Abstract 17161: Bradycardia Elicits a Secondary Cai Elevation During the Action Potential (AP) Plateau Which is Spatially Heterogeneous, Prolongs AP Durations (APD) Further, Enhances Dispersion of Repolarization (DOR) and May Explain the Arrhythmogenic Properties of Bradycardia

Abstract

Introduction: Bradycardia is known to prolong APD and DOR and is a factor that promotes arrhythmia in long QT type 2. In numerous conditions, spontaneous Ca 2+ release from sarcoplasmic reticulum has been shown to trigger early afterdepolarizations, ectopic activity that initiate arrhythmias, but the interplay between secondary Ca 2+ elevation (SCE) and membrane excitability has not been demonstrated in bradycardia. Objectives: To correlate voltage-depolarization during the AP plateau to SCE during bradycardia. Methods: Dual optical mapping of intracellular calcium transient (CaT) and AP was performed in Langendorff perfused rabbit hearts. After AV node ablation, CaT and AP dynamics were investigated at physiological (120 beats per minute (bpm)) and slow heart rate (50 bpm). Results: Upon changing HR from 120 to 50 bpm, APD gradually increased with a time-constant of 53.8±8.9 s, consistent with clinical QT measurements. The shift from 120 to 50 bpm elicited SCE during the AP plateau that was a) regionally heterogeneous, b) associated with enhanced depolarization of the AP plateau and was reversed by pacing at 120 bpm. Regional differences of SCE at 50 bpm were significantly increased (P<0.01, n=7) and were correlated with dispersion of APD (r=0.9277±0.03, n=7). SCE and APD prolongation were more pronounced at the base of right ventricles than the apex of left ventricles (P<0.01, n=7) (Figure). Suppression of SCE with K201 (1 µM/L) (to stabilize RyR2) reduced APD (P<0.01, n=5) and DOR (P<0.02, n=5). The molecular basis of the spatial distribution of SCE is currently being correlated to the intrinsic distributions of Ca 2+ handling channels and transporters (Cav1.2α, RyR2, NCX and SERCA2a) Conclusion: These data show for the first time that bradycardia elicits SCE which contributes to AP prolongation and its spatial heterogeneity increases DOR. These changes explain why bradycardia is a critical factor to trigger Torsade de Pointes in LQT2.