Brugada syndrome (BrS) is associated with a loss of Na + channel function and an increased incidence of rapid polymorphic ventricular tachycardia (VT) and sudden cardiac death. A programmed electrical stimulation (PES) technique assessed arrhythmic tendency in Langendorff-perfused wild-type (WT) and genetically modified (Scn5a+/−) 'loss-of-function' murine hearts in the presence and absence of flecainide and quinidine, and the extent to which Scn5a+/− hearts model the human BrS. Extra-stimuli (S2), applied to the right ventricular epicardium, followed trains of pacing stimuli (S1) at progressively reduced S1-S2 intervals.

Long QT(3) (LQT3) syndrome is associated with incomplete Na + channel inactivation, abnormal repolarization kinetics and prolonged cardiac action potential duration (APD). Electrophysiological effects of flecainide and quinidine were compared in Langendorff-perfused wild-type (WT), and genetically modified (Scn5a+/∆) murine hearts modelling LQT3. Extra stimuli (S2) following trains of pacing stimuli (S1) applied to the right ventricular epicardium triggered ventricular tachycardia (VT) in 16 out of 28 untreated Scn5a+/∆ and zero out of 12 WT hearts. Paced electrogram fractionation analysis then demonstrated increased electrogram durations (EGD), expressed as EGD ratios, in arrhythmogenic Scn5a+/∆ hearts, and prolonged ventricular effective refractory periods in initially non-arrhythmogenic Scn5a+/∆ hearts. Nevertheless, comparisons of epicardial and endocardial monophasic action potential recordings demonstrated negative transmural repolarization gradients in both groups, giving ∆APD 90 values at 90% repolarization of −20.88 ± 1.93 ms (n = 11) and −16.91 ± 1.43 ms (n = 23), respectively. Flecainide prevented initiation of VT in 13 out of 16 arrhythmogenic Scn5a+/∆ hearts, reducing EGD ratio and restoring ∆APD 90 to + 7.55 ± 2.24 ms (n = 9) (P < 0.05). VT occurred in four out of eight non-arrhythmogenic Scn5a+/∆ hearts in the presence of quinidine, which increased EGD ratio but left ∆APD 90 unchanged. In contrast (P < 0.05), WT hearts had positive ∆APD 90 values (+ 11.72 ± 2.17 ms) (n = 20). Flecainide then increased arrhythmic tendency and EGD ratio but conserved ∆APD 90 ; reduced EGD ratios and unaltered ∆APD 90 values accompanied the lower arrhythmogenicity associated with quinidine treatment. In addition to the changes in EGD ratio shown by WT hearts, these findings attribute arrhythmogenesis and its modification by flecainide and quinidine to alterations in ∆APD 90 in Scn5a+/∆ hearts. This is consistent with a hypothesis in which incomplete Na + channel inactivation in Scn5a+/∆ hearts generates functional substrates dependent on altered refractoriness that cause abnormalities in activation and conduction of subsequent cardiac impulses. Any spatial heterogeneities between the epicardial and endocardial layers would thus cause fragmentation of the activation wavefront and contribute to electrogram spreading.

Aims: We resolved roles for early afterdepolarizations (EADs) and transmural gradients of repolarization in arrhythmogenesis in Langendorff-perfused hypokalaemic murine hearts paced from the right ventricular epicardium. Methods: Left ventricular epicardial and endocardial monophasic action potentials (MAPs) and arrhythmogenic tendency were compared in the presence and absence of the L-type Ca 2+ channel blocker nifedipine (10 nm-1 lm) and the calmodulin kinase type II inhibitor KN-93 (2 lm).Results: All the hypokalaemic hearts studied showed prolonged epicardial and endocardial MAPs, decreased epicardial-endocardial APD 90 difference, EADs, triggered beats and ventricular tachycardia (VT) (n ¼ 6). In all spontaneously beating hearts, 100 (but not 10) nm nifedipine reduced both the incidence of EADs and triggered beats from 66.9 AE 15.7% to 28.3 AE 8.7% and episodes of VT from 10.8 AE 6.3% to 1.2 AE 0.7% of MAPs (n ¼ 6 hearts, P < 0.05); 1 lm nifedipine abolished all these phenomena (n ¼ 6). In contrast programmed electrical stimulation (PES) still triggered VT in six of six hearts with 0, 10 and 100 nm but not 1 lm nifedipine. 1 lm nifedipine selectively reduced epicardial (from 66.1 AE 3.4 to 46.2 AE 2.5 ms) but not endocardial APD 90 , thereby restoring DAPD 90 from )5.9 AE 2.5 to 15.5 AE 3.2 ms, close to normokalaemic values. KN-93 similarly reduced EADs, triggered beats and VT in spontaneously beating hearts to 29.6 AE 8.9% and 1.7 AE 1.1% respectively (n ¼ 6) yet permitted PESinduced VT (n ¼ 6), in the presence of a persistently negative DAPD 90 . Conclusions: These findings empirically implicate both EADs and triggered beats alongside arrhythmogenic substrate of DAPD 90 in VT pathogenesis at the whole heart level.

Aim: We explored the anti-arrhythmic efficacy of K + channel activation in the hypokalaemic murine heart using NS1643 and nicorandil, compounds which augment I Kr and I KATP respectively. Methods: Left ventricular epicardial and endocardial monophasic action potentials were compared in normokalaemic and hypokalaemic preparations in the absence and presence of NS1643 (30 lm) and nicorandil (20 lm). Results: Spontaneously beating hypokalaemic hearts (3 mm K + ) all elicited early afterdepolarizations (EADs) and episodes of ventricular tachycardia (VT). Perfusion with NS1643 and nicorandil suppressed EADs and VT in 7 of 13 and five of six hypokalaemic hearts. Provoked arrhythmia studies using programmed electrical stimulation induced VT in all hypokalaemic hearts, but failed to do so in 7 of 13 and five of six hearts perfused with NS1643 and nicorandil respectively. These anti-arrhythmic effects were accompanied by reductions in action potential duration at 90% repolarization (APD 90 ) and changes in the transmural gradient of repolarization, reflected in DAPD 90 . NS1643 and nicorandil reduced epicardial APD 90 from 68.3 AE 1.1 to 56.5 AE 4.1 and 51.5 AE 1.5 ms, respectively, but preserved endocardial APD 90 in hypokalaemic hearts. NS1643 and nicorandil thus restored DAPD 90 from )9.6 AE 4.3 ms under baseline hypokalaemic conditions to 3.9 AE 4.1 and 9.9 AE 2.1 ms, respectively, close to normokalaemic values. Conclusion: These findings demonstrate, for the first time, the anti-arrhythmic efficacy of K + channel activation in the setting of hypokalaemia.NS1643 and nicorandil are anti-arrhythmic through the suppression of EADs, reductions in APD 90 and restorations of DAPD 90 .