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Background: Biventricular pacing (BVP) from multiple left ventricular (LV) sites could enhance the efficacy of cardiac resynchronization therapy (CRT) by engaging a greater myocardial mass., Objectives: The goal of this study was to evaluate the acute hemodynamic effect of various multisite pacing (MSP) configurations against conventional BVP., Methods: Twenty patients with nonischemic dilated cardiomyopathy and left bundle branch block (mean age: 59 ± 14 years; LV ejection fraction: 27% ± 6%; native QRS: 171 ± 16 milliseconds) were investigated during a routine CRT implant procedure. In addition to conventional right atrial and right ventricular leads, 2 quadripolar leads were placed in the distant coronary venous branches. LV hemodynamics was evaluated by using a micromanometer-tipped catheter during atrioventricular BVP with 4 LV lead configurations: single-lead conventional BVP; single-lead multipoint pacing; triventricular pacing from distal dipoles of 2 LV leads; and maximum MSP (MSP-Max) from 4 dipoles of 2 LV leads., Results: Compared with right atrial pacing, any BVP configuration produced a significant increase in the maximal LV diastolic pressure rise (LVdP/dT Max ) (a median relative increase of 28% [IQR: 8%-45%], 25% [IQR: 18%-46%], 36% [IQR: 18%-54%], and 38% [IQR: 28%-58%], respectively; all, P < 0.001). MSP-Max but no other multisite BVP generated a significant increase of the maximal LVdP/dT Max than conventional BVP (P = 0.041). Increased LVdP/dT Max during MSP-Max was associated with greater LV diameter and lower LV ejection fraction, independently of the QRS width., Conclusions: The study shows the hemodynamic advantage of a novel dual-vein MSP-Max configuration that could be useful for CRT in patients with advanced LV remodeling., Competing Interests: Funding Support and Author Disclosures This work was funded by the research grant NV18-02-00080 of the grant agency AZV of the Ministry of Health of the Czech Republic. Dr Kautzner has received personal fees from Abbott, Bayer, Biosense Webster, Biotronik, Boehringer Ingelheim, Cath Vision, Medtronic, Pfizer, and ProMed CS for lectures, advisory boards, and consultancy. Dr Sramko has received speaker honoraria from Amomed, Bayer, Boehringer Ingelheim, Medtronic, and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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-Cx43 368 ). Luzindole abolished the melatonin antiarrhythmic effect, slowed conduction, decreased total Cx43, protein kinase Cε and P-Cx43 368 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.

Inverse ECG imaging methods typically require 32-250 leads to create body surface potential maps (BSPM), limiting their routine clinical use. This study evaluated the accuracy of PaceView inverse ECG method to localize the left or right ventricular (LV and RV, respectively) pacing leads using either a 99-lead BSPM or the 12-lead ECG. A 99-lead BSPM was recorded in patients with cardiac resynchronization therapy (CRT) during sinus rhythm and sequential LV/RV pacing. The non-contrast CT was performed to localize precisely both ECG electrodes and CRT leads. From a BSPM, nine signals were selected to obtain the 12-lead ECG. Both BSPM and 12-lead ECG were used to localize the RV and LV lead, and the localization error was calculated. Consecutive patients with dilated cardiomyopathy, previously implanted with a CRT device, were enrolled (n = 19). The localization error for the RV/LV lead was 9.0 [IQR 4.8-13.6] / 7.7 [IQR 0.0-10.3] mm using the 12-lead ECG and 9.1 [IQR 5.4-15.7] / 9.8 [IQR 8.6-13.1] mm for the BSPM. Thus, the noninvasive lead localization using the 12-lead ECG was accurate enough and comparable to 99-lead BSPM, potentially increasing the capability of 12-lead ECG for the optimization of the LV/RV pacing sites during CRT implant or for the most favorable programming., (© 2023. The Author(s).)

Aims: The standard deviation of activation time (SDAT) derived from body surface maps (BSMs) has been proposed as an optimal measure of electrical dyssynchrony in patients with cardiac resynchronization therapy (CRT). The goal of this study was two-fold: (i) to compare the values of SDAT in individual CRT patients with reconstructed myocardial metrics of depolarization heterogeneity using an inverse solution algorithm and (ii) to compare SDAT calculated from 96-lead BSM with a clinically easily applicable 12-lead electrocardiogram (ECG)., Methods and Results: Cardiac resynchronization therapy patients with sinus rhythm and left bundle branch block at baseline (n = 19, 58% males, age 60 ± 11 years, New York Heart Association Classes II and III, QRS 167 ± 16) were studied using a 96-lead BSM. The activation time (AT) was automatically detected for each ECG lead, and SDAT was calculated using either 96 leads or standard 12 leads. Standard deviation of activation time was assessed in sinus rhythm and during six different pacing modes, including atrial pacing, sequential left or right ventricular, and biventricular pacing. Changes in SDAT calculated both from BSM and from 12-lead ECG corresponded to changes in reconstructed myocardial ATs. A high degree of reliability was found between SDAT values obtained from 12-lead ECG and BSM for different pacing modes, and the intraclass correlation coefficient varied between 0.78 and 0.96 (P < 0.001)., Conclusion: Standard deviation of activation time measurement from BSM correlated with reconstructed myocardial ATs, supporting its utility in the assessment of electrical dyssynchrony in CRT. Importantly, 12-lead ECG provided similar information as BSM. Further prospective studies are necessary to verify the clinical utility of SDAT from 12-lead ECG in larger patient cohorts, including those with ischaemic cardiomyopathy., Competing Interests: Conflict of interest: J.K. reports personal fees from Biosense Webster, Biotronik, Medtronic, Abbott, Boehringer Ingelheim, Cath Vision, Pfizer, and ProMed CS for lectures, advisory boards, and consultancy. P.M.v.D. is an owner of ECG Excellence BV and Peacs BV. Other authors have nothing to declare., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Melatonin treatment was reported to reduce the risk of cardiac arrhythmias, and crucial for this antiarrhythmic action was the effect of melatonin on activation spread. The aim of the present study was evaluation of the mechanisms of this activation enhancement. Experiments were performed in a total of 123 control and melatonin-treated (10 mg/kg, daily, for 7 days) male Wistar rats. In epicardial mapping studies (64 leads, interlead distance 0.5 mm) in the anesthetized animals, activation times (ATs) were determined in each lead as dV/dt minimum during QRS complex under sinus rhythm. Epicardial pacing was performed to measure conduction velocity (CV) across the mapped area. Average left ventricular ATs were shorter in the treated animals as compared to the controls, whereas the minimal epicardial ATs indicating the duration of activation propagation via the ventricular conduction system did not differ between the groups. CV was higher in the treated groups indicating that melatonin affected conduction via contractile myocardium The area of Cx43-derived fluorescence, as well as the expression of Cx43 protein, was similar in ventricles in the control and melatonin-treated groups. Expression of Gja1 gene transcripts encoding Cx43, was increased in the last group. An uncoupling agent octanol modified myocardial conduction properties (time of activation, action potential upstroke velocity, passive electrotonic phase duration) similarly in both groups. On the other hand, the expression of both Scn5a gene transcripts encoding Nav1.5 proteins, as well as peak density of transmembrane sodium current were increased in the ventricular myocytes from the melatonin-treated animals. Thus, a week-long melatonin treatment caused the increase of conduction velocity via enhancement of sodium channel proteins expression and increase of sodium current in the ventricular myocytes., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: A reliable electrocardiographic predictor of ventricular fibrillation (VF) in patients with ST elevation myocardial infarction (STEMI) is lacking so far. Previous experimental/simulation study suggested a terminal T-wave inversion (TTWI) in ischemia-related ECG leads corresponding to anterior infarct localization as an independent predictor of reperfusion VF (rVF). This T-wave characteristic has never been tested as a rVF predictor in clinical settings. The aim of this study was to test if terminal T-wave inversion (TTWI) at admission ECG (before reperfusion) can serve as a predictor of ventricular fibrillation during reperfusion (rVF) in patients with anterior STEMI undergoing primary PCI., Methods and Results: Study population included consecutive patients with anterior infarct localization admitted for primary PCI (n = 181, age 65 [57; 76] years, 66% male). Of those, 14 patients had rVF (rVF group, age 59 [47; 76] years, 64% male) and patients without rVF comprised the No-rVF group (n = 167, age 65 [57; 76] years, 66% male). Association of TTWI with rVF was analyzed using logistic regression analysis adjusted for relevant clinical and electrocardiographic covariates. The prevalence of TTWI in rVF group was 62% comparing to 23% in the No-rVF group, p = 0.005. TTWI was associated with increased risk of rVF (OR 5.51; 95% CI 1.70-17.89; p = 0.004) and remained a significant predictor after adjustment for age, gender, history of MI prior to index admission, VF before reperfusion, T peak -T end , maximal ST elevation, and QRS duration (OR 23.49; 95% CI 3.14-175.91; p = 0.002)., Conclusions: The terminal T-wave inversion in anterior leads before PCI independently predicted rVF in patients with anterior MI thus confirming the previous experimental/simulation findings., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The role of a border zone in arrhythmogenesis is not fully understood. In this study we evaluated independent contributions of action potential duration (APD) and dispersion of repolarization (DOR) across the normal/ischemic border to the development of ventricular tachycardia and/or fibrillation (VT/VF). Ischemia-reperfusion episodes were induced in anesthetized rats by transient coronary occlusion. Unipolar electrograms were recorded from ischemic and perfused areas using a 64-lead array to obtain activation times (ATs), repolarization times (RTs), activation-repolarization intervals (ARIs, a surrogate for APD) and dispersion of repolarization (DOR, as a difference between the earliest and latest RTs). Pinacidil (0.3 mg/kg) and glibenclamide (2 mg/kg) were applied to reduce DOR and to clamp APD at a lower and upper levels, respectively. In the control animals, APD shortened in the ischemic zone, DOR increased to 9 ± 3 ms, and VT/VF developed at reperfusion (6 out of 10). Pre-occlusion application of glibenclamide prolonged APD in the ischemic and perfused zones, decreased DOR to 5 ± 2 ms and did not affect VT/VF development (4 out of 11). Post-occlusion infusion of pinacidil shortened APD in the perfused zone, decreased DOR to 6 ± 3 ms and VT/VF incidence (2 out of 11). Extrasystolic burden at reperfusion was associated with VT/VF incidence in logistic regression analysis (β = 1.182, 95%CI 1.008 - 1.386, p = 0.04) and was lesser (p < 0.01) in the pinacidil group as compared to the control and glibenclamide groups. In conclusion, the results of this study suggest that the APDs in the perfused zone were a superior arrhythmogenic factor in respect to DOR in the present ischemia-reperfusion model.

The mechanism of reentrant ventricular tachyarrhythmias complicating acute myocardial ischemia is largely based on the interaction between an arrhythmogenic substrate and triggers. Melatonin was proposed as an antiarrhythmic medication and was shown to ameliorate the arrhythmogenic substrate. Also, melatonin provides a sympatholytic effect in different settings and might attenuate ectopic activity, which provides reentry triggers. In the present study, we aimed at evaluating the melatonin effects on cardiac sympathetic activity and the incidence of premature ventricular beats during the episode of ischemia-reperfusion. Experiments were done in a total of 26 control and 28 melatonin-treated (10 mg/kg, daily, for 7 days) male rats. Sympathetic fibers density was assessed by glyoxylic acid-induced fluorescence. Continuous electrocardiograms recording was performed during ischemia-reperfusion episodes (5 min/5 min, respectively) induced by reversible coronary occlusion. Myocardial expression of tyrosine hydroxylase, a rate-limiting enzyme of catecholamine biosynthesis was assessed by Western blotting. No differences in the state of sympathetic innervation were observed in histochemical analysis. However, Western blotting analysis demonstrated that melatonin treatment suppressed tyrosine hydroxylase expression in the non-ischemic (p < 0.05 versus control) but not ischemic regions of myocardium. The melatonin-treated animals had longer RR-intervals in the baseline state than the control animals (264 ± 48 ms versus 237 ± 33 ms, p = 0.044, respectively), but this difference decayed during the period of ischemia due to the increase of heart rate in the treated group. The number of premature ventricular beats did not differ between the control and treated groups during the ischemic and reperfusion periods. One-week melatonin pretreatment caused a slight peripheral sympatholytic effect that attenuated during ischemia and completely disappeared by the onset of reperfusion. The slight expression of sympathetic downregulation was associated with the lack of any effect of melatonin on extrasystolic burden. Collectively, the data suggest that melatonin cannot target the triggers of reentrant arrhythmias.

The effect of preventive administration of melatonin on the arrhythmogenic substrate in the myocardium was studied in the rabbit model of acute ischemia/reperfusion in vivo. The animals treated with melatonin 60 min before ischemia induction had shorter median activation time compared to the control group (p=0.039), less pronounced shortening of repolarization durations in the ischemic zone during coronary occlusion (p=0.008), and more complete recovery of repolarization during reperfusion (p=0.027). In the melatonin group, the dispersion of repolarization was less than in the control group during both ischemic period (p=0.043) and reperfusion (p=0.038). Thus, preventive administration of melatonin mitigated the arrhythmogenic substrate in the heart under conditions of 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.

In this study we tested a hypothesis that reperfusion ventricular tachyarrhythmias can be modified by direct control of repolarization duration in the perfused myocardium during ischemic exposure. After induction of coronary occlusion, three groups of rats were given agencies affecting repolarization duration tetraethylammonium (TEA) 4 mg/kg, n = 9; pinacidil (Pin) 0.3 mg/kg, n = 11, and saline as placebo (control) n = 10. Unipolar electrograms were recorded from ischemic and perfused areas using an array of 64-electrodes to obtain activation times (ATs), repolarization times (RTs), activation-repolarization intervals (ARIs) and dispersion of repolarization (DOR). During ischemia/reperfusion ARIs in perfused area did not change in the control, significantly increased in the TEA and decreased in the Pin group in respect to baseline, whereas ARIs significantly decreased in the ischemic zone in all groups. DOR also significantly increased in all groups at ischemia and reperfusion. The incidence and total arrhythmia score of reperfusion tachyarrhythmias were significantly greater in TEA group compared to Pin and control groups. In multivariate regression analysis, incidence of VT/VFs and total arrhythmia score were associated with ARIs in the perfused area. Thus, the effect on repolarization durations in the perfused area modified the incidence and severity of the reperfusion-induced ventricular tachyarrhythmias.

The effects of therapeutic or preventive-therapeutic administration of water-soluble echinochrome analog U-441 on arrhythmia severity assessed by a set of myocardial spatio-temporal depolarization and repolarization parameters were examined on the model of acute myocardial ischemia in cats. Coronary occlusion increased activation time and decreased repolarization time in the ischemic zone; in addition, it increased both global and borderline (local) dispersions of repolarization. The linear regression model showed that only activation time values measured at the initial state and at termination of occlusion were associated with total arrhythmia score during ischemia (regression coefficient β=0.338, 95%CI=0.074-0.602, p=0.015 and β=0.720, 95%CI=0.323-1.117, p=0.001, respectively). The study revealed no association between administration of echinochrome analog U-441 and arrhythmia severity.

Background: Aim of the study was to find out which myocardial repolarization parameters predict reperfusion ventricular tachycardia and fibrillation (VT/VF) and determine how these parameters express in ECG., Methods: Coronary occlusion and reperfusion (30/30min) was induced in 24 cats. Local activation and end of repolarization times (RT) were measured in 88 intramyocardial leads. Computer simulations of precordial electrograms were performed., Results: Reperfusion VT/VF developed in 10 animals. Arrhythmia-susceptible animals had longer RTs in perfused areas [183(177;202) vs 154(140;170) ms in susceptible and resistant animals, respectively, P<0.05]. In logistic regression analysis, VT/VFs were associated with prolonged RTs in the perfused area (OR 1.068; 95% CI 1.012-1.128; P=0.017). Simulations demonstrated that prolonged repolarization in the perfused/border zone caused precordial terminal T-wave inversion., Conclusions: The reperfusion VT/VFs were independently predicted by the longer RT in the perfused zone, which was reflected in the terminal negative phase of the electrocardiographic T-wave., (Copyright © 2017. Published by Elsevier Inc.)

In the present study we investigated the contribution of ventricular repolarization time (RT) dispersion (the maximal difference in RT) and RT gradients (the differences in RT in apicobasal, anteroposterior and interventricular directions) to T-wave flattening in a setting of experimental diabetes mellitus. In 9 healthy and 11 diabetic (alloxan model) open-chest rabbits, we measured RT in ventricular epicardial electrograms. To specify the contributions of apicobasal, interventricular and anteroposterior RT gradients and RT dispersion to the body surface potentials we determined T-wave voltage differences between modified upper- and lower-chest precordial leads (T-wave amplitude dispersions, TWAD). Expression of RT gradients and RT dispersion in the correspondent TWAD parameters was studied by computer simulations. Diabetic rabbits demonstrated flattened T-waves in precordial leads associated with increased anteroposterior and decreased apicobasal RT gradients (P<0.05) due to RT prolongation at the apex. For diabetics, simulations predicted the preserved T-vector length and altered sagittal and longitudinal TWAD proven by experimental measurements. T-wave flattening in the diabetic rabbits was not due to changes in RT dispersion, but reflected the redistributed ventricular repolarization pattern with prolonged apical repolarization resulting in increased anteroposterior and decreased apicobasal RT gradients.

Aims of the study were to compare the development of electrocardiographic responses of the ischemia-induced heterogeneities of activation and repolarization in the ventricular myocardium of normal and diabetic animals. Body surface ECGs and unipolar electrograms in 64 epicardial leads were recorded before and during 20 min after the ligation of the left anterior descending artery in diabetic (alloxan model, 4 weeks, n=8) and control (n=8) rabbits. Activation times (ATs), end of repolarization times (RTs) and repolarization durations (activation-recovery intervals, ARIs) were determined in ischemic and periischemic zones. In contrast to the controls, the diabetic rabbits demonstrated the significant prolongation of ATs and shortening of ARIs (P<0.05) during ischemia in the affected region resulting in the development and progressive increase of the ARI and RT gradients across the ischemic zone boundary. The alterations of global and local dispersions of the RTs in diabetics correlated with the T(peak)-T(end) interval changes in the limb leads ECGs. In the ischemic conditions, the diabetic animals differed from the controls by the activation delay, significant repolarization duration shortening, and the increase of local repolarization dispersion; the latter could be assessed by the T(peak)-T(end) interval measurements in the body surface ECGs.

Background: It is unclear whether the Tpeak-Tend interval is an index of the transmural or the total dispersion of repolarization., Methods: We examined the Tpeak-Tend interval using a computer model of the rabbit heart ventricles based on experimentally measured transmural, apicobasal, and interventricular gradients of action potential duration., Results: Experimentally measured activation-recovery intervals increased from apex to base, from the left ventricle to the right ventricle, and in the apical portion of the left ventricle from epicardium to endocardium and from the right side of septum to the left side. The simulated Tpeak corresponded to the earliest end of repolarization, whereas the Tend corresponded to the latest end of repolarization. The different components of the global repolarization dispersion were discerned by simulation., Conclusions: The Tpeak-Tend interval corresponds to the global dispersion of repolarization with distinct contributions of the apicobasal and transmural action potential duration gradients and apicobasal difference in activation times., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Augmented hemodynamic load increases the risk of arrhythmogenesis by modulating cardiac repolarization duration. We hypothesized that the intervention on the autonomic tone may affect the load-dependent changes in ventricular repolarization. Activation-recovery intervals were measured in unipolar electrograms simultaneously recorded from 64 ventricular epicardial leads, in a total of 26 chinchilla rabbits in resting conditions, and after 1 and 10 min of aortic stenosis. Eleven animals were given atropine and propranolol before the loading. The short-term stenosis decreased the activation-recovery intervals in the right ventricle, whereas the prolonged overload increased the repolarization duration in both ventricles. The treatment with the β-adrenergic and M-cholinergic blockers prolonged the activation-recovery intervals, especially at the left ventricle, attenuating the apicobasal and interventricular gradients of repolarization duration seen in the baseline state. Further ventricular loading shortened the repolarization duration in both ventricles in animals with autonomic blockade. Thus, the autonomic tone was shown to be essential for the development of repolarization heterogeneity across the ventricles. The autonomic blockade transformed the biphasic changes of activation-recovery intervals into their monophasic shortening at aortic stenosis.

Overload of the cardiac left ventricle causes opposite local changes in repolarization duration (activation-recovery intervals) on the right- and left-ventricular epicardium, which depend on the duration of overload. The activation-recovery intervals on the right-ventricular lateral surface decrease after 1-min overload, but increase after 10-min overload. The length of activation-recovery intervals on the lateral surface of the left-ventricular apex increases after 10-min aortic stenosis more markedly in comparison with that after 1-min overload. Decrease/increase of local lengths of activation-recovery intervals results in modification of the general sequence of cardiac ventricular surface repolarization.