Effects of L-type Ca2+ channel antagonism on ventricular arrhythmogenesis in {Delta}KPQ Scn5a (long QT 3) murine hearts. [J Physiol] Journal article

Ventricular arrhythmogenesis in long QT3 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 DeltaKPQ 1505-1507 deletion in the SCN5A gene. Monophasic action potentials (MAPs) were recorded from epicardial and endocardial surfaces of intact, Langendorff-perfused Scn5a+/Delta hearts. In untreated Scn5a+/Delta hearts, epicardial APD90 was 60.0 +/- 0.9 ms compared with 46.9 +/- 1.6 ms in 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+/Delta 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+/Delta 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 microM nifedipine respectively (P<0.05, n=5), giving an effective IC50 concentration of 79.3 nM. Programmed electrical stimulation (PES) induced VT in all 5 Scn5a+/Delta 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+/Delta hearts following perfusion with 10 nM, 100 nM, 300 nM and 1 microM nifedipine respectively. Patch clamp studies in isolated ventricular myocytes from Scn5a+/Delta and WT hearts confirmed that nifedipine (300 nM) completely suppressed the inward Ca(2+) 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+/Delta and WT hearts following perfusion with nifedipine at 1 nM, 10 nM, 100 nM, 300 nM and 1 microM nifedipine concentrations. We conclude that L-type Ca(2+) channel antagonism thus exerts specific anti-arrhythmic effects in Scn5a+/Delta hearts through suppression of EADs.

J Physiol