Dispersion Of Repolarization Time Research Articles

Demonstration of Arrhythmia Substrate-Associated Dispersion of Repolarization by Epicardial Unipolar Mapping in Brugada Syndrome

BackgroundEpicardial unipolar mapping has not been thoroughly investigated in Brugada syndrome (BrS). ObjectivesThis study aims to examine the characteristics of epicardial unipolar potentials in BrS and investigate the differences from overt cardiomyopathy. MethodsEpicardial mapping was performed in 8 patients with BrS and 6 patients with cardiomyopathy. We investigated the J-wave amplitudes using unipolar recordings at delayed potential (DP) sites via bipolar recordings. The repolarization time (RT) at and around the DP recording sites was measured, and maximum dispersion of the RT divided by the distance was defined as the RT dispersion index. ResultsEpicardial mapping at baseline revealed significantly higher J-wave amplitude with bipolar DP in patients with BrS than in patients with cardiomyopathy. J-wave amplitude ≥0.42 mV had 99.1% sensitivity and 100% specificity for diagnosing BrS. The RT dispersion index was significantly higher in patients with BrS than in patients with cardiomyopathy at baseline. In all patients with BrS, coved-type unipolar electrograms without negative T waves (short RT) appeared close to coved-type electrograms with negative T waves (long RT) at the DP recording sites after pilsicainide administration. Thus, a steep RT dispersion was observed in this region, and ventricular arrhythmias emerged from this shorter RT area in all 3 patients with BrS in whom ventricular arrhythmias were induced. ConclusionsBipolar DP-related prominent unipolar J waves and steep repolarization gradients may be more specific for characterizing BrS than for overt cardiomyopathy. Ventricular arrhythmias in BrS are associated with a steep repolarization gradient, indicating phase 2 re-entry as a possible cause.

PO-01-143 HYPOTHERMIA-INDUCED J-WAVES AND ARRHYTHMIAS ARE ASSOCIATED WITH AN EXACERBATION OF REPOLARIZATION RATHER THAN CONDUCTION HETEROGENEITY IN HUMAN HEARTS

The cardiac effects of hypothermia have been studied for many years since the initial discovery of the electrocardiographic J-wave in a case of accidental hypothermia. However, the precise mechanisms underlying the origin of the hypothermic J-wave and associated arrhythmias in man are still debated. A limited number of ex vivo animal studies have focused on the transmural repolarization dispersion, but do not provide global mapping of ventricular activation and repolarization heterogeneities. To map hypothermia-induced electrophysiological changes at a tissue level and study the mechanisms of initiation and maintenance of arrhythmias. Optical mapping experiments were performed on isolated right ventricles (RV) from pigs (N=7) and humans obtained through our organ donation program (N=3 control subjects; N=1 SCN5A BrS-associated mutant subject). Epi- and endocardial (EPI and ENDO) action potential conduction and repolarization properties were assessed at different pacing frequencies and arrhythmias were mapped and quantified at baseline (37°C), during severe hypothermia (29°C), and after a return to normothermia. Hypothermia induced a reversible prolongation of global action potential duration at 80% of repolarization (APD80) in pigs (EPI: +27%, ENDO: +21%; p<0.01) and humans (+45% in both EPI and ENDO), an increase in APD80 dispersion, and steepness of APD restitution curve. Repolarization time dispersion was increased in both species (pigs: +94%, p<0.001 in EPI and +79%, p<0.05 in ENDO; humans: +97% in EPI and +14% in ENDO). The total activation time was significantly prolonged in pigs (EPI: +58%, p<0.001; ENDO: +46%, p<0.01) but not in humans. Arrhythmogenicity was further increased in human ventricles (+43% of spontaneous arrhythmias in pigs versus +100% in humans), which always displayed defibrillation-resistant arrhythmias. In the carrier of a SCN5A mutant, hypothermia additionally potentiated epicardial localized conductive disorders already detected at baseline. Our results indicate that, in humans, and contrary to pigs, the hypothermic J-wave and associated arrhythmogenesis result more from an exacerbation of repolarization rather than conduction heterogeneity. Pre-existing localized conduction heterogeneities within pathological hearts can however contribute to the J-wave phenotype during hypothermia.

Noninvasive unipolar electrogram T-wave upslope is an accurate marker of local refractoriness in explanted hearts with drug-induced repolarization dispersion

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): French National Research Agency Matthijs Cluitmans is supported by a Veni grant from the Netherlands Organization for Scientific Research Background The relationship between T-wave morphology in local unipolar electrograms (UEGs) as mapped with noninvasive electrocardiographic imaging (ECGI) and local repolarization time (RT) has not been validated in pronounced RT dispersion. Purpose To study the time of upslope of the T-wave (Tup) in epicardial UEGs mapped with ECGI as a marker of time of local refractoriness (trefr, a surrogate for RT) in intact hearts with RT dispersion. Methods Six pig hearts were Langendorff-perfused with selective perfusion of the LAD artery and submersed in a torso-shaped tank containing 256 electrodes on the torso surface (panel A). RT was prolonged in the non-LAD regions by infusing dofetilide (‘Dof’) and shortened in the LAD region using pinacidil (‘Pin’). Tup was determined in both invasive UEGs (recorded with epicardial electrodes) and in noninvasive UEGs (reconstructed with ECGI). Programmed stimulation was used to determine trefr, defined as the shortest coupling interval with capture. Both metrics were determined relative to the common pacing spike. Results In all six hearts, selective dofetilide and pinacidil infusion resulted in delayed trefr and Tup in the non-LAD region, and shortened invasive trefr and noninvasive Tup in the LAD region, respectively (panel B and C). Over all 59 observations, Tup showed high agreement with trefr (values close to line of identity, panel D) with strong correlation (r = 0.91). This finding was independent of T-wave polarity (positive, negative or biphasic). Conclusion The moment of steepest upslope of the T-wave in a noninvasively reconstructed UEG accurately reflects end of local refractoriness in intact hearts, in case of pronounced RT dispersion. Under these circumstances, when local RT is defined by moment of re-excitability (allowing to link it to conduction block and re-entry), ECGI T-wave upslope can be taken as a truthful marker for local RT. Abstract Figure. Results

Parameter variations in personalized electrophysiological models of human heart ventricles.

The objectives of this study were to evaluate the accuracy of personalized numerical simulations of the electrical activity in human ventricles by comparing simulated electrocardiograms (ECGs) with real patients' ECGs and analyzing the sensitivity of the model output to variations in the model parameters. We used standard 12-lead ECGs and up to 224 unipolar body-surface ECGs to record three patients with cardiac resynchronization therapy devices and three patients with focal ventricular tachycardia. Patient-tailored geometrical models of the ventricles, atria, large vessels, liver, and spine were created using computed tomography data. Ten cases of focal ventricular activation were simulated using the bidomain model and the TNNP 2006 cellular model. The population-based values of electrical conductivities and other model parameters were used for accuracy analysis, and their variations were used for sensitivity analysis. The mean correlation coefficient between the simulated and real ECGs varied significantly (from r = 0.29 to r = 0.86) among the simulated cases. A strong mean correlation (r > 0.7) was found in eight of the ten model cases. The accuracy of the ECG simulation varied widely in the same patient depending on the localization of the excitation origin. The sensitivity analysis revealed that variations in the anisotropy ratio, blood conductivity, and cellular apicobasal heterogeneity had the strongest influence on transmembrane potential, while variation in lung conductivity had the greatest influence on body-surface ECGs. Futhermore, the anisotropy ratio predominantly affected the latest activation time and repolarization time dispersion, while the cellular apicobasal heterogeneity mainly affected the dispersion of action potential duration, and variation in lung conductivity mainly led to changes in the amplitudes of ECGs and cardiac electrograms. We also found that the effects of certain parameter variations had specific regional patterns on the cardiac and body surfaces. These observations are useful for further developing personalized cardiac models.

Prolonged action potential duration and dynamic transmural action potential duration heterogeneity underlie vulnerability to ventricular tachycardia in patients undergoing ventricular tachycardia ablation.

AimsDifferences of action potential duration (APD) in regions of myocardial scar and their borderzones are poorly defined in the intact human heart. Heterogeneities in APD may play an important role in the generation of ventricular tachycardia (VT) by creating regions of functional block. We aimed to investigate the transmural and planar differences of APD in patients admitted for VT ablation.Methods and resultsSix patients (median age 53 years, five male); (median ejection fraction 35%), were studied. Endocardial (Endo) and epicardial (Epi) 3D electroanatomic mapping was performed. A bipolar voltage of <0.5 mV was defined as dense scar, 0.5–1.5 mV as scar borderzone, and >1.5 mV as normal. Decapolar catheters were positioned transmurally across the scar borderzone to assess differences of APD and repolarization time (RT) during restitution pacing from Endo and Epi. Epi APD was 173 ms in normal tissue vs. 187 ms at scar borderzone and 210 ms in dense scar (P < 0.001). Endocardial APD was 210 ms in normal tissue vs. 222 ms in the scar borderzone and 238 ms in dense scar (P < 0.01). This resulted in significant transmural RT dispersion (ΔRT 22 ms across dense transmural scar vs. 5 ms in normal transmural tissue, P < 0.001), dependent on the scar characteristics in the Endo and Epi, and the pacing site.ConclusionAreas of myocardial scar have prolonged APD compared with normal tissue. Heterogeneity of regional transmural and planar APD result in localized dispersion of repolarization, which may play an important role in initiating VT.

The assessment of electrophysiological indices and ECG parameters as predictors of fatal arrhythmias under ischemia/reperfusion setting in multivariate regression model.

IntroductionThere are many factors predisposing to arrhythmia. The reentry mechanism is determined by dispersion of repolarization, unidirectional conduction block and activation slowing which can be documented as QRS widening. Similarly, the duration of repolarization and heart rate could favor the triggered activity or afterdepolarization proarrhythmic mechanism. The great interest for clinically application is the evaluation of noninvasive markers of fatal arrhythmias such as Tpeak‐Tend interval, QT dispersion and others but often they give unsatisfactory or conflicting results.The aim of the study was to find out which of the electrophysiological indices and ECG parameters contribute significantly to the genesis of fatal arrhythmias under experimental coronary occlusion and reperfusion using multivariate regression model.MethodsUsing needle plunge electrodes unipolar electrograms were recorded in intramural ventricular layers of 24 anesthetized open‐chest cats. Activation times (ATs) as dV/dt min during QRS, end of repolarization times (RTs) as dV/dt max during ST‐T, and activation‐recovery intervals (ARIs) as the time interval between the ATs and RTs were measured in total of 88 myocardial leads. The global, apicobasal, border RT dispersions were calculated as electrophysiological indices. The data were obtained at baseline, at 1 and 30 min of coronary occlusion and at 1 and 30 min of reperfusion.ResultsThe ventricular tachycardia and/or ventricular fibrillation (VT/VF) arose in a total of 10 animals at 1–5 minutes after reperfusion onset. During ischemia RTs progressively decreased and ATs increased in the ischemic zone and then progressively restored during reperfusion (P&lt;0.05). The global, apicobasal, border dispersion of repolarization, QRS, Tpeak‐Tend intervals increased in all animals during ischemia and at the reperfusion onset (P&lt;0.05). Under ischemia/reperfusion episode, the VT/VF group of animals demonstrated the greater global, border, apicobasal dispersion of RT, RTs in nonischemic and ischemic areas, QRS and Tpeak‐Tend intervals, and the lower heart rate as compared with the nonVT/VF animals (P&lt;0.05). Using the multivariate logistic regression analysis we assessed the association between the dispersions of RT, RTs and ATs of ischemic and nonischemic zone under the 1 min of reperfusion and the occurrence of VT/VF. It was found that RTs of nonischemic zone (P=0.024) and global dispersion of RT (P=0.046) demonstrated significant association with the reperfusion VT/VF. The following ECG parameters as predictors of arrhythmias were tested (heart rate, Tpeak‐Tend, QRS and QTc intervals, Tpeak‐Tend/QT ratio). The QRS interval (P=0.01) and heart rate (P=0.009) were found to have the significant link with the occurrence of VT/VF.ConclusionThe multivariate regression model showed that the genesis of VT/VF was independently predicted by the repolarization duration in nonischemic area and the global dispersion of repolarization at the reperfusion onset. The QRS and heart rate were the independent ECG predictors of the occurrence of reperfusion VT/VF.Support or Funding InformationThe study was supported by the Program for Fundamental Research of RAS project № AAAA‐A17‐117012310154‐6, № AAAA‐A18‐118012290365‐2.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Mechanism of electrocardiographic T-wave flattening in diabetes mellitus: experimental and simulation study.

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.

56-03: Increased arrhythmia vulnerability in KChIP2 knock-out mice is explained by different spatial dispersion of ventricular repolarization and location of cardiac stimulation

Purpose of the study: Downregulation of ventricular K+ channel-interacting protein 2 (KChIP2) and loss of the transient outward K+ current (Ito), is observed in failing hearts. In this study, we investigate the impact of KChIP2 and heart failure (HF) on action potential duration (APD) and repolarization time (RT) in mouse hearts. We hypothese that a dispersion of RT will provoke arrhythmias if cardiac pacing is performed from the region with the shortest RT. Method used: HF in WT and KChIP2-/- mice was induced by transverse aortic constriction and verified by echocardiography. Regional activation time (AT), APD and RT (=AT + APD) were subsequently measured in isolated, perfused and apically paced hearts using floating microelectrodes. Finally, in-vivo intracardiac pacing of the right ventricle tested arrhythmia vulnerability. Summary of results: Within the left ventricle, APD is longer at the base in KChIP2-/- hearts (n = 6) when compared to WT (n = 6) (APD90: 52.4 ± 5.3 vs. 37.6 ± 3.8 ms, p < 0.05). However, including the AT, the apico-basal dispersion of RT in KChIP2-/- hearts is not different from WT. KChIP2-/- hearts have a larger interventricular dispersion of APD (Δ-APD90: 18.7 ± 4.8 vs. 6.1 ± 1.5 ms, p < 0.05), which translates into a larger left-to-right ventricular dispersion of RT compared to WT hearts (Δ-RT: 22.7 ± 6.7 vs. 5.0 ± 1.5 ms, p < 0.05). HF prolongs AT and APD in WT and KChIP2-/- hearts, and makes spatial dispersion of RT comparable. Pacing the right ventricle of KChIP2-/- control mice to test if pacing from a region with a shorter RT will provoke arrhythmias revealed significant increased arrhythmia vulnerability in these mice. Conclusion: Absence of KChIP2 leads to a prolongation of the left ventricular action potential and an increased interventricular dispersion of RT. HF alters the APD gradients, but reduces the differences in spatial dispersion of RT between WT and KChIP2-/- hearts. Finally, the location of cardiac pacing is crucial when evaluating arrhythmia vulnerability.

Abstract 13875: Torsade de Pointes Arrhythmias Arise at the Site of Maximal Heterogeneity of Repolarization in the Chronic Complete AV-block Dog

Introduction: The chronic complete atrioventricular block (CAVB) dog model is highly sensitive for drug-induced Torsade de Pointes (TdP) arrhythmias. Focal mechanisms have been considered as trigger for the onset of TdP, however, its exact mechanism remains unclear. In this study, detailed mapping of the heart was performed to assess intraventricular heterogeneity of repolarization in relation to the initation of TdP. Methods: In 6 animals, 48 needles, each containing 4 electrodes, were inserted in the ventricles. During right ventricular apex pacing (cycle length: 1000-1500ms) local unipolar electrograms were recorded before and after administration of dofetilide. Activation- and repolarization times (RT) were measured at baseline and before occurrence of the first TdP or at 5 minutes after start of dofetilide infusion in inducible and non-inducible dogs. Maximal RT differences were calculated in the left ventricle 1) within adjacent electrodes in different planes (transmural, apex-base, anterior-posterior) and 2) within a square of 4 needles (3D dispersion). Results: TdP could be induced in 3 out of 6 animals. No difference in mean RT was observed between inducible and non-inducible dogs both at baseline (343±30 vs. 345±17ms) and after dofetilide administration (582±73 vs. 508±15ms). Maximal dispersion of RT was not different between both groups at baseline: 36±32 vs. 32±7ms (transmural), 50±20 vs. 42±9ms (apex-base), 71±28 vs. 47±13ms (anterior-posterior), 83±19 vs. 70±6ms (3D dispersion). After dofetilide infusion anterior-posterior (203±28 vs. 142±34ms, p=0.04) and 3D dispersion (268±41 vs. 176±48ms, p=0.03) showed a higher RT difference in the inducible animals. No differences were observed for transmural (124±14 vs. 116±18ms, p=0.557) and apex-base dispersion (142±12 vs. 121±23ms, p=0.229). The initiating beat of the TdP arose consistently from the region with the largest local spatial dispersion of repolarization moments. Conclusion: TdP arises from a region with maximal heterogeneity of repolarization and animals susceptible for TdP demonstrate higher RT differences. These results suggest that a certain gradient of repolarization moments is required in order to initiate TdP in CAVB dogs.

Abstract 11490: Increased Late Sodium Current Contributes to Excess Prolongation of Canine Ventricular Repolarization Induced by Dofetilide

Introduction: Drugs are screened for delayed rectifier potassium current (IKr) blockade to predict QT prolongation and proarrhythmic potential, but recent in vitro cell studies have shown chronic exposure (hours) to some IKr blockers (e.g. dofetilide, D) prolongs repolarization by increasing late sodium current (INa-L) via PI3 kinase inhibition. Hypothesis: Chronic D administration to intact dogs prolongs repolarization by blocking IKr and increasing INa-L. Methods: We continuously infused D into 6 dogs (6-9 μg/kg bolus+6-9 μg/kg/h IV infusion) for 7h, maintaining D plasma levels within the therapeutic range(2.4±0.2 to 5.2±0.6ng/ml). Acute and chronic D effects on action potential duration (APD) were studied in canine left ventricular (LV) subendocardial slabs using microelectrode techniques. Results: D infusion increased QTc and repolarization time (RT) continuously from baseline to 7h (Table). The INa-L blocker lidocaine (2mg/kg bolus) reduced all variables at 6.5h&gt;0.5h (Table) (e.g. QTc: 19±2% vs 8±1%, P&lt;.05). Chronic, but not acute, D increased apico-basal dispersion of RT, and lidocaine significantly attenuated this effect (Table). In LV subendocardium in vitro, D superfusion (0.2 μM) increased APD at 90% repolarization (APD90) from 232±8ms at baseline to 303±7 at 0.5h (P&lt;.05) and 372±6 at 6.5h (P&lt;.05 vs .5h)(n=6). Lidocaine (20 μM) decreased APD90 by 8±1% at 0.5h and 23±1% at 6.5h (P&lt;.05). In comparison, moxifloxacin (100 μM), an IKr blocker with no effect on INa-L increased APD90 from 216±3ms to 282±5 at 1h (P&lt;.05), and 289±5 at 6.5h (P&gt;.05 vs 1h). Lidocaine reduced APD90 equally by 8% at both 1h and 6.5h (P&gt;.05 for 1h vs 6.5h). Conclusions: Chronic D prolongs ventricular repolarization by blocking Ikr and increasing INa-L. Acquired LQT during chronic D dosing may be attributable to the INa-L increase, highlighting the need to include time and INa-L in evaluating the PI3K inhibition-derived proarrhythmic potential of new drugs.

Transmural APD gradient synchronizes repolarization in the human left ventricular wall.

The duration and morphology of the T wave predict risk for ventricular fibrillation. A transmural gradient in action potential duration (APD) in the ventricular wall has been suggested to underlie the T wave in humans. We hypothesize that the transmural gradient in APD compensates for the normal endocardium-to-epicardium activation sequence and synchronizes repolarization in the human ventricular wall. We made left ventricular wedge preparations from 10 human donor hearts and measured transmural activation and repolarization patterns by optical mapping, while simultaneously recording a pseudo-ECG. We also studied the relation between local timings of repolarization with the T wave in silico. During endocardial pacing (1 Hz), APD was longer at the subendocardium than at the subepicardium (360 ± 17 vs. 317 ± 20 ms, P < 0.05). The transmural activation time was 32 ± 4 ms and resulted in final repolarization of the subepicardium at 349 ± 18 ms. The overall transmural dispersion in repolarization time was smaller than that of APD. During epicardial pacing, the dispersion in repolarization time increased, whereas that of APD remained similar. The morphology of the T wave did not differ between endocardial and epicardial stimulation. Simulations explained the constant T wave morphology without transmural APD gradients. The intrinsic transmural difference in APD compensates for the normal cardiac activation sequence, resulting in more homogeneous repolarization of the left ventricular wall. Our data suggest that the transmural repolarization differences do not fully explain the genesis of the T wave.

Interventricular dispersion in repolarization causes bifid T waves in dogs with dofetilide-induced long QT syndrome.

Long QT2 (LQT2) syndrome is characterized by bifid (or notched) T waves, whose mechanism is not understood. The purpose of this study was to test whether increased interventricular dispersion of repolarization induces bifid T waves. We simultaneously recorded surface ECG and unipolar electrograms at baseline and after dofetilide in a canine model of dofetilide-induced LQT2 (6 male mongrel dogs). Standard ECG variables, T-wave duration, and moments of peaks of bifid T waves (Tp1 and Tp2) were correlated with moments of local repolarization. Epicardial electrograms were recorded over the left ventricular (LV) and right ventricular (RV) anterior walls (11 × 11 electrode grid, 5-mm interelectrode distance). In 5 of the 6 hearts, we also recorded intramural unipolar electrograms (n = 4-7 needles per heart). In each unipolar recording, we determined activation time, repolarization time (RTs), and activation-recovery interval. In addition, we studied RT response to heart rate changes. Dofetilide prolonged QT and QTc, induced bifid T waves in 4 of 6 animals, and prolonged RT heterogeneously in LV and RV, resulting in increased interventricular and LV intraventricular RT dispersion. Dofetilide did not induce a disparate response in activation-recovery interval across the transmural axis. Dofetilide-induced separation of RT across the RV-LV interface concurred with the moments of T-wave peaks. Dofetilide-induced steepening of restitution slopes was larger in LV than RV. Dofetilide-induced bifid T waves result from interventricular RT dispersion.

Electrocardiographic T Wave and its Relation With Ventricular Repolarization Along Major Anatomical Axes

The genesis of the electrocardiographic T wave is incompletely understood and subject to controversy. We have correlated the ventricular repolarization sequence with simultaneously recorded T waves. Nine pig hearts were Langendorff-perfused (atrial pacing, cycle length 650 ms). Local activation and repolarization times were derived from unipolar electrograms sampling the ventricular myocardium. Dispersion of repolarization time was determined along 4 anatomic axes: left ventricle (LV)-right ventricle (RV), LV:apico-basal, LV:anterior-posterior, and LV:transmural. The heart was immersed in a fluid-filled bucket containing 61 electrodes to determine Tp (Tpeak in lead of maximum integral), TpTe (Tp to Tend), and TpTe_total (first Tpeak in any lead to last Tend in any lead). Repolarization was nonlinearly distributed in time. RT25 (time at which 25% of sites were repolarized, 288±26 ms) concurred with Tp. TpTe was 38±8 ms, and TpTe_total was 75±9 ms. TpTe_total correlated with dispersion of repolarization time in the entire heart (73±18 ms), but not with dispersion of repolarization times along individual axes (LV-RV, 66±17 ms; LV:apico-basal, 51±18 ms; LV:anterior-posterior, 51±27 ms; mean LV:transmural, 14±7 ms; all n=9). We provide a correlation between local repolarization and T wave in a pseudo-ECG. Repolarization differences along all anatomic axes contribute to the T wave. TpTe_total represents total dispersion of repolarization. At Tp, ≈25% of ventricular sites have been repolarized.

Modulation of regional dispersion of repolarization and T-peak to T-end interval by the right and left stellate ganglia

Left stellate or right stellate ganglion stimulation (LGSG or RSGS, respectively) is associated with ventricular tachyarrhythmias; however, the electrophysiological mechanisms remain unclear. We assessed 1) regional dispersion of myocardial repolarization during RSGS and LSGS and 2) regional electrophysiological mechanisms underlying T-wave changes, including T-peak to T-end (Tp-e) interval, which are associated with ventricular tachyarrhythmia/ventricular fibrillation. In 10 pigs, a 56-electrode sock was placed around the heart, and both stellate ganglia were exposed. Unipolar electrograms, to asses activation recovery interval (ARI) and repolarization time (RT), and 12-lead ECG were recorded before and during RSGS and LSGS. Both LSGS and RSGS increased dispersion of repolarization; with LSGS, the greatest regional dispersion occurred on the left ventricular (LV) anterior wall and LV apex, whereas with RSGS, the greatest regional dispersion occurred on the right ventricular posterior wall. Baseline, LSGS, and RSGS dispersion correlated with Tp-e. The increase in RT dispersion, which was due to an increase in ARI dispersion, correlated with the increase in Tp-e intervals (R(2) = 0.92 LSGS; and R(2) = 0.96 RSGS). During LSGS, the ARIs and RTs on the lateral and posterior walls were shorter than the anterior LV wall (P < 0.01) and on the apex versus base (P < 0.05), explaining the T-wave vector shift posteriorly/inferiorly. RSGS caused greater ARI and RT shortening on anterior versus lateral or posterior walls (P < 0.01) and on base versus apex (P < 0.05), explaining the T-wave vector shift anteriorly/superiorly. LSGS and RSGS cause differential effects on regional myocardial repolarization, explaining the ECG T-wave morphology. Sympathetic stimulation, in line with its proarrhythmic effects, increases Tp-e interval, which correlates with increases in myocardial dispersion of repolarization.

Mechano-electrical feedback explains T-wave morphology and optimizes cardiac pump function: Insight from a multi-scale model

In the ECG, T- and R-wave are concordant during normal sinus rhythm (SR), but discordant after a period of ventricular pacing (VP). Experiments showed that the latter phenomenon, called T-wave memory, is mediated by a mechanical stimulus. By means of a mathematical model, we investigated the hypothesis that slow acting mechano-electrical feedback (MEF) explains T-wave memory. In our model, electromechanical behavior of the left ventricle (LV) was simulated using a series of mechanically and electrically coupled segments. Each segment comprised ionic membrane currents, calcium handling, and excitation–contraction coupling. MEF was incorporated by locally adjusting conductivity of L-type calcium current (gCaL) to local external work. In our set-up, gCaL could vary up to 25%, 50%, 100% or unlimited amount around its default value. Four consecutive simulations were performed: normal SR (with MEF), acute VP, sustained VP (with MEF), and acutely restored SR. MEF led to T-wave concordance in normal SR and to discordant T-waves acutely after restoring SR. Simulated ECGs with a maximum of 25–50% adaptation closely resembled those during T-wave memory experiments in vivo and also provided the best compromise between optimal systolic and diastolic function. In conclusion, these simulation results indicate that slow acting MEF in the LV can explain a) the relatively small differences in systolic shortening and mechanical work during SR, b) the small dispersion in repolarization time, c) the concordant T-wave during SR, and d) T-wave memory. The physiological distribution in electrophysiological properties, reflected by the concordant T-wave, may serve to optimize cardiac pump function.

Electrocardiographic estimates of action potential durations and transmural repolarization time gradients in healthy subjects and in acute coronary syndrome patients—profound differences by sex and by presence vs absence of diagnostic ST elevation

Action potential duration (APD) changes increasing repolarization time (RT) dispersion are potentially arrhythmogenic. A repolarization model developed from electrocardiographic data of 5376 healthy men and women was used to derive parameter estimates for APD and RT and their transmural gradients (RT grad and APD grad, respectively) in myocardial infarction patients, 126 with and 658 without diagnostic ST elevation (STEMI and NSTEMI, respectively). The model uses, as covariates, rate-adjusted QT and QT peak intervals (QT a and QT pa, respectively) and diagonal crossmural RT grad derived as T p-T xd, the interval from T p to the inflection point at descending limb of global T wave. An additional parameter is Θ(T|T ref), the spatial angle between a subject's T vector and the average T vector of the normal reference group. If Θ(T|T ref) >0, QT pa is assigned to RT epi and QT pa + RT grad to RT endo, with RT epi and RT endo assignments reversed if Θ(T|T ref) ≤0. Parameter estimates for APD epi and APD endo were shorter in men than in women (by 17 ms and 14 ms, respectively, P < .001 for both). Compared to the reference group, RT epi in the STEMI group was shortened by 14 ms in men and by 18 ms in women ( P < .001 for both) with a lesser decrease in RT endo suggesting predominantly subepicardial ischemia. In NSTEMI only RT endo was shortened, by 6 ms in males ( P < .01) and 10 ms in females ( P < .001), suggesting subendocardial ischemia. RT grad signifying local crossmural RT dispersion was prolonged in STEMI by 8 ms in men and by 11 ms in men ( P < .001 for both). RT grad was not changed significantly in NSTEMI. Rate-adjusted T p-T e interval signifying global RT dispersion was increased in both MI and in both sex groups ( P <.001 for all). In conclusion, QT prolongation observed in NSTEMI without prolongation of RT grad and APD epi suggests a delay during terminal repolarization, and in contrast, in STEMI, QT is not changed significantly in spite of prolonged RT grad because of shortened APD epi and RT epi. These repolarization abnormalities are not revealed by QT alone but readily by the repolarization model.

Interaction of Activation–Repolarization Coupling and Restitution Properties in Humans

Dynamic modulation of repolarization is important in arrhythmogenesis. An inverse relation exists in myocardium between activation time (AT) and action potential duration (APD). We hypothesized that resulting gradients of APD and diastolic interval (DI) interact with restitution properties and modulate the timing of repolarization. Activation-recovery intervals (ARI) were acquired from reconstructed noncontact unipolar electrograms from the left ventricular endocardium in 9 patients (7 male) with normal ventricles. At a basic paced cycle length (median, 450 ms), ARIs shortened along the path of activation, with a mandatory reciprocal increase of DIs. In the median patient, this range of DIs started at 230 ms at the site of earliest activation and increased to 279 ms at the site of latest activation at a basic cycle length of 450 ms. Four consecutive standard S1 to S2 restitution curves were performed. At sites with a longer ARI (and therefore shorter DI) close to the site of stimulation, premature stimulation produced more shortening of ARIs; therefore, the time course of restitution was steeper than at more distal sites. At normal heart rate, the decrease in ARIs along the conduction pathway compensated for later activation. Thus, dispersion in repolarization time (RT) is smaller than dispersion in ARI in a heart with a steep negative AT-ARI relationship. This protective effect is lost in hearts without such a relationship. In the patients with a steep AT-ARI relationship at basic cycle length, this relation is lost after premature stimulation and is a function of prematurity. Thus, dispersion in RT is larger after shortly coupled extra stimuli in patients with a steep AT-ARI relationship. A complex interplay exists between activation-repolarization coupling and restitution properties, largely driven by ARI and DI gradients. This plays a significant role in the dynamics of repolarization in humans.

Is there a significant transmural gradient in repolarization time in the intact heart?

Is there a significant transmural gradient in repolarization time in the intact heart?

Intercellular coupling through gap junctions masks M cells in the human heart.

M cells have been described in many mammalian species. They are thought to be relevant for the genesis of long QT intervals, afterdepolarizations and for dispersion in action potential duration and in repolarization time. Their role in the human heart is subject to debate. We simulated action potential propagation in a strand of transversally oriented myocytes running from endocardium towards epicardium through the left ventricular free wall. The characteristics of the myocytes were either based on the Priebe-Beuckelmann ventricular cell model or on the Luo-Rudy ventricular cell model. The former model is based on the latter and includes adaptations in order to mimic the human ventricular myocyte. The amount and location of M cells as well as the intercellular coupling through gap junctions were varied. Also, we assessed action potential duration in a Langendorff-perfused explanted human heart and in a wedge preparation obtained from such a heart. At low, but physiological intercellular coupling conductance, the inclusion of M cells leads to a much longer 'QT interval' in the simulations than in the in vivo or isolated human heart. Dispersion in repolarization time becomes unphysiologically large when M cells are included in the strand and is also substantially larger than in the in vivo or isolated human heart. At stronger intercellular coupling this effect disappears. The manifestation of M cells is absent in the human heart, probably by effective intercellular coupling, turning them functionally "invisible".

Dispersion of atrial repolarization in patients with paroxysmal atrial fibrillation.

To study the role of the dispersion of atrial repolarization (DAR) in the genesis of atrial fibrillation (AF), monophasic action potentials (MAP) were recorded simultaneously from a catheter at the high lateral right atrium (HLRA) and a catheter moving around the high, middle and low lateral right atrium (RA) the high, anterior and posterior septal RA and the RA appendage in 15 patients with paroxysmal AF and 15 patients with atrioventricular nodal re-entry tachycardia (AVNRT) or concealed Wolff-Parkinson-White syndrome (WPW) without history of AF. After recordings during sinus rhythm (SR), MAPs were recorded during programmed stimulation (PS) via the HLRA catheter at a drive cycle length (CL) of 500 ms. Thus, MAPs were recorded simultaneously from 2 sites at a time and sequentially from 4 to 12 sites during SR, drive pacing and PS. Taking the MAP at the HLRA as reference, the dispersion of repolarization time (dispersion of RT) and its two components, the dispersions of activation time (dispersion of AT) and MAP duration (dispersion of MAP duration) among the 4 to 12 sites were calculated and taken as parameters of DAR. During SR and PS, the maximal dispersion of RT was significantly greater in AF than in control patients, 113+/-49 ms vs 50+/-28 ms (P<0.001) and 114+/-56 vs 70+/-43 ms (P<0.05) respectively. The increased dispersion of RT in the AF group was caused by increases in both dispersion of MAP duration and dispersion of AT. During SR and PS, DAR increased in patients with paroxysmal AF due to increases in dispersion of MAP duration and dispersion of AT, which suggests the involvement of both repolarization and conduction disturbances in the development of paroxysmal AF.