Effects of L-type Ca2+ channel antagonism on ventricular arrhythmogenesis in murine hearts containing a modification in the Scn5a gene modelling human long QT syndrome 3

摘要

Ventricular arrhythmogenesis in long QT 3 syndrome (LQT3) involves both triggered activity and re-entrant excitation arising from delayed ventricular repolarization. Effects of specific L-type Ca²⁺ channel antagonism were explored in a gain-of-function murine LQT3 model produced by a ΔKPQ 1505–1507 deletion in the SCN5A gene. Monophasic action potentials (MAPs) were recorded from epicardial and endocardial surfaces of intact, Langendorff-perfused Scn5a+/Δ hearts. In untreated Scn5a+/Δ hearts, epicardial action potential duration at 90% repolarization (APD90) was 60.0 ± 0.9 ms compared with 46.9 ± 1.6 ms in untreated wild-type (WT) hearts (P < 0.05; n = 5). The corresponding endocardial APD90 values were 52.0 ± 0.7 ms and 53.7 ± 1.6 ms in Scn5a+/Δ and WT hearts, respectively (P > 0.05; n = 5). Epicardial early afterdepolarizations (EADs), often accompanied by spontaneous ventricular tachycardia (VT), occurred in 100% of MAPs from Scn5a+/Δ but not in any WT hearts (n = 10). However, EAD occurrence was reduced to 62 ± 7.1%, 44 ± 9.7%, 10 ± 10% and 0% of MAPs following perfusion with 10 nm, 100 nm, 300 nm and 1 μm nifedipine, respectively (P < 0.05; n = 5), giving an effective IC50 concentration of 79.3 nm. Programmed electrical stimulation (PES) induced VT in all five Scn5a+/Δ hearts (n = 5) but not in any WT hearts (n = 5). However, repeat PES induced VT in 3, 2, 2 and 0 out of 5 Scn5a+/Δ hearts following perfusion with 10 nm, 100 nm, 300 nm and 1 μm nifedipine, respectively. Patch clamp studies in isolated ventricular myocytes from Scn5a+/Δ and WT hearts confirmed that nifedipine (300 nm) completely suppressed the inward Ca²⁺ current but had no effect on inward Na⁺ currents. No significant effects were seen on epicardial APD90, endocardial APD90 or ventricular effective refractory period in Scn5a+/Δ and WT hearts following perfusion with nifedipine at 1 nm, 10 nm, 100 nm, 300 nm and 1 μm nifedipine concentrations. We conclude that L-type Ca²⁺ channel antagonism thus exerts specific anti-arrhythmic effects in Scn5a+/Δ hearts through suppression of EADs.