Bradycardia alters Ca dynamics enhancing dispersion of repolarization and arrhythmia risk

Kim JJ, Němec J, Papp R, Strongin R, Abramson JJ, Salama G. Bradycardia alters Ca dynamics enhancing dispersion of repolarization and arrhythmia risk. Am J Physiol Heart Circ Physiol 304: H848–H860, 2013. First published January 11, 2013; doi:10.1152/ajpheart.00787.2012.—Bradycardia prolongs action potential (AP) durations (APD adaptation), enhances dispersion of repolarization (DOR), and promotes tachyarrhythmias. Yet, the mechanisms responsible for enhanced DOR and tachyarrhythmias remain largely unexplored. Ca transients and APs were measured optically from Langendorff rabbit hearts at high (150 150 m) or low (1.5 1.5 cm) magnification while pacing at a physiological (120 beats/min) or a slow heart rate (SHR 50 beats/min). Western blots and pharmacological interventions were used to elucidate the regional effects of bradycardia. As a result, bradycardia (SHR 50 beats/min) increased APDs gradually (time constant f¡s 48 9.2 s) and caused a secondary Ca release (SCR) from the sarcoplasmic reticulum during AP plateaus, occurring at the base on average of 184.4 9.7 ms after the Ca transient upstroke. In subcellular imaging, SCRs were temporally synchronous and spatially homogeneous within myocytes. In diastole, SHR elicited variable asynchronous sarcoplasmic reticulum Ca release events leading to subcellular Ca waves, detectable only at high magnification. SCR was regionally heterogeneous, correlated with APD prolongation (P 0.01, n 5), enhanced DOR (r 0.9277 0.03, n 7), and was gradually reversed by pacing at 120 beats/min along with APD shortening (P 0.05, n 5). A stabilizer of leaky ryanodine receptors (RyR2), 3-(4-benzylcyclohexyl)-1-(7methoxy-2,3-dihydrobenzo[f][1,4]thiazepin-4(5H)-yl)propan-1-one (K201; 1 M), suppressed SCR and reduced APD at the base, thereby reducing DOR (P 0.02, n 5). Ventricular ectopy induced by bradycardia (n 5/15) was suppressed by K201. Western blot analysis revealed spatial differences of voltage-gated L-type Ca channel protein (Cav1.2 ), Na -Ca exchange (NCX1), voltage-gated Na channel (Nav1.5), and rabbit ether-a-go-go-related (rERG) protein [but not RyR2 or sarcoplasmic reticulum Ca ATPase 2a] that correlate with the SCR distribution and explain the molecular basis for SCR heterogeneities. In conclusion, acute bradycardia elicits synchronized subcellular SCRs of sufficient magnitude to overcome the source-sink mismatch and to promote afterdepolarizations.