Ranolazine Facilitates Termination of Ventricular Tachyarrhythmia Associated With Acute Myocardial Ischemia Through Suppression of Late INa-Mediated Focal Activity.

BACKGROUND: Ventricular tachycardia/fibrillation (VT/VF) associated with acute myocardial ischemia is the most common cause of sudden cardiac death, but its underlying mechanisms are incompletely understood. It is hypothesized that late Na+current (INa) contributes to arrhythmogenic activity in ischemic myocardium.Methods and Results:Langendorff-perfused rabbit hearts with regional ischemia in ventricles were optically mapped. Perfusion with ranolazine (10 µmol/L), a selective inhibitor of lateINa, significantly reduced excitation frequency and facilitated termination of VT/VF induced after occlusion of the left main coronary trunk. The activation pattern during ischemic VT/VF was characterized by breakthrough-type excitations (BEs) from multiple origins, predominantly in the ischemic border zone (BZ) and occasional short-lived rotors. Ranolazine perfusion significantly reduced the incidence of BEs in the BZ. Rotors tended to decrease with progression of ischemia and disappeared after ranolazine perfusion. During constant pacing, ranolazine attenuated ischemia-induced shortening of action potentials in the BZ without affecting conduction velocity, probably due toIKrinhibition. In intact hearts without coronary occlusion, ranolazine (10 µmol/L) terminated aconitine-induced VT by inhibiting focal arrhythmogenic activity in the injection site. CONCLUSIONS: LateINa-mediated focal arrhythmogenic activity plays important roles in the maintenance of ischemic VT/VF in isolated rabbit hearts. Suppression of lateINaby ranolazine may be a promising therapeutic strategy to reduce arrhythmic death during the acute phase of myocardial infarction.

Partial IK1 blockade destabilizes spiral wave rotation center without inducing wave breakup and facilitates termination of reentrant arrhythmias in ventricles.

It has been reported that blockade of the inward rectifier K(+) current (IK1) facilitates termination of ventricular fibrillation. We hypothesized that partial IK1 blockade destabilizes spiral wave (SW) re-entry, leading to its termination. Optical action potential (AP) signals were recorded from left ventricles of Langendorff-perfused rabbit hearts with endocardial cryoablation. The dynamics of SW re-entry were analyzed during ventricular tachycardia (VT), induced by cross-field stimulation. Intercellular electrical coupling in the myocardial tissue was evaluated by the space constant. In separate experiments, AP recordings were made using the microelectrode technique from right ventricular papillary muscles of rabbit hearts. Ba(2+) (10-50 µM) caused a dose-dependent prolongation of VT cycle length and facilitated termination of VT in perfused hearts. Baseline VT was maintained by a stable rotor, where an SW rotated around an I-shaped functional block line (FBL). Ba(2+) at 10 µM prolonged I-shaped FBL and phase-singularity trajectory, whereas Ba(2+) at 50 µM transformed the SW rotation dynamics from a stable linear pattern to unstable circular/cycloidal meandering. The SW destabilization was not accompanied by SW breakup. Under constant pacing, Ba(2+) caused a dose-dependent prolongation of APs, and Ba(2+) at 50 µM decreased conduction velocity. In papillary muscles, Ba(2+) at 50 µM depolarized the resting membrane potential. The space constant was increased by 50 µM Ba(2+) Partial IK1 blockade destabilizes SW rotation dynamics through a combination of prolongation of the wave length, reduction of excitability, and enhancement of electrotonic interactions, which facilitates termination of ventricular tachyarrhythmias.

Opposing effects of bepridil on ventricular repolarization in humans. Inhomogeneous prolongation of the action potential duration vs flattening of its restitution kinetics.

BACKGROUND: Bepridil is highly effective in the treatment of atrial fibrillation, but its clinical usefulness is limited by a potential risk for the drug-induced Torsades de pointes (TdP) in association with its Class III action. METHODS AND RESULTS: Monophasic action potentials (MAPs) were recorded from the right ventricular outflow tract (RVOT) and apex (RVA) in 9 patients treated with bepridil (172 +/-26 mg/day) and 10 control patients. Bepridil significantly increased the steady-state MAP durations at 90% repolarization (MAPD(90S) in a rate-independent manner at pacing cycle lengths ranging from 330 to 750 ms. The bepridil-induced prolongation of the MAPD(90) was greater in RVOT (approximately 13%) than RVA (approximately 8%). Bepridil flattened the MAPD(90) restitution slope estimated by an S1-S2 protocol in both the RVOT (0.65 +/-0.22 vs 0.95 +/-0.38) and RVA (0.65 +/-0.14 vs 0.94 +/-0.29). The T(peak-end) interval in the ECG was increased by bepridil for S1 but not S2 at the shortest diastolic interval to produce a ventricular response. CONCLUSIONS: Bepridil produces an inhomogeneous prolongation of the MAPDs, but flattens their restitution kinetics in the human ventricle. The former effect would favor the functional reentry predisposing to TdP, whereas the latter one would counteract that by reducing the dynamic instability of the repolarization.

Right ventricular septal pacing preserves long-term left ventricular function via minimizing pacing-induced left ventricular dyssynchrony in patients with normal baseline QRS duration.

BACKGROUND: Right ventricular septal (RVS) pacing is an alternative to right ventricular apical (RVA) pacing, but there is limited information about its influence on long-term left ventricular (LV) synchrony and function. METHODS AND RESULTS: A total of 55 patients undergoing dual-chamber pacemaker implantation with normal QRS duration and preserved LV function at baseline were included in the study. The right ventricular lead was implanted on the septum where it would produce the shortest QRS duration possible in 40 patients and in the apex in 15. The time-to-peak systolic velocity (T(sys)) was measured in 12 segments of the LV wall by tissue Doppler imaging. After a long (approximately 4 years) follow-up period, the LV ejection fraction (LVEF) decreased significantly in patients with RVA pacing but not in those with RVS pacing. Paced QRS duration was significantly shorter during RVS than RVA pacing. T(sys) dispersion among the 12 LV segments was significantly smaller during RVS than RVA pacing. There was a positive correlation between the paced QRS duration and T(sys) dispersion (R=0.65, P<0.0001). The pacing-induced decrease in LVEF was positively correlated with the degree of T(sys) dispersion (R=0.42, P=0.008). CONCLUSIONS: RVS pacing guided by the paced QRS morphology preserves long-term LV function via minimizing LV dyssynchrony.

Verapamil eliminates the hierarchical nature of activation frequencies from the pulmonary veins to the atria during paroxysmal atrial fibrillation.

BACKGROUND: There is evidence that verapamil promotes the persistence of paroxysmal atrial fibrillation (AF). Little is known about the underlying mechanisms. OBJECTIVE: The purpose of this study was to determine the effect of verapamil on dominant frequencies (DFs) in the pulmonary veins (PVs) and atria during paroxysmal AF with reference to its potential arrhythmogenicity. METHODS: Forty-three patients with paroxysmal AF were studied. Bipolar electrograms were recorded simultaneously during AF from the right atrial free wall (RAFW), coronary sinus (CS) and three PVs, or two PVs and the left atrial appendage (LAA). The DFs were obtained by fast Fourier transform analysis before and after infusion of verapamil (0.1 mg/kg, intravenously). RESULTS: At baseline, the maximum DF among the PVs (6.9 +/- 0.9 Hz) was significantly higher than the DF in the RAFW (6.2 +/- 0.7 Hz), CS (5.7 +/- 0.5 Hz), or LAA (5.9 +/- 0.7 Hz) (P<.01); there was a substantial PV-to-atrial DF gradient (RAFW 0.7 +/- 0.9, CS 1.1 +/- 0.7, LAA 0.7 +/- 0.9 Hz). Verapamil increased the atrial DF to 6.9 +/- 0.8, 6.6 +/- 0.7, and 7.2 +/- 1.0 Hz in the RAFW, CS, and LAA, respectively (P<.0001) but did not affect the maximum PV DF (7.1 +/- 0.7 Hz). The PV-to-atrial DF gradient was eliminated after verapamil (RAFW 0.2 +/- 0.8, CS 0.5 +/- 0.6, LAA -0.4 +/- 0.8 Hz; P<.01 vs. baseline). CONCLUSION: Verapamil increases the activation frequency in the atria but not in the PVs, eliminating the PV-to-atrial DF gradient during paroxysmal AF.