Blockade of Melatonin Receptors Abolishes Its Antiarrhythmic Effect and Slows Ventricular Conduction in Rat Hearts.

Melatonin has been reported to cause myocardial electrophysiological changes and prevent ventricular tachycardia or fibrillation (VT/VF) in ischemia and reperfusion. We sought to identify electrophysiological targets responsible for the melatonin antiarrhythmic action and to explore whether melatonin receptor-dependent pathways or its antioxidative properties are essential for these effects. Ischemia was induced in anesthetized rats given a placebo, melatonin, and/or luzindole (MT1/MT2 melatonin receptor blocker), and epicardial mapping with reperfusion VT/VFs assessment was performed. The oxidative stress assessment and Western blotting analysis were performed in the explanted hearts. Transmembrane potentials and ionic currents were recorded in cardiomyocytes with melatonin and/or luzindole application. Melatonin reduced reperfusion VT/VF incidence associated with local activation time in logistic regression analysis. Melatonin prevented ischemia-related conduction slowing and did not change the total connexin43 (Cx43) level or oxidative stress markers, but it increased the content of a phosphorylated Cx43 variant (P-Cx43368). Luzindole abolished the melatonin antiarrhythmic effect, slowed conduction, decreased total Cx43, protein kinase Cε and P-Cx43368 levels, and the IK1 current, and caused resting membrane potential (RMP) depolarization. Neither melatonin nor luzindole modified INa current. Thus, the antiarrhythmic effect of melatonin was mediated by the receptor-dependent enhancement of impulse conduction, which was associated with Cx43 phosphorylation and maintaining the RMP level.

Seasonal changes of electrophysiological heterogeneities in the rainbow trout ventricular myocardium.

INTRODUCTION: Thermal adaptation in fish is accompanied by morphological and electrophysiological changes in the myocardium. Little is known regarding seasonal changes of spatiotemporal organization of ventricular excitation and repolarization processes. We aimed to evaluate transmural and apicobasal heterogeneity of depolarization and repolarization characteristics in the rainbow trout in-situ ventricular myocardium in summer and winter conditions. METHODS: The experiments were done in summer-acclimatized (SA, 18°C, n = 8) and winter-acclimatized (WA, 3°C, n = 8) rainbow trout (Oncorhynchus mykiss). 24 unipolar electrograms were recorded with 3 plunge needle electrodes (eight lead terminals each) impaled into the ventricular wall. Activation time (AT), end of repolarization time (RT), and activation-repolarization interval (ARI, a surrogate for action potential duration) were determined as dV/dt min during QRS-complex, dV/dt max during T-wave, and RT-AT difference, respectively. RESULTS: The SA fish demonstrated relatively flat apicobasal and transmural AT and ARI profiles. In the WA animals, ATs and ARIs were longer as compared to SA animals (p≤0.001), ARIs were shorter in the compact layer than in the spongy layer (p≤0.050), and within the compact layer, the apical region had shorter ATs and longer ARIs as compared to the basal region (p≤0.050). In multiple linear regression analysis, ARI duration was associated with RR-interval and AT in SA and WA animals. The WA animals additionally demonstrated an independent association of ARIs with spatial localization across the ventricle. CONCLUSION: Cold conditions led to the spatial redistribution of repolarization durations in the rainbow trout ventricle and the formation of repolarization gradients typically observed in mammalian myocardium.

Contribution of Depolarization and Repolarization Changes to J-Wave Generation and Ventricular Fibrillation in Ischemia.

Background: Activation delay in ischemic myocardium has been found to contribute to J-wave appearance and to predict ventricular fibrillation (VF) in experimental myocardial infarction. However, the role of ischemia-related repolarization abnormalities in J-wave generation remains unclear. Objectives: The objective of our study was to assess a contribution of myocardial repolarization changes to J-wave generation in the body surface ECG and VF in a porcine acute myocardial infarction model. Methods: In 22 anesthetized pigs, myocardial ischemia was induced by occlusion of the left anterior descending coronary artery (LAD, n = 14) and right coronary artery (RCA, n = 8). Body surface ECGs were recorded simultaneously with intramyocardial unipolar electrograms led from flexible electrodes positioned across the left ventricular (LV) wall, interventricular septum (IVS), and right ventricular (RV) wall at apical, middle and basal levels of the ventricles (a total of 48 leads). Local activation times (ATs) and activation-repolarization intervals (ARIs, differences between dV/dt maximum during T-wave and dV/dt minimum during QRS) were measured. Results: J-waves appeared in left precordial leads (in 11 out of 14 animals with LAD occlusion) and right precordial leads (in six out of eight animals with RCA occlusion). During ischemic exposure, ATs prolonged, and the activation delay was associated with J-wave development (OR = 1.108 95% CI 1.072-1.144; p < 0.001) and VF incidence (OR = 1.039 95% CI 1.008-1.072; p = 0.015). ARIs shortened in the ischemic regions (in the IVS under LAD-occlusion and the lateral RV base under RCA-occlusion). The difference between maximal ARI in normal zones and ARI in the ischemic zones (ΔARI) was associated with J-wave appearance (OR = 1.025 95% CI 1.016-1.033, p < 0.001) independently of AT delay in multivariate logistic regression analysis. Conclusions: Both AT delay and increase of ΔARIs contributed to the development of J-wave in body surface ECG. However, only AT delay was associated with VF occurrence.

Association Between Antiarrhythmic, Electrophysiological, and Antioxidative Effects of Melatonin in Ischemia/Reperfusion.

Melatonin is assumed to confer cardioprotective action via antioxidative properties. We evaluated the association between ventricular tachycardia and/or ventricular fibrillation (VT/VF) incidence, oxidative stress, and myocardial electrophysiological parameters in experimental ischemia/reperfusion under melatonin treatment. Melatonin was given to 28 rats (10 mg/kg/day, orally, for 7 days) and 13 animals received placebo. In the anesthetized animals, coronary occlusion was induced for 5 min followed by reperfusion with recording of unipolar electrograms from ventricular epicardium with a 64-lead array. Effects of melatonin on transmembrane potentials were studied in ventricular preparations of 7 rats in normal and "ischemic" conditions. Melatonin treatment was associated with lower VT/VF incidence at reperfusion, shorter baseline activation times (ATs), and activation-repolarization intervals and more complete recovery of repolarization times (RTs) at reperfusion (less baseline-reperfusion difference, ΔRT) (p < 0.05). Superoxide dismutase (SOD) activity was higher in the treated animals and associated with ΔRT (p = 0.001), whereas VT/VF incidence was associated with baseline ATs (p = 0.020). In vitro, melatonin led to a more complete restoration of action potential durations and resting membrane potentials at reoxygenation (p < 0.05). Thus, the antioxidative properties of melatonin were associated with its influence on repolarization duration, whereas the melatonin-related antiarrhythmic effect was associated with its oxidative stress-independent action on ventricular activation.

Prolongation of The Activation Time in Ischemic Myocardium is Associated with J-wave Generation in ECG and Ventricular Fibrillation.

J-wave pattern has been recognized as an arrhythmic risk marker, particularly in myocardial infarction patients. Mechanisms underlying J-wave development in ischemia remain unknown. In myocardial infarction model, we evaluated activation time delay as a prerequisite of J-wave appearance and predictor of ventricular fibrillation. Body surface ECGs and myocardial unipolar electrograms were recorded in 14 anesthetized pigs. 48 intramural leads were positioned across ventricular free walls and interventricular septum. Myocardial ischemia was induced by ligation of the left anterior descending coronary artery and the recordings were done during 40-minute coronary occlusion. The local activation times were determined as instants of dV/dt minimum during QRS complex in unipolar electrograms. During occlusion, ventricular local activation time prolonged in the middle portion of the left ventricular free wall, and basal and middle portions of septum, while J-waves appeared in precordial leads in 11 animals. In logistic regression and ROC curve analyses, activation time delay at a given time-point was associated with J-wave development, and a longer activation time was associated with ventricular fibrillation appearance. In experimental coronary occlusion, activation delay in ischemic myocardium was associated with generation of the J waves in the body surface ECG and predicted ventricular fibrillation.

Functional role of myocardial electrical remodeling in diabetic rabbits.

The objective of the study was to investigate the role of electrical remodeling of the ventricular myocardium in hemodynamic impairment and the development of arrhythmogenic substrate. Experiments were conducted with 11 healthy and 12 diabetic (alloxan model, 4 weeks) rabbits. Left ventricular pressure was monitored and unipolar electrograms were recorded from 64 epicardial leads. Aortic banding was used to provoke arrhythmia. The diabetic rabbits had prolonged QTc, with activation-recovery intervals (surrogates for repolarization durations) being relatively short on the left ventricular base and long on the anterior apical portions of both ventricles (P < 0.05). In the diabetic rabbits, a negative correlation (-0.726 to -0.817) was observed between dP/dt(max), dP/dt(min), and repolarization dispersions. Under conditions of systolic overload (5 min), tachyarrhythmias were equally rare and the QTc and activation-recovery intervals were shortened in both groups (P < 0.05), whereas QRS was prolonged in the diabetic rabbits only. The repolarization shortening was more pronounced on the apex, which led to the development of apicobasal and interventricular end of repolarization gradients in the healthy animals, and to the flattening of the repolarization profile in the diabetic group. Thus, the diabetes-related pattern of ventricular repolarization was associated with inotropic and lusitropic impairment of the cardiac pump function.

The contribution of ventricular apicobasal and transmural repolarization patterns to the development of the T wave body surface potentials in frogs (Rana temporaria) and pike (Esox lucius).

The study aimed at the simultaneous determination of the transmural and apicobasal differences in the repolarization timing and the comparison of the contributions of these two repolarization gradients to the development of the body surface T wave potentials in animals with the single heart ventricle (fishes and amphibians). Unipolar potentials were measured on the body surface, epicardium and in the intramural (subepicardial, Epi; midmyocardial; and subendocardial, Endo) ventricular layers of 9 pike and 8 frogs. Activation times, repolarization times and activation-recovery intervals were determined. A transmural gradient in repolarization durations in frogs (Endo>Epi, P<0.024) corresponds to the gradient in repolarization times. No significant transmural difference in repolarization duration is observed in pike that produces a repolarization sequence from Endo to Epi (Endo

Epicardial activation-to-repolarization coupling differs in the local areas and on the entire ventricular surface.

HYPOTHESIS: Local and global activation-to-repolarization coupling differ from each other. Experiments were done in 12 dogs and 7 frogs. Activation times (ATs), end of repolarization times (RTs), and activation-recovery intervals (ARIs) were measured in 24 or 64 leads on the entire ventricular surface and on the epicardial patch 5 × 5 mm. The ARI and RT dispersions were greater than AT dispersion on the entire ventricular epicardium but not in the local patch. Both ATs and ARIs were inversely related to each other in the patch but not necessarily on the entire epicardium. The RT sequence depended on the AT sequence within the local patch but not on the entire surface. The contributions of the AT sequence and ARI distribution to the RT sequence was determined by the AT/ARI dispersion ratio. Thus, the AT sequence strongly influenced the RT sequence of the local epicardial fragment but not of the entire ventricular surface.