Bradycardia alters Ca²⁺dynamics enhancing dispersion of repolarization and arrhythmia risk

Abstract

Kim JJ, Němec J, Papp R, Strongin R, Abramson JJ, Salama G. Bradycardia alters Ca 2ϩ 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 2ϩ transients and APs were measured optically from Langendorff rabbit hearts at high (150 ϫ 150 m 2 ) or low (1.5 ϫ 1.5 cm 2 ) magnification while pacing at a physiological (120 beats/min) or a slow heart rate (SHR ϭ 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 ϭ 48 Ϯ 9.2 s) and caused a secondary Ca 2ϩ release (SCR) from the sarcoplasmic reticulum during AP plateaus, occurring at the base on average of 184.4 Ϯ 9.7 ms after the Ca 2ϩ transient upstroke. In subcellular imaging, SCRs were temporally synchronous and spatially homogeneous within myocytes. In diastole, SHR elicited variable asynchronous sarcoplasmic reticulum Ca 2ϩ release events leading to subcellular Ca 2ϩ waves, detectable only at high magnification. SCR was regionally heterogeneous, correlated with APD prolongation (P Ͻ 0.01, n ϭ 5), enhanced DOR (r ϭ 0.9277 Ϯ 0.03, n ϭ 7), and was gradually reversed by pacing at 120 beats/min along with APD shortening (P Ͻ 0.05, n ϭ 5). A stabilizer of leaky ryanodine receptors (RyR2), 3-(4-benzylcyclohexyl)-1-(7-methoxy-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 Ͻ 0.02, n ϭ 5). Ventricular ectopy induced by bradycardia (n ϭ 5/15) was suppressed by K201. Western blot analysis revealed spatial differences of voltage-gated L-type Ca 2ϩ channel protein (Cav1.2␣), Na ϩ -Ca 2ϩ exchange (NCX1), voltage-gated Na ϩ channel (Nav1.5), and rabbit ether-a-go-go-related (rERG) protein [but not RyR2 or sarcoplasmic reticulum Ca 2ϩ 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. action potential adaptation; arrhythmia; bradycardia; optical mapping; secondary Ca 2ϩ release BRADYCARDIA, DEFINED AS heart rate (HR) Ͻ 60 beats/min in adult humans (12), is usually a normal adaptive response to conditions of low metabolic demand, such as rest and sleep. Bradycardia due to pathological conditions, e.g., sick sinus syndrome, atrioventricular (AV) nodal disease, or conduction system disease, is common in clinical practice and frequently causes symptoms because of inappropriately low cardiac output. Less frequently, profound bradycardia, usuall...

Vagal modulation of dispersion of repolarisation in the rabbit heart

“…The same result was generated using the bidomain 356 implementation (see Supplementary Table 1) and rate-dependence of 357 APD dispersion was conserved, with little change, following a ± 10% 358 alteration in cell-to-cell coupling and peak conductance of major ionic 359 channels (see Supplementary Table 2). of acute bradycardic pacing [4]. It is already well established that slow 402 pacing rates increase ventricular DOR [2][3][4][5] and, in the present study, 403 we demonstrate that a similar increase in dispersion is associated with 404 vagally mediated bradycardia.…”

“…of acute bradycardic pacing [4]. It is already well established that slow 402 pacing rates increase ventricular DOR [2][3][4][5] and, in the present study, 403 we demonstrate that a similar increase in dispersion is associated with 404 vagally mediated bradycardia.…”

“…Slowing of rate is associated with an increase in the spatiotemporal dispersion of repolarisation 48 (DOR) in electrically paced hearts [2][3][4][5]. However, stimulation of the 49 vagus nerve, which mediates the slowing of heart rate in vivo, has 50 been reported to reverse the sequence of ventricular repolarisation, 51 without altering the magnitude of DOR, in isolated rabbit hearts [6].…”

Electrophysiological effects of right and left vagal nerve stimulation on the ventricular myocardium

“…Overall, both right and left VNS caused small increases in DOR on the epicardium. This may be due to the bradycardia caused by VNS (28) or to the more sparse density of parasympathetic nerve fibers on the epicardium (51). In fact, functional parasympathetic innervation of the endocardium was greater than the epicardium, consistent with a histological study (51) showing that the endocardium has a greater density of parasympathetic fibers.…”

A case of sudden death after Japanese encephalitis vaccination

“…Vasovagal syncope has been documented to occur following immunization, most commonly among adolescents, and the observation of patients is recommended to prevent secondary severe injury after syncope [36,37]. Though vasovagal syncope itself is benign, bradycardia can prolong the QT interval by delaying cellular repolarization [38,39]. Thus syncope can be a risk factor of cardiac dysfunction in patients treated with psychotropic drugs causing prolongation of the QT interval [40].…”