Pharmacological separation of early afterdepolarizations from arrhythmogenic substrate in ΔKPQ Scn5a murine hearts modelling human long QT 3 syndrome

AIM: To perform an empirical, pharmacological, separation of early afterdepolarizations (EADs) and transmural gradients of repolarization in arrhythmogenesis in a genetically modified mouse heart modelling human long QT syndrome (LQT) 3. METHODS: Left ventricular endocardial and epicardial monophasic action potentials and arrhythmogenic tendency were compared in isolated wild type (WT) and Scn5a+/Δ hearts perfused with 0.1 and 1 μm propranolol and paced from the right ventricular epicardium. RESULTS: All spontaneously beating bradycardic Scn5a+/Δ hearts displayed EADs, triggered beats and ventricular tachycardia (VT; n = 7), events never seen in WT hearts (n = 5). Perfusion with 0.1 and 1 μm propranolol suppressed all EADs, triggered beats and episodes of VT. In contrast, triggering of VT persisted following programmed electrical stimulation in 6 of 12 (50%), one of eight (12.5%), but six of eight (75%) Scn5a+/Δ hearts perfused with 0, 0.1 and 1 μm propranolol respectively in parallel with corresponding alterations in repolarization gradients, reflected in action potential duration (ΔAPD(90)) values. Thus 0.1 μm propranolol reduced epicardial but not endocardial APD(90) from 54.7 ± 1.6 to 44.0 ± 2.0 ms, restoring ΔAPD(90) from −3.8 ± 1.6 to 3.5 ± 2.5 ms (all n = 5), close to WT values. However, 1 μm propranolol increased epicardial APD(90) to 72.5 ± 1.2 ms and decreased endocardial APD(90) from 50.9 ± 1.0 to 24.5 ± 0.3 ms, increasing ΔAPD(90) to −48.0 ± 1.2 ms. CONCLUSION: These findings empirically implicate EADs in potentially initiating spontaneous arrhythmogenic phenomena and transmural repolarization gradients in the re-entrant substrate that would sustain such activity when provoked by extrasystolic activity in murine hearts modelling human LQT3 syndrome.