P3492Carvedilol and its analogue VK-II-86 attenuate stretch-induced manifestations of mechanoelectric feedback

Background Mechanical stretch modifies Ca2+ handling and myocardial electrophysiology, favoring arrhythmogenesis. The store-overload-induced Ca2+ release (SOICR) through the ryanodine receptor (RyR2) seems to be implicated in this deleterious effect. Carvedilol and its analogue VK-II-86 (which does not have significant beta-blocking effects) suppress SOCIR by directly reducing the open duration of the cardiac RyR2, and could modulate calcium-related changes produced by myocardial stretch. Purpose The aim of this study was to investigate, by the ventricular fibrillation (VF) spectral analysis, whether carvedilol and VK-II-86 prevents stretch-induced arrhythmogenic effects. Methods The VF modifications induced by acute stretch were studied in Langendorff-perfused rabbit hearts using epicardial multiple electrodes under control conditions (n=10), during carvedilol infusion (0.1 and 1 μM) (n=10) and during VK-II-86 infusion (0.1 and 1 μM) (n=10). Spectral techniques were used to establish the baseline and stretch characteristics in the three series above mentioned: VF dominant frequency (DF) and VF spectral concentration (SpC) were determined. A two-factor ANOVA test was used and significance was reached when p<0.05. Results Myocardial stretch significantly increased DF with respect to pre-stretch values in control conditions (13.3±1.2 vs. 16.1±3.0 Hz, p<0.05) and during the perfusion of 0.1μM carvedilol (11.6±1.5 vs. 13.6±2.9 Hz, p<0.05) and 0.1μM VK-II-86 (13.2±2.2 vs. 16.2±4.1 Hz, p<0.05). However, the maximum concentration of both drugs (1μM) abolished this stretch-induced VF acceleration (carvedilol: 6.9±2.2 vs. 7.3±2.6 Hz, ns; VK-II-86: 7.0±1.4 vs. 7.1±0.6 Hz, ns). The significant stretch-induced decrease in SpC in control conditions (31.4±8.6 vs. 23.2±6.4%, p<0.01) was attenuated under 0.1μM carvedilol (0.1μM: 27.6±8.4 vs. 23.5±6.1%, ns) and 0.1μM VK-II-86 (24.7±5.4 vs. 21.2±3.9%, ns), but not under 1μM of both drugs (carvedilol: 41.3±11.3 vs. 30.3±5.7%, p<0.05; VK-II-86: 34.7±7.2 vs. 28.3±3.9%, p<0.01). Nevertheless, during stretch, arrhythmia regularity and organization was greater (higher SpC) under the highest concentration of carvedilol (p<0.01) and VK-II-86 (p<0.05) than in control conditions (control: 23.2±6.4%, carvedilol 1μM: 30.3±5.7%, VK-II-86 1μM: 28.3±3.9%). Conclusion Carvedilol and its analogue VK-II-86 abolished the changes in VF activation frequency produced by myocardial stretch at the highest studied concentration, and also attenuated the stretch-induced activation heterogeneity at the lowest concentration. The similarity in the effects of both drugs on the stretch-induced alterations would imply that its protective effect is due to its ability to inhibit store-overload-induced calcium release.