Effects of L‐type Ca 2+ channel antagonism on ventricular arrhythmogenesis in murine hearts containing a modification in the Scn5a gene modelling human long QT syndrome 3

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 Ca 2+ 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 (APD 90 ) 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 APD 90 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 n m , 100 n m , 300 n m and 1 μ m nifedipine, respectively ( P < 0.05; n = 5), giving an effective IC 50 concentration of 79.3 n m . 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 n m , 100 n m , 300 n m and 1 μ m nifedipine, respectively. Patch clamp studies in isolated ventricular myocytes from Scn5a +/Δ and WT hearts confirmed that nifedipine (300 n m ) completely suppressed the inward Ca 2+ current but had no effect on inward Na + currents. No significant effects were seen on epicardial APD 90 , endocardial APD 90 or ventricular effective refractory period in Scn5a +/Δ and WT hearts following perfusion with nifedipine at 1 n m , 10 n m , 100 n m , 300 n m and 1 μ m nifedipine concentrations. We conclude that L‐type Ca 2+ channel antagonism thus exerts specific anti‐arrhythmic effects in Scn5a +/Δ hearts through suppression of EADs.