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JTV-519 is a 1,4-benzothiazepine derivative with multichannel effects that inhibits Ca2+ release from the sarcoplasmic reticulum and stabilizes the closed state of the ryanodine receptor, preventing myocardial damage and the induction of arrhythmias during Ca2+ overload. Mechanical stretch increases cellular Na+ inflow, activates the reverse mode of the Na+/Ca2+ exchanger, and modifies Ca2+ handling and myocardial electrophysiology, favoring arrhythmogenesis. This study aims to determine whether JTV-519 modifies the stretch-induced manifestations of mechanoelectric feedback. The ventricular fibrillation ( VF) modifications induced by acute stretch were studied in Langendorff-perfused rabbit hearts using epicardial multiple electrodes under control conditions (n=9) or during JTV-519 perfusion: 0.1 μmol/L (n=9) and 1 μmol/L (n=9). Spectral and mapping techniques were used to establish the baseline, stretch and post-stretch VF characteristics. JTV-519 slowed baseline VF and decreased activation complexity. These effects were dose-dependent (baseline VF dominant frequency: control=13.9±2.2 Hz; JTV 0.1 μmol/L=11.1±1.1 Hz, P<.01; JTV 1 μmol/L=6.6±1.1 Hz, P<.0001). The stretch-induced acceleration of VF (control=38.8%) was significantly reduced by JTV-519 0.1 μmol/L (19.8%) and abolished by JTV 1 μmol/L (−1.5%). During stretch, the VF activation complexity index was reduced in both JTV-519 series (control=1.60±0.15; JTV 0.1 μmol/L=1.13±0.3, P<.0001; JTV 1 μmol/L=0.57±0.21, P<.0001), and was independently related to VF dominant frequency ( R=.82; P<.0001). The fifth percentile of the VF activation intervals, conduction velocity and wavelength entered the multiple linear regression model using dominant frequency as the dependent variable ( R=−.84; P<.0001). In conclusion, JTV-519 slowed and simplified the baseline VF activation patterns and abolished the stretch-induced manifestations of mechanoelectric feedback. [ABSTRACT FROM AUTHOR]

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Background: Few experimental studies have analyzed the effects of selective radiofrequency (RF) lesions upon ventricular fibrillation (VF). The RF-induced isolation of selected zones would make it possible to determine whether these zones are essential for existence of the arrhythmia. Methods: In 31 Langendorff-perfused rabbit hearts, the characteristics and inducibility of VF were analyzed before and after the induction of RF lesions comprising: (1) the posterior zone of the septum and of the walls of both ventricles (n = 10); (2) the anterior zone of the septum and of the walls of both ventricles (n = 11); and (3) the midseptal zone (n = 10). Results: Complete isolation of the zone encompassed by the lesions was obtained in 5, 6, and 5 experiments of series 1, 2, and 3, respectively. In these experiments, the arrhythmia was only induced from within the zone encompassed by the lesions in one experiment belonging to series 2 (P < 0.05 with respect to baseline). In contrast, in all but one of the cases in series 2, VF could be induced from outside the isolated zone (ns vs baseline). Partial isolation was obtained in five experiments of each series. In these experiments, on pacing from within the partially isolated zone, sustained VF was not induced in any experiment (P < 0.05 with respect to baseline), while in all cases VF could be induced on pacing from the external zone (ns vs baseline). Conclusion: In the experimental model used, the three zones studied were not essential for maintaining VF. In most cases, their partial or total isolation avoided inducibility of the arrhythmia in those zones, though not in the remaining myocardium. [ABSTRACT FROM AUTHOR]

Introduction: We hypothesize that local modifications in electrophysiological properties, when confined to zones of limited extent, induce few changes in the global activation process during ventricular fibrillation (VF). To test this hypothesis, we produced local electrophysiological modifications by stretching a circumscribed zone of the left ventricular wall in an experimental model of VF. Methods and Results: In 23 Langendorff-perfused rabbit hearts frequency, time–frequency and time-domain techniques were used to analyze the VF recordings obtained with two epicardial multiple electrodes before, during, and after local stretching produced with a left intraventricular device. Acute local stretching accelerated VF in the stretched zone reversibly and to a variable degree, depending on the magnitude of stretch and the time elapsed from its application. In the half time (5 minutes) of the analyzed period, a longitudinal lengthening of 12.1 ± 4.5% (vertical axis) and 11.8 ± 6.2% (horizontal axis) in the stretched zone produced an increase in the dominant frequency (DFr) (15.2 ± 1.9 versus 18.8 ± 2.5 Hz, P < 0.0001), a decrease in mean VV interval (63 ± 8 versus 53 ± 6 msec, P < 0.001), and an increase in the complexity of the activation maps—with more areas of conduction block and more breakthrough patterns (23% versus 37%, P < 0.01), without significant changes in the percentages of complete reentry patterns (9% versus 9%, ns). Simultaneously, in the nonstretched zone, no variations were observed in the DFr (15.2 ± 2.1 versus 15.3 ± 2.5 Hz, ns), mean VV intervals (66 ± 8 versus 65 ± 8 msec, ns), or types and percentages of maps with breakthrough (25% versus 20%, ns) or reentry patterns (12% versus 8%, ns). No significant correlation was observed between the DFr in the two zones (R = 0.24, P = 0.40). Conclusion: Local stretching increases the electrophysiological heterogeneity of myocardium and accelerates and increases the complexity of VF in the stretched area, without significantly modifying the occurrences of the types of VF activation patterns in the nonstretched zone. [ABSTRACT FROM AUTHOR]