Refractory dispersion promotes conduction disturbance and arrhythmias in a Scn5a +/− mouse model

Abstract

Accentuated right ventricular (RV) gradients in action potential duration (APD) have been implicated in the arrhythmogenicity observed in Brugada syndrome in studies assuming that ventricular effective refractory periods (VERPs) vary in concert with APDs. The present experiments use a genetically modified mouse model to explore spatial heterogeneities in VERP that in turn might affect conduction velocity, thereby causing arrhythmias. Activation latencies, APDs and VERPs recorded during programmed S1S2 protocols were compared in RV and left ventricular (LV) epicardia and endocardia of Langendorff-perfused wild-type (WT) and Scn5a+/− hearts. Scn5a+/− and WT hearts showed similar patterns of shorter VERPs in RV than LV epicardia, and in epicardia than endocardia. However, Scn5a+/− hearts showed longer VERPs, despite shorter APD90s, than WT in all regions examined. The pro- and anti-arrhythmic agents flecainide and quinidine increased regional VERPs despite respectively decreasing and increasing the corresponding APD90s particularly in Scn5a+/− RV epicardia. In contrast, Scn5a+/− hearts showed greater VERP gradients between neighbouring regions, particularly RV transmural gradients, than WT (9.1 ± 1.1 vs. 5.7 ± 0.5 ms, p < 0.05, n = 12). Flecainide increased (to 21 ± 0.9 ms, p < 0.05, n = 6) but quinidine decreased (to 4.5 ± 0.5 ms, p < 0.05, n = 6) these gradients, particularly across the Scn5a+/− RV. Finally, Scn5a+/− hearts showed greater conduction slowing than WT following S2 stimuli, particularly with flecainide administration. Rather than arrhythmogenesis resulting from increased transmural repolarization gradients in an early, phase 2, reentrant excitation mechanism, the present findings implicate RV VERP gradients in potential reentrant mechanisms involving impulse conduction slowed by partial refractoriness.

Epac‐induced ryanodine receptor type 2 activation inhibits sodium currents in atrial and ventricular murine cardiomyocytes

“…The present findings thus implicate conduction velocity secondary to compromised Na + current as a source for arrhythmic substrate under conditions of acutely perturbed cytosolic Ca 2+ homeostasis, reconstructing the altered conduction previously reported in Na v 1.5 haplo‐insufficient, Scn5a +/− murine models for Brugada Syndrome . They also complement previous findings in murine hearts chronically modelling catecholaminergic polymorphic ventricular tachycardia (CPVT).…”

“…Such findings suggest that acutely altered Ca 2+ homeostasis might result in arrhythmic substrate arising from delayed conduction, as previously suggested for the pro‐arrhythmic Brugada syndrome in contrast to the recovery abnormalities associated with the LQT syndromes . The pro‐arrhythmic effects of acute abnormalities in cardiomyocyte Ca 2+ homeostasis provoked by adrenergic stimulation, caffeine‐mediated RyR2 stimulation or modified extracellular Ca 2+ entry, have hitherto been primarily associated with arrhythmic triggering by delayed afterdepolarisation effects arising from the consequently altered Na + –Ca 2+ exchanger activity.…”

Optogenetic determination of the myocardial requirements for extrasystoles by cell type-specific targeting of ChannelRhodopsin-2

“…5C). This latter value was indistinguishable from those values obtained with conventional electrical stimulation (54).…”

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

“…The same pattern of I to distribution is present in the rodent heart . A greater expression of I to in RV myocytes contributes to a shorter APD in the RV compared to the LV chamber in rats and mice …”

“…Although quinidine was shown to increase the dispersion of ventricular repolarization in perfused rabbit heart, other studies reported no effect, or reduced repolarization gradients in the same animal model. Quinidine was found to reduce the transmural dispersion of refractoriness in a mouse heart, and had no effect on APD dispersion in canine RV; these changes suggest an antiarrhythmic (rather than proarrhythmic) profile of action.…”