Ranolazine stabilizes cardiac ryanodine receptors: a novel mechanism for the suppression of early afterdepolarization and torsades de pointes in long QT type 2.

BACKGROUND: Ranolazine (Ran) is known to inhibit multiple targets, including the late Na(+)current, the rapid delayed rectifying K(+)current, the L-type Ca(2+)current, and fatty acid metabolism. Functionally, Ran suppresses early afterdepolarization (EADs) and torsades de pointes (TdP) in drug-induced long QT type 2 (LQT2) presumably by decreasing intracellular [Na(+)](i) and Ca(2+)overload. However, simulations of EADs in LQT2 failed to predict their suppression by Ran. OBJECTIVE: To elucidate the mechanism(s) whereby Ran alters cardiac action potentials (APs) and cytosolic Ca(2+)transients and suppresses EADs and TdP in LQT2. METHODS: The known effects of Ran were included in simulations (Shannon and Mahajan models) of rabbit ventricular APs and Ca(2+)transients in control and LQT2 models and compared with experimental optical mapping data from Langendorff rabbit hearts treated with E4031 (0.5 µM) to block the rapid delayed rectifying K(+)current. Direct effects of Ran on cardiac ryanodine receptors (RyR2) were investigated in single channels and changes in Ca(2+)-dependent high-affinity ryanodine binding. RESULTS: Ran (10 µM) alone prolonged action potential durations (206 ± 4.6 to 240 ± 7.8 ms; P <0.05); E4031 prolonged action potential durations (204 ± 6 to 546 ± 35 ms; P <0.05) and elicited EADs and TdP that were suppressed by Ran (10 µM; n = 7 of 7 hearts). Simulations (Shannon but not Mahajan model) closely reproduced experimental data except for EAD suppression by Ran. Ran reduced open probability (P(o)) of RyR2 (half maximal inhibitory concentration = 10 ± 3 µM; n = 7) in bilayers and shifted half maximal effective concentration for Ca(2+)-dependent ryanodine binding from 0.42 ± 0.02 to 0.64 ± 0.02 µM with 30 µM Ran. CONCLUSIONS: Ran reduces P(o) of RyR2, desensitizes Ca(2+)-dependent RyR2 activation, and inhibits Ca(i) oscillations, which represents a novel mechanism for its suppression of EADs and TdP.

Increase in organization index predicts atrial fibrillation termination with flecainide post-ablation: spectral analysis of intracardiac electrograms.

AIMS: The mechanism of the action of flecainide in the termination of human atrial fibrillation (AF) is not fully understood. We studied the acute effects of flecainide on AF electrograms in the time and frequency domain to identify factors associated with AF termination. METHODS AND RESULTS: Patients who were still in AF at the end of catheter ablation for AF were given intravenous flecainide. Dominant frequency (DF) and organization index (OI) were obtained by fast Fourier transform of electrograms from the coronary sinus catheter over 10 s in AF, before and after flecainide infusion. Mean AF cycle length (CL) was also calculated. Twenty-six patients were studied (16 paroxysmal AF and 10 persistent AF). Seven converted to sinus rhythm (SR) with flecainide. In all patients, mean CL increased from 211 +/- 44 to 321 +/- 85 ms (P < 0.001). Mean DF decreased from 5.2 +/- 1.03 to 3.6 +/- 1.04 Hz (P < 0.001). Mean OI was 0.33 +/- 0.13 before and 0.32 +/- 0.11 after flecainide (P = 0.90). Comparing patients who converted to SR with those who did not, OI post-flecainide was 0.41 +/- 0.12 vs. 0.29 +/- 0.10 (P = 0.013), and the relative change in OI was 29 +/- 33 vs. -3.9 +/- 27% (P = 0.016), respectively. No significant difference was noted in the change in CL and DF in the two groups. CONCLUSION: Increase in OI, independent of changes to CL and DF, appears critical to AF termination with flecainide. Increase in OI holds promise as a sensitive predictor of AF termination.

Sympathetic nerve stimulation produces spatial heterogeneities of action potential restitution.

BACKGROUND: Restitution kinetics (RK) of action potential duration (APD) are classically studied by applying an extra impulse at varying diastolic intervals (DI) and might differ from RK elicited by sympathetic nerve stimulation (SNRK). OBJECTIVE: To measure 'Physiological' RK during gradual increases in heart rate caused by sympathetic nerve stimulation (SNS) and its possible spatial heterogeneities caused by non-uniform innervation of the myocardium. METHODS: The SNRK was measured from rabbit hearts with intact sympathetic innervation using optical mapping. APD versus DI were plotted from left ventricles during SNS, then with pacing using identical activation interval (AI) sequences. RESULTS: AI decreased (444 +/- 18 ms to 284 +/- 9 ms) in 25 s and recovered to baseline on SNS suspension (n = 10). APD versus DI plots were identical for SNS and pacing except that when maximum heart rate was reached, SNS elicited a further APD shortening compared with pacing. During SNS, APDs decreased from 216 +/- 9 ms to 154 +/- 7 ms (29% +/- 2%) at the base and from 206 +/- 12 ms to 158 +/- 7 ms (20% +/- 2%) at the apex. During pacing, APDs at the base decreased from 216 +/- 9 ms to 170 +/- 7 ms (21% +/- 1%, SNS versus pacing: P < .05). In contrast, RK were similar at the apex for SNS and pacing. During SNS, the extra APD shortening at the base was associated with longer segments of RK curves with negative slopes and extra DI prolongation. Perfusion with the I(Ks) inhibitor HMR 1556 (0.5 microM; n = 5) abolished differences in RK between SNS and pacing. Levels of KCNQ1 and tyrosine hydroxylase proteins were greater at the base than apex (n = 4), implying that apex-base distributions for I(Ks) and sympathetic innervation are congruent with SNRK heterogeneities. CONCLUSION: The findings shed further insights on heterogeneities of sympathetic nerves, RK, and the role of I(Ks) in cardiac repolarization.

Pulmonary Vein Isolation using a High Density Mesh Ablator Catheter: Incorporation of three-Dimensional Navigation and Mappin.

Background: We evaluated the use of a novel High Density Mesh Ablator (HDMA) catheter in combination with three-dimensional navigation for the treatment of paroxysmal atrial fibrillation. Methods: The HDMA catheter was used to carry out pulmonary vein isolation in a consecutive series of patients. Three-dimensional geometry of the left atrial-pulmonary vein (LA-PV) junctions were first created with the HDMA catheter. Ostial, proximal and distal sites within the pulmonary veins were tagged with catheter shadows on the created geometry to allow for re-interrogation of these exact sites after ablation. Results: The HDMA catheter was successfully used to create three dimensional geometry of the LA-PV junction in a total of 20 pulmonary veins which involved 5 patients. In all cases, ostial ablation alone was sufficient to achieve electrical isolation. No significant pulmonary vein stenosis was seen acutely after ablation. Conclusion: We describe the successful use of the novel HDMA catheter to create three-dimensional geometry of the LA-PV junction to assist with pulmonary vein isolation.

Autonomic nerve stimulation reverses ventricular repolarization sequence in rabbit hearts.

Sympathetic activity and spatial dispersion of repolarization (DOR) have been implicated as mechanisms that promote arrhythmia vulnerability; yet there are no direct measurements of the effects of autonomic nerve stimulation on DOR. Rabbit hearts were perfused in a Langendorff apparatus with full sympathetic and parasympathetic innervation and were optically mapped to measure action potential durations and DOR (apex-base) over the left ventricles. DOR was measured under sinus rhythm, during bilateral sympathetic nerve stimulation (SNS) and right and/or left vagus nerve stimulation and was compared with DOR during isoproterenol (100 nmol/L) or acetylcholine (1 micromol/L) infusion. In sinus rhythm, repolarization started at the apex and systematically progressed toward the base. SNS (10 to 15 Hz) increased DOR by 29% (from Deltaaction potential duration=17+/-0.7 to -22+/-1.6 ms, n=6) and reversed DOR as the direction of repolarization from apex-->base in sinus rhythm shifted to base-->apex in 5 to 15 seconds after SNS. DOR flipped back to its sinus rhythm DOR pattern 115+/-15 seconds after the interruption of SNS. During right or left vagus nerve stimulation, there was no change in the direction of DOR, but bilateral vagus nerve stimulation increased and reversed DOR to base-->apex direction. Infusion of isoproterenol or acetylcholine increased DOR but did not alter the direction of repolarization sequences. These findings demonstrate that bilateral autonomic activity (SNS or vagus nerve stimulation) cause reversible shifts of apex-base DOR and that the spatial heterogeneities of autonomic effects on the ventricles are most likely attributable to a greater innervation at the base than the apex of the heart.