Tengxian Liu

Phase 2 early afterdepolarization as a trigger of polymorphic ventricular tachycardia in acquired long-QT syndrome : direct evidence from intracellular recordings in the intact left ventricular wall.

Background—This study examined the role of phase 2 early afterdepolarization (EAD) in producing a trigger to initiate torsade de pointes (TdP) with QT prolongation induced by dl-sotalol and azimilide. The contribution of transmural dispersion of repolarization (TDR) to transmural propagation of EAD and the maintenance of TdP was also evaluated. Methods and Results—Transmembrane action potentials from epicardium, midmyocardium, and endocardium were recorded simultaneously, together with a transmural ECG, in arterially perfused canine and rabbit left ventricular preparations. dl-Sotalol preferentially prolonged action potential duration (APD) in M cells dose-dependently (1 to 100 &mgr;mol/L), leading to QT prolongation and an increase in TDR. Azimilide, however, significantly prolonged APD and QT interval at concentrations from 0.1 to 10 &mgr;mol/L but shortened them at 30 &mgr;mol/L. Unlike dl-sotalol, azimilide (>3 &mgr;mol/L) increased epicardial APD markedly, causing a diminished TDR. Although both dl-sotalol and azimilide rarely induced EADs in canine left ventricles, they produced frequent EADs in rabbits, in which more pronounced QT prolongation was seen. An increase in TDR by dl-sotalol facilitated transmural propagation of EADs that initiated multiple episodes of spontaneous TdP in 3 of 6 rabbit left ventricles. Of note, although azimilide (3 to 10 &mgr;mol/L) increased APD more than dl-sotalol, its EADs often failed to propagate transmurally, probably because of a diminished TDR. Conclusions—This study provides the first direct evidence from intracellular action potential recordings that phase 2 EAD can be generated from intact ventricular wall and produce a trigger to initiate the onset of TdP under QT prolongation.

Left Ventricular Hypertrophy Decreases Slowly but Not Rapidly Activating Delayed Rectifier Potassium Currents of Epicardial and Endocardial Myocytes in Rabbits

BackgroundDelayed rectifier K+ currents are critical to action potential (AP) repolarization. The present study examines the effects of left ventricular hypertrophy (LVH) on delayed rectifier K+ currents and their contribution to AP repolarization in both epicardial (Epi) and endocardial (Endo) myocytes. Methods and ResultsLVH was induced in rabbits by a 1-kidney removal, 1-kidney vascular clamping method. Slowly (IKs) and rapidly (IKr) activating delayed rectifier K+ currents were recorded by the whole-cell patch-clamp technique, and APs were recorded by the microelectrode technique. In normal rabbit left ventricular myocytes, IKs densities were larger in Epi than in Endo (1.1±0.1 versus 0.43±0.07 pA/pF), whereas IKr density was similar between Epi and Endo (0.31±0.05 versus 0.36±0.07 pA/pF) at 20 mV. LVH reduced IKs density to a similar extent (≈40%) in both Epi and Endo but had no significant effect on IKr in either Epi or Endo. Consequently, IKr was expected to contribute more to AP repolarization in LVH than in control. This was confirmed by specific IKr block with dofetilide, which prolonged AP significantly more in LVH than in control (31±3% versus 18±2% in Epi; 53±6% versus 32±4% in Endo at 2 Hz). In contrast, L-768,673 (a specific IKs blocker) prolonged AP less in LVH than in control. The very small IKs density in Endo with LVH is consistent with the greater incidence of early afterdepolarizations induced in this region by dofetilide. ConclusionsLVH induces a decrease in IKs density and increases the propensity to develop early afterdepolarizations, especially in Endo.

Assessment of the proarrhythmic potential of the novel antiarrhythmic agent AZD7009 and dofetilide in experimental models of torsades de pointes.

Background: This study examined the proarrhythmic potential of the novel antiarrhythmic agent AZD7009 and dofetilide.

Restoration of Normal Ventricular Electrophysiology in Renovascular Hypertensive Rabbits after Treatment with Losartan

Left ventricular hypertrophy (LVH) is associated with abnormal ventricular electrophysiology. We have shown complete regression of LVH and normalization of ventricular electrophysiology in renovascular hypertensive rabbits treated with captopril. To determine if angiotensin II type 1 receptor (AT1) blockade produces the same benefit, we treated hypertensive rabbits with losartan for 3 months. LVH was evaluated by heart-to-body weight ratio (HW/BW). Vulnerability to ventricular arrhythmia was assessed by ventricular fibrillation threshold (VFT) and dispersion of effective refractory period (ERP). The electrical properties of single left ventricular myocytes were characterized by action potential duration at 90% repolarization (APD90) and inward rectifier K+ current (IK1) density. Hypertensive rabbits treated with vehicle (LVH/Vehicle) had higher mean arterial pressure (MAP, 81 ± 2 vs. 60 ± 2 mm Hg) and HW/BW (2.71 ± 0.07 vs. 1.97 ± 0.04 g/kg), lower VFT (20 ± 1 vs. 39 ± 2 mA), larger dispersion of ERP (34 ± 3 vs. 14 ± 3 ms), longer APD90 (187 ± 6 vs. 162 ± 6 ms) and lower IK1 density compared with control rabbits. Hypertensive rabbits treated with losartan (LVH/Losartan) had HW/BW (2.36 ± 0.06 g/kg) between those of LVH/Vehicle and control rabbits, whereas MAP (65 ± 2 mm Hg), VFT (34 ± 2 mA), dispersion of ERP (19 ± 1 ms), APD90 (160 ± 6 ms), and IK1 density were significantly different from LVH/Vehicle but similar to control. We conclude that AT1 blockade in renovascular hypertensive rabbits normalizes ventricular electrophysiology.

Electrophysiologic effects of SB-237376: a new antiarrhythmic compound with dual potassium and calcium channel blocking action.

Combined potassium and calcium channel blocking activities are suggested to be the basis for antiarrhythmic efficacy with low proarrhythmic risk. The electrophysiologic effects of SB-237376 were investigated in single myocytes and arterially perfused wedge preparations of canine or rabbit left ventricles. The concentration-dependent prolongation of action potential duration (APD) and QT interval by SB-237376 was bell-shaped and the maximum response occurred at 1–3 &mgr;M. SB-237376 inhibited rapidly activating delayed rectifier K+ current (IKr) with an IC50 of 0.42 &mgr;M and use-dependently blocked L-type Ca2+ current (ICa,L) at high concentrations. The SB-237376 (3 &mgr;M) induced phase-2 early afterdepolarizations (EADs) in five of six rabbit wedge preparations but none of six canine wedge preparations. This is probably due to larger increases of APD, QT interval, and transmural dispersion of repolarization (TDR) in rabbits than dogs. Based on the drug effects on QT interval, TDR, and EAD in rabbit ventricular wedge preparations, a scoring system predicted lower proarrhythmic risk for SB-237376 than for dl-sotalol, a specific IKr blocker. In conclusion, SB-237376 increases APD, QT interval, and TDR mainly by IKr inhibition. These effects are self-limited due to SB-237376–induced ICa,L blockade at high concentrations, which may explain its lower proarrhythmic risk than dl-sotalol.

Electrophysiological properties of HBI-3000: a new antiarrhythmic agent with multiple-channel blocking properties in human ventricular myocytes.

HBI-3000 (sulcardine sulfate) has been shown to suppress various ventricular arrhythmias in animal models. The electrophysiological properties of HBI-3000 were investigated using standard microelectrode and patch-clamp techniques in single human ventricular myocytes. HBI-3000 led to concentration-dependent suppression of dofetilide-induced early afterdepolarizations in single nonfailing human ventricular myocytes and early afterdepolarizations seen in failing ventricular myocytes. The concentration-dependent prolongation of action potential duration (APD) by HBI-3000 was bell shaped with maximum response occurring around 10 μM. Interestingly, HBI-3000 at the concentration of 10 μM modestly prolonged the APD at all 3 basic cycle lengths. The slope of APD-cycle length curve of HBI-3000 was only slightly steeper than that of control (88.8 ± 7.7 ms/s vs. 78.9 ± 5.2 ms/s in control, n = 8, P > 0.05). HBI-3000 only showed a minimal use-dependent prolongation of the APD in human ventricular myocytes. HBI-3000 inhibited fast sodium current (INa-F), late sodium channel (INa-L), L-type calcium current (ICa-L), and rapidly activating delayed rectifier K+ current (IKr) in single human ventricular myocytes. The estimated half-maximal inhibitory concentration values of INa-F, INa-L, ICa-L, and IKr were 48.3 ± 3.8, 16.5 ± 1.4, 32.2 ± 2.9, and 22.7 ± 2.5 μM, respectively. The ion channel profile and electrophysiological properties of HBI-3000 are similar to those of ranolazine and chronic amiodarone (reduced INa-F, INa-L, ICa-L, and IKr). HBI-3000 may be a promising antiarrhythmic agent with low proarrhythmic risk.