractory period. We have evaluated the ability of this system to control RA and reduce arrhythmia susceptibility, in vivo. Results: R-wave triggered pacing can induce RA, the magnitude of which can be modulated by varying the amplitude, pulse width, and size of the pacing vector. Using a swine model (n=9), we demonstrate that to induce a 1 µV change in the alternans voltage on the body surface, coronary sinus and left ventricle leads, requires a delivered charge of 0.04±0.02, 0.05±0.025, and 0.06±0.033 µC, respectively, while to induce a one unit change of the K score , requires a delivered charge of 0.93±0.73, 0.32±0.29, and 0.33±0.37 µC, respectively. For all body surface and intracardiac leads, both Δ(alternans voltage) and ΔK score between baseline and R-wave triggered paced beats increases consistently with an increase in the pacing pulse amplitude, pulse width, and vector spacing. Additionally, we show that the proposed method can be used to suppress spontaneously occurring alternans (n=7), in the presence of myocardial ischemia. Suppression of RA by pacing during the absolute refractory period results in a significant reduction in arrhythmia susceptibility, evidenced by a lower S rank score during programmed ventricular stimulation compared with baseline before ischemia. Conclusions: We have developed and evaluated a novel closed-loop method to dynamically modulate RA in a swine model. Our data suggest that suppression of RA directly reduces arrhythmia susceptibility and reinforces the concept that RA plays a critical role in the pathophysiology of arrhythmogenesis.