Repolarization Gradients Research Articles

High Density Isochronal Repolarisation Mapping (iREM) and Reentry Vulnerability Estimation for Scar-related VT Ablation: Mechanistic Basis, Clinical Application and Challenges.

Alterations in repolarisation gradients and increased heterogeneity are key electrophysiological determinants of ventricular arrhythmogenesis across a variety of aetiologies with and without structural heart disease. High-density repolarisation mapping to localise these repolarisation abnormalities could improve characterisation of the individual arrhythmogenic substrate and inform more targeted ablation. Yet, due to challenges posed by intrinsic features of human cardiac repolarisation itself as well as technical and practical limitations, they are not routinely assessed, and traditional substrate mapping techniques remain strictly limited to determining conduction abnormalities. Here, we provide an overview of the mechanistic role of repolarisation alterations in ventricular re-entry arrhythmias followed by a description of a clinical workflow that enables high-density repolarisation mapping during VT ablations using existing clinical tools. We describe step-by-step guidance of how-to set-up and generate repolarisation maps illustrating the approach in case examples of structural normal and abnormal hearts. Furthermore, we discuss how repolarisation mapping could be combined with existing substrate mapping approaches, including isochronal late activation mapping, to delineate sites of increased re-entry vulnerability, that may represent targets for ablation without the requirement for VT induction. Finally, we review challenges and pitfalls and ongoing controversies in relation to repolarisation mapping and discuss the need for future technical and analytical improvements in repolarisation mapping to integrate into ventricular substrate mapping strategies. Repolarisation mapping remains investigational and future research efforts need to be focused on prospective trials to establish the additional diagnostic value and its role in clinical ablation procedures.

Repolarization gradient induces local depolarization abnormalities in Brugada Syndrome

Abstract Background Transmural voltage gradient in right ventricular outflow tract (RVOT) induces diagnostic ECG-phenotype in Brugada syndrome(BrS). Moreover, RVOT depolarization abnormalities have been described as contributors to BrS phenotype and arrhythmogenesis. Purpose To investigate the effect of ajmaline administration on J-elevation of RVOT unipolar signals in BrS patients. Moreover, we wanted to assess whether ajmaline-induced unipolar J-point elevation variations induced local depolarization abnormalities. Methods 21 BrS patients with spontaneous type-1 ECG pattern were enrolled. Due to the absence of BrS ECG pattern at the study, patients underwent RV endocardial mapping with the CARTO3 system, before (PRE) and after (POST) ajmaline administration. The PRE and POST data were exported from CARTO and converted into Matlab format using OpenEP. J-elevation for each point was calculated as the amplitude of the unipolar signal at J wave with respect to baseline. Activation time (AT) of each point was defined as the difference between local depolarization (minimum dV/dt of the unipolar signal) and surface ECG depolarization (time of the minimum signal on V2). With an automatic algorithm, corresponding PRE and POST points were selected. The difference between POST and PRE of each parameter was calculated to obtain the differential values delta-J and delta-AT. Differential values were then interpolated on the mesh of each subject to obtain 3D maps. The deltaJ map was divided into four intervals based on quartiles. We then selected a ROI 'IN' on a region with the greatest deltaJ variation, and a second ROI 'OUT' on the zone of lowest variation. The same ROIs were applied to the deltaAT map. The mean value of the respective differential parameters was extracted in each ROI. Results Greatest delta-J values were found in the RVOT/anterior wall. delta-J in the ROI 'IN' was greater than in the ROI 'OUT' (1.68 [1.11-2.28] vs 0.56 [0.38-0.93] mV, p<0.001). delta-AT in the ROI ‘IN’ was greater than in the ROI ‘OUT’ (27.96 [20.39-44.89] vs 7.62 [4.24-16.69] ms, p<0.001). A good correlation was found between delta-J and delta-AT, considering the data for the two ROIs together (Spearman R coefficient=0.71, p<0.001). Conclusions Our study shows that the repolarization gradient, evaluated by localized delta-J increase in RVOT, justifies BrS ECG phenotype and local depolarization abnormalities. A strong correlation was present in these RVOT areas between J-elevation variation and slow conducting zones.

REPOLARIZATION GRADIENT CAUSES LOCAL DEPOLARIZATION ABNORMALITIES IN BRUGADA SYNDROME

Abstract Background Transmural voltage gradient in RVOT induces ECG–phenotype in Brugada syndrome(BrS). Moreover,RVOT depolarization abnormalities have been described as contributors to BrS phenotype and arrhythmogenesis. Purpose To investigate the effect of ajmaline administration on J–elevation of RVOT unipolar signals in BrS patients. Moreover,we wanted to assess whether ajmaline–induced unipolar J–point elevation variations induced local depolarization abnormalities. Methods 21 BrS patients with spontaneous type–1 ECG pattern were enrolled. Due to the absence of BrS ECG pattern at the study, patients underwent RV endocardial mapping with the CARTO3 system, before (PRE) and after (POST) ajmaline administration. The data were exported from CARTO and converted into Matlab format using OpenEP. J–elevation for each point was calculated as the amplitude of the unipolar signal at J wave with respect to baseline. Activation time (AT) of each point was defined as the difference between local depolarization (minimum dV/dt of the unipolar signal) and surface ECG depolarization(time of the minimum signal on V2). With an automatic algorithm, corresponding PRE and POST points were selected. The difference between POST and PRE of each parameter was calculated to obtain the differential values delta–J and delta–AT. Differential values were then interpolated on the mesh of each subject to obtain 3D maps. The deltaJ map was divided into four intervals based on quartiles. We then selected a ROI ‘IN‘ on a region with the greatest deltaJ variation, and a second ROI ‘OUT‘ on the zone of lowest variation. The same ROIs were applied to the deltaAT map. The mean value of the respective differential parameters was extracted in each ROI. Results Greatest delta–J values were found in the RVOT/anterior wall. delta–J in the ROI ‘IN‘ was greater than in the ROI ‘OUT‘ (1.68 [1.11–2.28] vs 0.56 [0.38–0.93] mV, p<0.001). delta–AT in the ROI ‘IN’ was greater than in the ROI ‘OUT’ (27.96 [20.39–44.89] vs 7.62 [4.24–16.69] ms, p<0.001). A good correlation was found between delta–J and delta–AT, considering the data for the two ROIs together (Spearman R coefficient=0.71, p<0.001). Conclusions: Our study shows that the repolarization gradient, evaluated by localized delta–J increase in RVOT, justifies BrS ECG phenotype and local depolarization abnormalities. A strong correlation was present in these RVOT areas between J–elevation variation and slow conducting zones.

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.

Bariatric surgery partially reverses subclinical proarrhythmic structural, electrophysiological, and autonomic changes in obesity

BackgroundObesity confers higher risks of cardiac arrhythmias. The extent to which weight loss reverses subclinical proarrhythmic adaptations in arrhythmia-free obese individuals is unknown. ObjectiveThe purpose of this study was to study structural, electrophysiological, and autonomic remodeling in arrhythmia-free obese patients and their reversibility with bariatric surgery using electrocardiographic imaging (ECGi). MethodsSixteen arrhythmia-free obese patients (mean age 43 ± 12 years; 13 (81%) female participants; BMI 46.7 ± 5.5 kg/m2) had ECGi pre–bariatric surgery, of whom 12 (75%) had ECGi postsurgery (BMI 36.8 ± 6.5 kg/m2). Sixteen age- and sex-matched lean healthy individuals (mean age 42 ± 11 years; BMI 22.8 ± 2.6 kg/m2) acted as controls and had ECGi only once. ResultsObesity was associated with structural (increased epicardial fat volumes and left ventricular mass), autonomic (blunted heart rate variability), and electrophysiological (slower atrial conduction and steeper ventricular repolarization time gradients) remodeling. After bariatric surgery, there was partial structural reverse remodeling, with a reduction in epicardial fat volumes (68.7 cm3 vs 64.5 cm3; P = .0010) and left ventricular mass (33 g/m2.7 vs 25 g/m2.7; P < .0005). There was also partial electrophysiological reverse remodeling with a reduction in mean spatial ventricular repolarization gradients (26 mm/ms vs 19 mm/ms; P = .0009), although atrial activation remained prolonged. Heart rate variability, quantified by standard deviation of successive differences in R-R intervals, was also partially improved after bariatric surgery (18.7 ms vs 25.9 ms; P = .017). Computational modeling showed that presurgical obese hearts had a larger window of vulnerability to unidirectional block and had an earlier spiral-wave breakup with more complex reentry patterns than did postsurgery counterparts. ConclusionObesity is associated with adverse electrophysiological, structural, and autonomic remodeling that is partially reversed after bariatric surgery. These data have important implications for bariatric surgery weight thresholds and weight loss strategies.

The local ventricular repolarization gradients estimated from normal and abnormal ECGs

The local ventricular repolarization gradients estimated from normal and abnormal ECGs

Curvature-mediated source and sink effects on the genesis of premature ventricular complexes in long QT syndrome.

Premature ventricular complexes (PVCs) are spontaneous excitations occurring in the ventricles of the heart that are associated with ventricular arrhythmias and sudden cardiac death. Under long QT conditions, PVCs can be mediated by repolarization gradient (RG) and early afterdepolarizations (EADs), yet the effects of heterogeneities or geometry of the RG or EAD regions on PVC genesis remain incompletely understood. In this study, we use computer simulation to systematically investigate the effects of the curvature of the RG border region on PVC genesis under long QT conditions. We show that PVCs can be either promoted or suppressed by negative or positive RG border curvature depending on the source and sink conditions. When the origin of oscillation is in the source region and the source is too strong, a positive RG border curvature can promote PVCs by causing the source area to oscillate. When the origin of oscillation is in the sink region, a negative RG border curvature can promote PVCs by causing the sink area to oscillate. Furthermore, EAD-mediated PVCs are also promoted by negative border curvature. We also investigate the effects of wavefront curvature and show that PVCs are promoted by convex but suppressed by concave wavefronts; however, the effect of wavefront curvature is much smaller than that of RG border curvature. In conclusion, besides the increase of RG and occurrence of EADs caused by QT prolongation, the geometry of the RG border plays important roles in PVC genesis, which can greatly increase the risk of arrhythmias in cardiac diseases.NEW & NOTEWORTHY The effects of the curvature or geometry of the repolarization gradient region and wavefront curvature on the genesis of premature ventricular complexes are systematically investigated using computer modeling and simulation. Premature ventricular complexes can be promoted by either positive or negative curvature of the gradient region depending on the source and sink conditions. The underlying mechanisms of the curvature effects are revealed, which provides mechanistic insights into arrhythmogenesis in cardiac diseases.

Differential effects of mechano-electric feedback mechanisms on whole-heart activation, repolarization, and tension.

The human heart is subject to highly variable amounts of strain during day-to-day activities and needs to adapt to a wide range of physiological demands. This adaptation is driven by an autoregulatory loop that includes both electrical and the mechanical components. In particular, mechanical forces are known to feed back into the cardiac electrophysiology system, which can result in pro- and anti-arrhythmic effects. Despite the widespread use of computational modelling and simulation for cardiac electrophysiology research, the majority of in silico experiments ignore this mechano-electric feedback entirely due to the high computational cost associated with solving cardiac mechanics. In this study, we therefore use an electromechanically coupled whole-heart model to investigate the differential and combined effects of electromechanical feedback mechanisms with a focus on their physiological relevance during sinus rhythm. In particular, we consider troponin-bound calcium, the effect of deformation on the tissue diffusion tensor, and stretch-activated channels. We found that activation of the myocardium was only significantly affected when including deformation into the diffusion term of the monodomain equation. Repolarization, on the other hand, was influenced by both troponin-bound calcium and stretch-activated channels and resulted in steeper repolarization gradients in the atria. The latter also caused afterdepolarizations in the atria. Due to its central role for tension development, calcium bound to troponin affected stroke volume and pressure. In conclusion, we found that mechano-electric feedback changes activation and repolarization patterns throughout the heart during sinus rhythm and lead to a markedly more heterogeneous electrophysiological substrate. KEY POINTS: The electrophysiological and mechanical function of the heart are tightly interrelated by excitation-contraction coupling (ECC) in the forward direction and mechano-electric feedback (MEF) in the reverse direction. While ECC is considered in many state-of-the-art computational models of cardiac electromechanics, less is known about the effect of different MEF mechanisms. Accounting for calcium bound to troponin increases stroke volume and delays repolarization. Geometry-mediated MEF leads to more heterogeneous activation and repolarization with steeper gradients. Both effects combine in an additive way. Non-selective stretch-activated channels as an additional MEF mechanism lead to heterogeneous diastolic transmembrane voltage, higher developed tension and delayed repolarization or afterdepolarizations in highly stretched parts of the atria. The differential and combined effects of these three MEF mechanisms during sinus rhythm activation in a human four-chamber heart model may have implications for arrhythmogenesis, both in terms of substrate (repolarization gradients) and triggers (ectopy).

Electrophysiological mechanisms underlying T wave pseudonormalisation on stress ECGs in hypertrophic cardiomyopathy

BackgroundPseudonormal T waves may be detected on stress electrocardiograms (ECGs) in hypertrophic cardiomyopathy (HCM). Either myocardial ischaemia or purely exercise-induced changes have been hypothesised to contribute to this phenomenon, but the precise electrophysiological mechanisms remain unknown. MethodsComputational models of human HCM ventricles (n = 20) with apical and asymmetric septal hypertrophy phenotypes with variable severities of repolarisation impairment were used to investigate the effects of acute myocardial ischaemia on ECGs with T wave inversions at baseline. Virtual 12-lead ECGs were derived from a total of 520 biventricular simulations, for cases with regionally ischaemic K+ accumulation in hypertrophied segments, global exercise-induced serum K+ increases, and/or increased pacing frequency, to analyse effects on ECG biomarkers including ST segments, T wave amplitudes, and QT intervals. ResultsRegional ischaemic K+ accumulation had a greater impact on T wave pseudonormalisation than exercise-induced serum K+ increases, due to larger reductions in repolarisation gradients. Increases in serum K+ and pacing rate partially corrected T waves in some anatomical and electrophysiological phenotypes. T wave morphology was more sensitive than ST segment elevation to regional K+ increases, suggesting that T wave pseudonormalisation may sometimes be an early, or the only, ECG feature of myocardial ischaemia in HCM. ConclusionsIschaemia-induced T wave pseudonormalisation can occur on stress ECG testing in HCM before significant ST segment changes. Some anatomical and electrophysiological phenotypes may enable T wave pseudonormalisation due to exercise-induced increased serum K+ and pacing rate. Consideration of dynamic T wave abnormalities could improve the detection of myocardial ischaemia in HCM.

Modeling ventricular repolarization gradients in normal cases using the equivalent dipole layer

Background Electrical activity underlying the T-wave is less well understood than the QRS-complex. This study investigated the relationship between normal T-wave morphology and the underlying ventricular repolarization gradients using the equivalent dipole layer (EDL).Methods Body-surface-potential-maps (BSPM, 67‑leads) were obtained in nine normal cases. Subject specific MRI-based anatomical heart/torso-models with electrode positions were created. The boundary element method was used to account for the volume conductor effects. To simulate the measured T-waves, the EDL was used to apply different ventricular repolarization gradients: a) transmural, b) interventricular c) apico-basal and d) all three gradients (a-c) combined. The combined gradient (d) was optimized using an inverse procedure (Levenberg-Marquardt). Correspondence between simulated and measured T-waves was assessed using correlation coefficient (CC) and relative difference (RD).Results Realistic T-waves were simulated if repolarization times of: (a) the epicardium were smaller than the endocardium; (b) the left ventricle were smaller than the right ventricle and (c) the apex increased towards the base. The apico-basal gradient resulted in the highest correspondence between measured and simulated T-waves (CC = 0.84(0.81–0.91);RD = 0.68(0.60–0.71)) compared to a transmural gradient (CC = 0.77(0.71–0.80);RD = 1.46(0.82–1.75)) and an interventricular gradient (CC = 0.71(0.67–0.80);RD = 0.85(0.75–0.87)). All three gradients combined further improved the correspondence between measured and simulated T-waves (CC = 0.83(0.82–0.89);RD = 0.60(0.51–0.63)), especially after optimization (CC = 0.96(0.94–0.98);RD = 0.27(0.22–0.34)).Conclusion The application of all repolarization gradients combined resulted in the largest agreement between simulated and measured T-waves, followed by the apico-basal repolarization gradient. With these findings, we will optimize our EDL-based inverse procedure to assess repolarization abnormalities.

Abstract 11663: T Wave Alternans: A Clue in Plain Sight

Introduction: T-wave alternans (TWA) refers to the beat-to-beat variability in T-wave amplitudes or polarity on surface ECGs, and can signify susceptibility to malignant ventricular arrhythmias (VA). Aims: We present a case to emphasize the pathophysiology and clinical significance of this ECG finding. Case description: A 52 year-old female with history of HIV presents with shortness of breath and is treated for heart failure. In the ED, she has witnessed syncope and is found to have VT that progresses to VF. Resuscitation efforts are successful and include amiodarone loading. Figure 1A demonstrates baseline ECG on admission with a QTc of 495 ms. A few days later, an ECG reveals QTc of 696 ms with TWA (figure 1B). Shortly after, she develops polymorphic VT in the setting of long-short sequences and an R on T trigger (figure 1C) that is terminated with cardioversion. Review of pre-admission ECGs reveals that QTc prolongation occurred after initiation of a retroviral regimen that included rilpivirine and worsened with amiodarone. Both medications are discontinued, and she is eventually discharged with a QTc of 450 ms. Early theories for TWA's mechanism hypothesized that dispersion of refractoriness resulted in depolarization through alternating pathways and thus this phenomenon. Recent understanding further suggests that TWA occurs as a result of cellular alternans and variation in action potential duration due to dysregulation of repolarization. If discordant repolarization alternans ensues, whereby neighboring cells repolarize in opposite phases (long-short, short-long), the resultant repolarization gradient and heterogeneity in cellular repolarization serves as the substrate for VA; if a premature beat encounters refractory myocardium and unidirectional block occurs, a re-entrant excitation tachycardia can be initiated. Conclusions: TWA on ECG suggests myocardial electrical instability as a result of cellular repolarization inhomogeneity.

EN-452414-1 IMPACT OF MULTI-DIRECTIONAL PACING ON LATE SIGNAL ACTIVATION, ACTIVATION SLOWING AND REPOLARIZATION GRADIENTS TO LOCALIZE RE-ENTRANT VENTRICULAR TACHYCARDIA CIRCUITS IN A PORCINE INFARCT MODEL.

Optimal signal parameters and substrate mapping strategies for identifying key arrhythmogenic sites in ventricular tachycardia (VT) ablation are not established. To evaluate multi-directional pacing on the distribution of late signal activation, activation slowing and repolarization gradients in relation to critical sites of re-entrant VT, in a porcine infarct model. Electrophysiology studies were performed 4 weeks post-infarction in 13 pigs using the EnSite Precision system (Abbott, IL, USA), and the Advisor HD Grid (Abbott) multi-electrode catheter. Substrate maps were created during right ventricular (RV), left ventricular (LV), and biventricular pacing (BIV), and sinus rhythm (SR). Sites of early, mid-, and late-diastolic signals of induced VT’s were delineated. Off-line analysis compared these critical VT sites to algorithmically identified 20 most vulnerable sites of latest activation timing within and post-QRS, and the largest activation (GradAT) and activation recovery interval gradients (GradARI). 34 VTs were mapped with at least one diastolic recorded component, with a mean tachycardia cycle length of 236.5 ± 32.4 ms. 48 sinus rhythm and pacing maps were obtained, 10 using BIV pacing (mean points 375 ± 263), 13 using LV pacing (mean points 610 ± 334), 13 from RV pacing (mean points 603 ± 263) and 12 in sinus rhythm (mean points 1078 ± 654). Late potential (LP) mapping in sinus rhythm was taken as the established clinical standard for statistical comparison with all other protocols, displayed in Figure 1. GradARI using RV pacing provided the closest localization for VT exit and entrance, with a median distance of 10.6mm (IQR 5.0mm, p <0.05) and median 9.4mm (IQR 8.0mm, p <0.05) compared to LP in sinus rhythm, respectively. LAT with BIV pacing provided closest VT isthmus localization for VT isthmus, with a median of 5.5mm (IQR 7.15mm, p <0.05) compared to LP in sinus rhythm (Figure 1). A global sensitivity and specificity analysis was performed on all points. GradARI mapping in SR reported the highest AUC (area – under curve) for early diastolic VT signals (AUC 0.96, sensitivity 93%, specificity 91%), mid-diastolic signals (AUC 0.92, sensitivity 84%, specificity 88%) and late diastolic signals (AUC 0.92, sensitivity 88%, specificity 84%). Sites with the largest ARI gradients in sinus rhythm best predict critical sites of VT in this model, with the most effective protocol being RV pacing examining ARI gradients.

Bifurcations to transient and oscillatory excitations in inhomogeneous excitable media: Insights into arrhythmogenesis in long QT syndrome.

Ventricular arrhythmias are the leading cause of sudden cardiac death. Understanding the mechanisms of arrhythmia initiation is important for developing effective therapeutics for prevention. Arrhythmias can be induced via premature external stimuli or occur spontaneously via dynamical instabilities. Computer simulations have shown that a large repolarization gradient due to regional prolongation of the action potential duration can result in instabilities leading to premature excitations and arrhythmias, but the bifurcation remains to be elucidated. In this study we carry out numerical simulations and linear stability analyses using a one-dimensional heterogeneous cable consisting of the FitzHugh-Nagumo model. We show that a Hopf bifurcation leads to local oscillations, which, once their amplitudes are large enough, lead to spontaneous propagating excitations. Depending on the degree of heterogeneities, these excitations can range from one to many and to be sustained oscillations, manifesting as premature ventricular contractions (PVCs) and sustained arrhythmias. The dynamics depends on the repolarization gradient and the length of the cable. Complex dynamics is also induced by the repolarization gradient. The mechanistic insights from the simple model may help in the understanding of the genesis of PVCs and arrhythmias in long QT syndrome.

Arrhythmogenic Effects of Cardiac Memory.

Cardiac memory is the term used to describe an interesting electrocardiographic phenomenon. Whenever a QRS complex is wide and abnormal, such as during ventricular pacing, the T waves will also be abnormal and will point to the opposite direction of the wide QRS. If the QRS then normalizes, such as after cessation of ventricular pacing, the T waves will normalize as well, but at a later stage. The period of cardiac memory is the phase between the sudden normalization of the QRS and the eventual and gradual return of the T waves to their baseline morphology. Cardiac memory is assumed to be an innocent electrocardiographic curiosity. However, during cardiac memory, reduction of repolarizing potassium currents increases left ventricular repolarization gradients. Therefore, when cardiac memory occurs in patients who already have a prolonged QT interval (for whatever reason), it can lead to a frank long QT syndrome with QT-related ventricular arrhythmias (torsades de pointes). These arrhythmogenic effects of cardiac memory are not generally appreciated and are reviewed here for the first time.

Shark Fin Electrocardiogram in the Intensive Care Unit.

Shark Fin Electrocardiogram in the Intensive Care Unit.

The interplay of sex-specific electrophysiology and repolarization heterogeneity governs ventricular arrhythmia sustainability in women

Abstract Background The role of sex-specific electrophysiology in the development of lethal ventricular arrhythmia is poorly understood. Since female ventricles have a longer action potential duration (APD) than male ventricles, we hypothesized that female hearts are more vulnerable to sustained ventricular arrhythmia in the presence of known arrhythmogenic substrates. Purpose To determine if prolonged APD in females leads to sustained ventricular arrhythmia in the presence of left ventricular (LV) hypertrophy, diffuse fibrosis, and repolarization heterogeneity. Methods Magnetic resonance imaging (MRI) data were used to develop computational biventricular models of two aortic stenosis patients (male, 54 years; female, 64 years) before (LV hypertrophy) and 3 months after (regressed LV hypertrophy) aortic valve replacement (AVR). These patients were chosen since they exhibit reduced LV mass, less fibrosis, and no ventricular arrhythmias after AVR. The models were assigned sex-specific cellular electrophysiology and an apicobasal repolarization gradient derived from human data. Simulations of apical pacing with a cycle length (CL) of 750 ms were performed while APD at 90% repolarization (APD90) and repolarization time (activation time + APD90) were calculated. Reentrant arrhythmia was induced by rapidly pacing the LV with a 2 mm wide apicobasal line electrode at CL≤265 ms. The simulations were repeated in the presence of diffuse myocardial fibrosis derived from the MRI patient data, and repeated again with an apicobasal repolarization gradient reduced by ≈35%. Ventricular mass was calculated as the product of model volume and myocardial density. Results In hypertrophic ventricles with default apicobasal repolarization gradient, rapid pacing led to reentry that lasted longer in the female (&amp;gt;25 s) than in the male (1.0 s) ventricles. The duration of reentry increased in the presence of fibrosis in the male ventricles (male: 6.6 s; female &amp;gt;25 s) and decreased in the female ventricles when the apicobasal repolarization gradient was reduced (Figure). Sustained reentry (&amp;gt;25 s) was not observed in the ventricles with regressed hypertrophy, regardless of the presence of fibrosis or repolarization gradient. Average APD90 was longer in the female ventricles both before (male: 267±35 ms; female: 318±34 ms) and after (male: 272±35 ms; female: 328±38 ms) AVR. The female heart had lower myocardial mass than the male heart both before (280 vs. 406 g) and after AVR (227 vs. 310 g). Conclusion Longer APD and steeper apicobasal repolarization gradients in hypertrophic female ventricles resulted in sustained arrhythmia, despite their lower mass when compared to males. The absence of sustained reentry in the post-AVR models indicates a potential electrophysiological benefit of AVR and encourages future clinical studies to quantify sex-specific differences in spatial repolarization heterogeneity. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union's Horizon 2020 research and innovation program under the ERA-NET co-fund action No. 680969 with ANR (ERA-CVD SICVALVES) and Agence Nationale de la Recherche

Bariatric surgery reverses ventricular repolarisation heterogeneity in obesity: mechanistic insights into fat-related arrhythmic risk

Abstract Background Obesity is a growing global health problem that confers higher risks of atrial arrhythmias and sudden cardiac death. Despite this, the proarrhythmic substrate in obesity and its reversibility with weight loss has not been studied in-depth. Purpose To characterise the proarrhythmic substrate in obese patients, and its reversibility with bariatric surgery, using electrocardiographic imaging (ECGi). Methods ECGi was performed in 16 obese patients pre-bariatric surgery (PreSurg; mean age 43±12 years, 13 female) and 16 age- and sex-matched non-obese (lean) individuals (42±11 years). 12 of the 16 obese patients also underwent ECGi after bariatric surgery (PostSurg). Over 2000 atrial and ventricular epicardial electrograms were computed using high density body surface mapping (256-lead ECG) and heart-torso geometries from cardiac magnetic resonance imaging, by solving the inverse problem of electrocardiography. Local atrial and ventricular epicardial activation times (AT) were calculated as the steepest downslope of their respective activation complexes, and local ventricular repolarisation times (RT) as the steepest upslope of the T-wave. Atrial activation gradients (ATG) and ventricular repolarisation gradients (RTG) were calculated as the maximum difference within 10 mm radius divided by the corresponding distance. Results Body mass index was greater in PreSurg vs lean (46.7±5.5 vs 22.8±2.6 kg/m2, p&amp;lt;0.0001) and decreased with surgery (PostSurg 36.8±6.5 kg/m2, p&amp;lt;0.0001). Epicardial adipose tissue (EAT) was greater in PreSurg vs lean (83±56 vs 28±13 ml, p&amp;lt;0.0001) and decreased post-surgery (PostSurg 69±45 ml, p=0.0010). Total atrial AT was prolonged in PreSurg vs lean (62±15 vs 46±12 ms, p=0.0028), which persisted post-surgery (PostSurg 67±15 ms, p=0.86). Atrial ATG were also greater in PreSurg vs lean (26±11 vs 14±8 ms, p=0.0007) and did not change with weight loss (PostSurg 25±12, p=0.44). Ventricular RTG were greater in PreSurg vs lean (26±11 vs 15±7 ms/mm, p=0.0024) and decreased with weight loss (PostSurg 19±8, p=0.0009). Ventricular RTG were similar between PostSurg and lean (p=0.20). EAT from lean and PreSurg individuals correlated with atrial ATG (r=0.36, p=0.044) and ventricular RTG (r=0.54, p=0.0014). Ventricular AT were similar between lean (31±6 ms), PreSurg (34±5 ms) and PostSurg (35±9 ms); all p&amp;gt;0.05. Conclusion Steep ventricular repolarisation gradients and prolonged atrial activation contribute to the proarrhythmic substrate in obesity. Ventricular repolarisation gradients correlate with epicardial adiposity and both regress post-bariatric surgery. By contrast, atrial activation remains prolonged after weight loss. These results provide mechanistic insights into obesity-related arrhythmic risks and their reversibility with weight loss following bariatric surgery. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): British Heart FoundationNational Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC).

Dependence of epicardial T-wave on local activation voltage in Brugada syndrome.

Brugada syndrome (BrS) manifests as a spontaneous variability of the electrocardiographic marker suggesting a dynamic variability of the electrical substrate. A “coved J-ST” aspect can be explained by mechanisms primarily affecting repolarization, or secondary to defective activation.1 Animal models using pharmacological agents produce J-ST elevation through repolarization gradients, while in patients, evidence points to a slow-conductive structural substrate in the right ventricular outflow tract (RVOT) epicardium.

R-on-T and the initiation of reentry revisited: Integrating old and new concepts.

Initiation of reentry requires 2 factors: (1) a triggering event, most commonly focal excitations such as premature ventricular complexes (PVCs); and (2) a vulnerable substrate with regional dispersion of refractoriness and/or excitability, such as occurs during the T wave of the electrocardiogram when some areas of the ventricle have repolarized and recovered excitability but others have not. When the R wave of a PVC coincides in time with the Twave of the previous beat, this timing can lead to unidirectional block and initiation of reentry, known as the R-on-T phenomenon. Classically, the PVC triggering reentry has been viewed as arising focally from 1 region and propagating into another region whose recovery is delayed, resulting in unidirectional conduction block and reentry initiation. However, more recent evidence indicates that PVCs also can arise from the T wave itself. In the latter case, the PVC initiating reentry is not a separate event from the T wave but rather is causally generated from the repolarization gradient that manifests as the T wave. We call the former an "R-to-T" mechanism and the latter an "R-from-T" mechanism, which are initiation mechanisms distinct from each other. Both are important components of the R-on-T phenomenon and need to be taken into account when designing antiarrhythmic strategies. Strategies targeting suppression of triggers alone or vulnerable substrate alone may be appropriate in some instances but not in others. Preventing R-from-T arrhythmias requires suppressing the underlying dynamic tissue instabilities responsible for producing both triggers and substrate vulnerability simultaneously. The same principles are likely to apply to supraventricular arrhythmias.

Bariatric surgery reduces ventricular repolarisation gradients in obese patients - results from an electrocardiographic imaging study

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): National Institute for Health Research (NIHR) British Heart Foundation Background Obesity confers higher risks of atrial arrhythmias and is associated with abnormal ventricular repolarisation. Despite this, the proarrhythmic substrate in obesity and its reversibility with weight loss has not been studied in-depth. Purpose To characterise the proarrhythmic substrate in obese patients, and its reversibility with bariatric surgery, using electrocardiographic imaging (ECGi). Methods ECGi was performed in 8 obese patients before (PreOb) and after (PostOb) bariatric surgery (mean age 39+/-11years, 7 female), and in 8 age- and sex-matched non-obese controls (NOb) (40+/-11 years). ECGi recordings were made at rest, on exercise, and during recovery from exercise. For ECGi analysis, &amp;gt;2000 atrial and ventricular epicardial electrograms were calculated from body surface potential recordings from 256 sites and information from cardiac magnetic resonance imaging, by solving the inverse problem. Local atrial and ventricular epicardial activation times (AT) were calculated as the steepest downslope of their respective activation complexes, and local ventricular repolarisation times (RT) as the steepest upslope of the T-wave. Atrial activation gradients (ATG) and ventricular repolarisation gradients (RTG) were calculated as the maximum difference within 10mm radius divided by the corresponding Euclidean distance. Results BMI was greater in PreOb vs NOb (46.6+/-4.8 vs 23.8+/-2.6kg/m2, p&amp;lt;0.0001) and decreased with surgery (PostOb 35.3+/-4.2kg/m2, p&amp;lt;0.0001). Total atrial AT was prolonged in PreOb vs NOb (68+/-12 vs 45+/-10ms, p=0.016) and did not change post-surgery (PreOb vs PostOb: 68+/-12 vs 67+/-16ms, p=0.81). Atrial ATG were also greater in PreOb vs NOb: max 254+/-111 vs 106+/-58ms, p=0.035; mean 24+/-6 vs 12+/-6ms, p=0.0087) and did not change with weight loss (PreOb vs PostOb: max 254+/-111 vs 222+/-69ms/mm, p=0.61; mean 24+/-6 vs 21+/-7ms/mm, p=0.52). Ventricular RTG were greater in PreOb vs NOb (max: 287+/-73 vs 131+/-89ms/mm, p=0.012; mean: 33+/-10 vs 17+/-9ms/mm, p=0.0052). Ventricular RTG decreased with weight loss (PreOb vs PostOb: max 287+/-73 vs 151+/-54ms/mm, p=0.0070; mean: 33+/-10 vs 21+/-8ms/mm, p=0.018), and were similar between PostOb and NOb (max, p=0.81; mean p=0.58). Ventricular AT and RT were non-different in NOb, PreOb and PostOb. Conclusion Obesity is associated with pro-arrhythmic electrophysiological remodelling, including steeper ventricular repolarisation gradients and slower atrial activation. At 6 months post-bariatric surgery, there was a reduction in ventricular repolarisation gradients though atrial conduction abnormalities persisted. These findings provide a mechanistic insight into obesity-related arrhythmic risks and its potential reversibility with weight loss surgery.