Heterogeneity Of Repolarization Research Articles

The interpretation of field and LEAP potentials recorded from cardiomyocyte monolayers

Abstract Funding Acknowledgements None. Multi-electrode arrays (MEA) are the method of choice for electrophysiological characterization of cardiomyocyte monolayers. The field potentials recorded using a MEA are like extracellular electrograms recorded from ventricular myocardium using conventional electrodes. Nevertheless, different criteria are often used to interpret field potential and extracellular electrogram, which hampers correct interpretation and translation to the patient. To validate criteria for extracellular electrograms analysis applicable to field potentials, we used neonatal rat cardiomyocytes to generate monolayers. We recorded field potentials using a MEA and simultaneously recorded action potentials using sharp micro-electrodes. In parallel we recreated our experimental setting in silico and performed simulations. We demonstrate that the amplitude of the local RS-complex of a field potential correlated with conduction velocity, but only in the lower ranges of conduction velocities. The time of the peak of the T-wave of the field potentials correlated well with APD90 and the time of the steepest upslope with APD50. By injecting current into the monolayer, we could record a local extracellular action potential (LEAP). The LEAP was of low amplitude and highly depolarized, and the shape differed markedly from the shape of the local action potential. Criteria for interpreting extra cellular electrograms should also be applied to field potentials. This will provide a strong basis for analysis of heterogeneity in conduction velocity and repolarization in cultured monolayers of cardiomyocytes especially at low conduction velocities. A LEAP is not a recording of the local action potential but is generated by intracellular current provided by neighboring cardiomyocytes.

Prognostic significance of beat-to-beat variability of spatial heterogeneity of repolarisation analysed from 5-minute resting electrocardiogram in coronary artery disease

Abstract Background Data on the prognostic significance of temporal variability of spatial heterogeneity of electrocardiographic repolarisation in coronary artery disease (CAD) are limited. Purpose To evaluate the prognostic value of temporal variability of T-wave morphology analysed from 5-minute resting ECG in CAD. Methods The standard deviation (SD) of T-wave morphology dispersion (TMD-SD), the SD of T-wave heterogeneity (TWH-SD), and the SD of total cosine R-to-T (TCRT-SD) were analysed on beat-to-beat basis from a 5-minute period of resting 12-lead ECG obtained before a clinical stress test in 1702 patients with angiographically verified CAD and well-preserved left ventricular function. Results During an average of 8.7±2.2 years of follow-up, 60 (3.5 %) patients experienced sudden cardiac death (SCD) or were resuscitated from a sudden cardiac arrest (SCA), 69 (4.1 %) patients experienced non-sudden cardiac death (NSCD), and 161 (9.5 %) patients died due to non-cardiac death (NCD). TMD-SD was significantly higher in patients who experienced SCD/SCA compared with those without such an event (1.72 ± 2.00 vs. 1.12 ± 1.75, p= 0.01, respectively) and in patients who succumbed to NSCD compared with those without such an event (1.57 ± 1.74 vs. 1.12 ± 1.76, p=0.04, respectively), but did not differ significantly between patients who experienced NCD and those without such an event (1.16 ± 1.42 vs. 1.14 ± 1.79, p=0.86, respectively). After adjusting for relevant clinical risk factors in the Cox multivariate hazards model, TMD-SD retained its significant association with the risk of SCD/SCA (HR 1.119, 95 % CIs 1.015–1.233, p=0.024), but not with the risk of NSCD (HR 1.089, 95 % CIs 0.983–1.206, p=0.103). Conclusion TMD-SD, representing temporal variability of spatial heterogeneity of electrocardiographic repolarisation, is independently associated with the long-term risk of SCD/SCA in CAD patients with well-preserved left ventricular function.

High-resolution repolarization changes preceding short-coupled ectopy in idiopathic ventricular fibrillation, and effects of quinidine

Abstract Background Idiopathic ventricular fibrillation (VF) is linked to early repolarization, increased repolarization heterogeneity, and (short-coupled) premature ventricular complexes (PVCs). Quinidine, an antiarrhythmic drug with class-IA and -III effects, reduces the occurrence of PVCs and VF, but its effects on repolarization have not yet been studied at the whole-heart level in idiopathic-VF patients. Purpose To study dynamic changes in repolarization preceding short-coupled PVCs using noninvasive electrocardiographic imaging (ECGI) in a patient with idiopathic VF, and the antiarrhythmic effects of quinidine. Methods ECGI was performed during sinus rhythm in a 61-year-old male with an ICD (secondary prevention; 2.5 mg nebivolol daily) two days after recurrent idiopathic VF (Fig. A). This was done 1) at baseline, 2 minutes before short-coupled ectopy ("baseline"); 2) at baseline, 10 seconds before the short-coupled PVC ("pre PVC"); and 3) at 2 hours after start of quinidine 200 mg ("on-quinidine"). The ECGI procedure consisted of a 224-electrode body surface potential map and a contrast-enhanced CT scan to obtain torso and heart geometries. After reconstruction of epicardial unipolar electrograms (UEGs), local activation and repolarization times (ATs and RTs) were derived from UEGs by assessing the steepest downslope of the QRS complex and steepest upslope of the T waves, respectively, of 10-second signal-averaged beats. AT and RT duration (first to last AT or RT) were assessed. Results At baseline, QRS duration and QT interval measured 107 ms and 343 ms, respectively, on the standard 12-lead ECG. ECGI-derived epicardial AT duration was 72 ms, and RT histogram span 92 ms. The coupling interval of the PVC that triggered VF in the ICD readout was 340 ms (Fig. A). During 44 minutes of ECGI, 157 short-coupled PVCs from the moderator-band region were recorded (Fig. B; no tachycardia or VF). Just prior to a PVC, epicardial early repolarization at the PVC origin decreased by 26 ms (star in Figs. C-E), and the RT histogram broadened to 109 ms (Fig. E). While on-quinidine, (25 minutes; QRS duration 107 ms, QT interval 419 ms), epicardial repolarization was prolonged (Fig. C/D), also at the site of abnormal impulse formation. Quinidine had increased the epicardial AT duration to 79 ms, and RT histogram span to 133 ms. PVCs were completely suppressed. The patient remained free of sustained arrhythmias while on-quinidine. Conclusion(s) In this case of short-coupled idiopathic VF, epicardial early repolarization shortened momentarily prior to abnormal impulse formation. We found dynamic substrate-trigger characteristics that likely facilitate reentrant excitation. Quinidine prolonged the duration of epicardial activation and repolarization, suppressing the ectopy and VF recurrence.

Effects of ranolazine on the arrhythmic substrate in hypertrophic cardiomyopathy.

Introduction: Hypertrophic cardiomyopathy (HCM) is a leading cause of lethal arrhythmias in the young. Although the arrhythmic substrate has been hypothesised to be amenable to late Na+ block with ranolazine, the specific mechanisms are not fully understood. Therefore, this study aimed to investigate the substrate mechanisms of safety and antiarrhythmic efficacy of ranolazine in HCM. Methods: Computational models of human tissue and ventricles were used to simulate the electrophysiological behaviour of diseased HCM myocardium for variable degrees of repolarisation impairment, validated against in vitro and clinical recordings. S1-S2 pacing protocols were used to quantify arrhythmic risk in scenarios of (i) untreated HCM-remodelled myocardium and (ii) myocardium treated with 3µM, 6µM and 10µM ranolazine, for variable repolarisation heterogeneity sizes and pacing rates. ECGs were derived from biventricular simulations to identify ECG biomarkers linked to antiarrhythmic effects. Results: 10µM ranolazine given to models manifesting ventricular tachycardia (VT) at baseline led to a 40% reduction in number of VT episodes on pooled analysis of >40,000 re-entry inducibility simulations. Antiarrhythmic efficacy and safety were dependent on the degree of repolarisation impairment, with optimal benefit in models with maximum JTc interval <370ms. Ranolazine increased risk of VT only in models with severe-extreme repolarisation impairment. Conclusion: Ranolazine efficacy and safety may be critically dependent upon the degree of repolarisation impairment in HCM. For moderate repolarisation impairment, reductions in refractoriness heterogeneity by ranolazine may prevent conduction blocks and re-entry. With severe-extreme disease substrates, reductions of the refractory period can increase re-entry sustainability.

Prognostic significance of beat-to-beat variability of spatial heterogeneity of repolarization analyzed from a 5-minute resting electrocardiogram in coronary artery disease

BackgroundData on the prognostic significance of temporal variability of spatial heterogeneity of electrocardiographic repolarization in coronary artery disease (CAD) are limited. ObjectiveThe purpose of this study was to evaluate the prognostic value of temporal variability of T-wave morphology analyzed from a 5-minute resting electrocardiogram in CAD. MethodsThe standard deviation (SD) of T-wave morphology dispersion (TMD-SD) and the SD of total cosine R-to-T were analyzed on a beat-to-beat basis from a 5-minute period of the standard resting 12-lead electrocardiogram obtained before the clinical stress test in 1702 patients with angiographically verified CAD and well-preserved left ventricular function. ResultsDuring an average of 8.7 ± 2.2 years of follow-up, 60 patients experienced sudden cardiac death/arrest (SCD/SCA) (3.5%), 69 patients nonsudden cardiac death (NSCD) (4.1%), and 161 patients noncardiac death (9.5%). TMD-SD was significantly higher in patients who experienced SCD/SCA than in other patients (1.72 ± 2.00 vs 1.12 ± 1.75; P = .01) and higher in patients who succumbed to NSCD than in other patients (1.57 ± 1.74 vs 1.12 ± 1.76; P = .04), but it did not differ significantly between patients who experienced noncardiac death and those without such an event (1.16 ± 1.42 vs 1.14 ± 1.79; P = .86). In the Cox multivariable hazards model, TMD-SD retained its significant association with the risk of SCD/SCA (hazard ratio 1.119; 95% confidence interval 1.015–1.233; P = .024) but not with the risk of NSCD (hazard ratio 1.089; 95% confidence interval 0.983–1.206; P = .103). ConclusionTMD-SD is independently associated with the long-term risk of SCD/SCA in patients with CAD.

Interpretation of field and LEAP potentials recorded from cardiomyocyte monolayers.

Multielectrode arrays (MEAs) are the method of choice for electrophysiological characterization of cardiomyocyte monolayers. The field potentials recorded using an MEA are like extracellular electrograms recorded from the myocardium using conventional electrodes. Nevertheless, different criteria are used to interpret field potentials and extracellular electrograms, which hamper correct interpretation and translation to the patient. To validate the criteria for interpretation of field potentials, we used neonatal rat cardiomyocytes to generate monolayers. We recorded field potentials using an MEA and simultaneously recorded action potentials using sharp microelectrodes. In parallel, we recreated our experimental setting in silico and performed simulations. We show that the amplitude of the local RS complex of a field potential correlated with conduction velocity in silico but not in vitro. The peak time of the T wave in field potentials exhibited a strong correlation with APD90 while the steepest upslope correlated well with APD50. However, this relationship only holds when the T wave displayed a biphasic pattern. Next, we simulated local extracellular action potentials (LEAPs). The shape of the LEAP differed markedly from the shape of the local action potential, but the final duration of the LEAP coincided with APD90. Criteria for interpretation of extracellular electrograms should be applied to field potentials. This will provide a strong basis for the analysis of heterogeneity in conduction velocity and repolarization in cultured monolayers of cardiomyocytes. Finally, a LEAP is not a recording of the local action potential but is generated by intracellular current provided by neighboring cardiomyocytes and is superior to field potential duration in estimating APD90.NEW & NOTEWORTHY We present a physiological basis for the interpretation of multielectrode array-derived, extracellular, electrical signals.

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.

Evaluation of electrocardiogram findings and inflammatory parameters in patients with benign paroxysmal positional vertigo.

Benign Paroxysmal Positional Vertigo (BPPV) is a common vestibular disorder characterized by brief episodes of intense vertigo, often accompanied by nausea and nystagmus. The frontal QRS-T (fQRS-T) angle, a novel indicator of ventricular depolarization and repolarization heterogeneity, has garnered attention due to its potential to reveal insights into cardiac function. This study aimed to investigate the potential relationship between the fQRS-T angle and inflammation markers in individuals with BPPV. The study encompassed 49 BPPV patients and 51 healthy individuals as a control group. Laboratory assessments were conducted to measure inflammation parameters. Electrocardiogram (ECG) data was analyzed, focusing on conduction parameters including fQRS-T angle, QRS duration, QT interval, and corrected QT interval. The study revealed that the fQRS-T angle was significantly higher in BPPV patients compared to the control group (p<.001). Moreover, inflammation markers such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and C-reactive protein-to-albumin ratio (CAR) were notably elevated in BPPV patients (p<.001, for all). The findings of the correlation analysis demonstrated a strong association between NLR and the fQRS-T angle (r=.718, p<.001). Additionally, the results of the linear regression analysis indicated that NLR positively predicted the fQRS-T angle (p<.001). The study's outcomes have underscored a significant increase in the fQRS-T angle among BPPV patients, suggesting altered ventricular repolarization dynamics. The strong correlation between NLR and the fQRS-T angle raises intriguing possibilities of inflammation's potential role in influencing cardiac electrophysiology. The study contributes to the growing body of evidence suggesting that BPPV might have implications beyond its immediate vestibular manifestations.

Effect of dapagliflozin on ventricular repolarization in patients with heart failure with reduced ejection fraction.

Whether sodium-glucose cotransporter-2 inhibitors (SGLT2is) reduce ventricular arrhythmias and sudden cardiac death is controversial. Ventricular repolarization heterogeneity is associated with ventricular arrhythmias; however, the effect of SGLT2is on ventricular repolarization in patients with heart failure with reduced ejection fraction (HFrEF) has not been fully investigated. We prospectively evaluated 31 HFrEF patients in sinus rhythm who were newly started on dapagliflozin 10mg/day. Changes in QT interval, corrected QT interval (QTc), QT dispersion (QTD), corrected QTD (QTcD), T peak to T end (TpTe), TpTe/QT ratio, and TpTe/QTc ratio were evaluated at 1-year follow-up. QT interval, QTc interval, QTD, QTcD, TpTe, and TpTe/QTc ratio decreased significantly at 1-year follow-up (427.6 ± 52.6ms vs. 415.4 ± 35.1ms; p = 0.047, 437.1 ± 37.3ms vs. 425.6 ± 22.7ms; p = 0.019, 54.1 ± 11.8ms vs. 47.6 ± 14.7ms; p = 0.003, 56.0 ± 11.2ms vs. 49.4 ± 12.3ms; p = 0.004, 98.0 ± 15.6ms vs. 85.5 ± 20.9ms; p = 0.018, and 0.225 ± 0.035 vs. 0.202 ± 0.051; p = 0.044, respectively). TpTe/QT ratio did not change significantly (0.231 ± 0.040 vs. 0.208 ± 0.054; p = 0.052). QT interval, QTD, and TpTe were significantly reduced 1year after dapagliflozin treatment in patients with HFrEF. The beneficial effect of dapagliflozin on the heterogeneity of ventricular repolarization may contribute to the suppression of ventricular arrhythmias.Registry information https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000049428 . Registry number: UMIN000044902.

Theoretical prediction of early afterdepolarization-evoked triggered activity formation initiating ventricular reentrant arrhythmias

Background and ObjectiveExcessive prolongation of QT interval on ECGs in patients with congenital/acquired long QT syndrome and heart failure is a sign suggesting the development of early afterdepolarization (EAD), an abnormal repolarization in the action potential of ventricular cardiomyocytes. The development of EAD has been believed to be a trigger for fatal tachyarrhythmia, which can be a risk for sudden cardiac death. The role of EAD in triggering ventricular tachycardia (VT) remains unclear. The aim of this study was to elucidate the mechanism of EAD-induced triggered activity formation that leads to the VT such as Torsades de Pointes. MethodsWe investigated the relationship between EAD and tachyarrhythmia initiation by constructing homogeneous myocardial sheet models consisting of the mid-myocardial cell version of a human ventricular myocyte model and performing simulations of excitation propagation. ResultsA solitary island-like (clustering) occurrence of EADs in the homogeneous myocardial sheet could induce a focal excitation wave. However, reentrant excitation, an entity of tachyarrhythmia, was not able to be triggered regardless of the EAD cluster size when the focal excitation wave formed a repolarization potential difference boundary consisting of only a convex surface. The discontinuous distribution of multiple EAD clusters in the ventricular tissue formed a specific repolarization heterogeneity due to the repolarization potential difference, the shape of which depended on EAD cluster size and placed intervals. We found that the triggered activity was formed in such a manner that the repolarization potential difference boundary included a concave surface. ConclusionsThe formation of triggered activity that led to tachyarrhythmia required not only the occurrence of EAD onset-mediated focal excitation wave but also a repolarization heterogeneity-based specific repolarization potential difference boundary shape formed within the tissue.

Predictive value of the frontal QRS-T angle for a permanent pacemaker requirement in patients undergoing transcatheter aortic valve implantation.

Despite recent advances, the requirement for permanent pacemaker (PPM) implantation after transcatheter aortic valve implantation (TAVI) remains high. The frontal QRS-T angle (fQRS-Ta) indicates ventricular electrical instability as well as ventricular depolarization and repolarization heterogeneity. The predictive value of fQRS-Ta for the PPM requirement after TAVI is lacking. Therefore, we aimed to investigate the predictive value of baseline fQRS-Ta for the requirement of PPM after TAVI. This is a retrospective study conducted at a single tertiary care center. The patients were divided into two groups: those who required a pacemaker (PPM group) and those who did not (No-PPM group). The optimal fQRS-Ta cut-off value for predicting a PPM requirement was determined by using receiver operating characteristic (ROC) curve analysis. Univariate and multivariate Cox regression analyses were used to determine the independent predictors of post-TAVI PPM placement. Final study population consisted of 184 patients. The mean age of the patients was 79.41 ± 7.88 years, and 61% (n = 113) were women. Twenty-seven patients who required PPM after TAVI were considered as the 'PPM group'. The baseline frontal QRS and T axes did not differ between the groups, but the fQRS-Ta was significantly higher in the PPM group. ROC analysis performed for the prediction of post-TAVI PPM need, the fQRS-Ta cut-off value was found to be 100.5 with a sensitivity of 74.1% and a specificity of 60.5% [AUC (95% CI): 0.637 (0.520 - 0.755), p: 0.023]. In multivariate analysis, age [HR (95% CI): 1.071 (1.005 - 1.142), p: 0.034] and fQRS-Ta [HR (95% CI): 2.509 (1.084 - 6.399), p: 0.044] were identified as independent risk factors for PPM requirement after TAVI. This study demonstrated that age and baseline fQRS-Ta were independent predictors of PPM requirements after TAVI in patients with aortic stenosis.

The effect of dapagliflozin therapy on ventricular repolarization parameters in electrocardiography in patients with diabetic cardiovascular disease

BackgroundDapagliflozin is an agent that has both antihyperglycemic effects and is significantly associated with a lower risk of cardiovascular events in patients with diabetes mellitus (DM). However, there is insufficient data and information about the effect of dapagliflozin on electrocardiographic (ECG) parameters. AimThe effects of dapagliflozin on ventricular repolarization parameters have not been fully elucidated yet. This study aimed to investigate whether dapagliflozin has a positive effect on ventricular repolarization heterogeneity parameters in patients with type 2 DM. MethodWe retrospectively enrolled 140 patients with a known diagnosis of type 2 DM who were newly prescribed dapagliflozin in addition to standard anti-diabetic therapy. The patients were divided into two groups according to whether they had cardiovascular disease (CVD). The effect of dapagliflozin treatment on ventricular repolarization parameters (frontal plane QRST angle, Tp-e interval, Tp-e/QTc, QTc, and QTc dispersion) was investigated, patient groups were compared before and after treatment. ResultsAmong 140 patients, 70 (50 %) had CVD and 70 (50 %) did not have CVD. Dapagliflozin treatment resulted in significant reductions in ventricular repolarization parameters over the study period in the CVD group with diabetes. Mean fQRST angle, Tp-e interval, Tp-e/QTc, QTc, and QTc dispersion were significantly lower than baseline values at 6-month follow-up visits in the CVD group (61.61 ± 9.22° vs 52.55 ± 8.31°, 74.45 ± 16.06 msec vs 63.27 ± 13.99 msec, 0.19 ± 0.03 vs 0.16 ± 0.03, 384.12 ± 47.93 msec vs 356.15 ± 43.31 mesc, 55.28 ± 5.50 msec vs 48.08 ± 6.48 msec for all pairwise comparisons p < 0.001). ConclusionSimilar antihyperglycemic effects were found with dapagliflozin treatment in patients with and without CVD. However, significant reductions in ventricular repolarization parameters were observed only in patients with CVD.

Sex-specific repolarization heterogeneity in mouse left ventricle: Optical mapping combined with mathematical modeling predict the contribution of specific ionic currents.

Ventricular repolarization shows notable sex-specificity, with female sex being associated with longer QT-intervals in electrocardiography irrespective of the species studied. From a clinical point of view, women are at a greater risk for drug-induced torsade de pointes and symptomatic long-QT syndrome. Here, we present an optical mapping (OM) approach to reveal sex-specific action potential (AP) heterogeneity in a slice preparation of mouse hearts. Left ventricular epicardial repolarization in female versus male mice shows longer and, interindividually, more variable AP duration (APD), yielding a less prominent transmural APD gradient. By combining OM with mathematical modeling, we suggest a significant role of IKto,f and IKur in AP broadening in females. Other transmembrane currents, including INaL , only marginally affect basal APD. As in many cardiac pathophysiologies, increasing [Ca2+ ]i poses a risk for arrhythmia, the response of AP morphology to enhanced activation of L-type calcium channels (LTCC) was assessed in a sex-selective manner. Both APD and its variation increased significantly more in female versus male mice after pharmacological LTCC activation, which we hypothesize to be due to sex-specific INaL expression based on mathematical modeling. Altogether, we demonstrate a more delayed repolarization of LV epicardium, a leveled LV transmural APD gradient, and a more pronounced epicardial APD response to Ca2+ influx in females versus males. Mathematical modeling quantifies the relative contributions of selected ionic currents to sex-specific AP morphology under normal and pathophysiological conditions.

Repolarization changes following left bundle branch area pacing versus conventional biventricular pacing in patients with dyssynchronous heart failure

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation. Background Biventricular pacing (BiVP) is the standard treatment for patients with dyssynchronous heart failure. Despite the effectiveness of BiVP, 6% of patients develop ventricular tachyarrhythmia’s (VTAs) within one year following implantation. The relationship between BiVP and the development of VTAs is still under debate. The left-sided epicardium-to-endocardium activation during BiVP creates a nonphysiological activation and repolarization and might provoke VTAs. A relatively new treatment option is left bundle branch area pacing (LBBAP), in which the physiological activation of the left ventricle is restored. We hypothesize that LBBAP leads to a more homogenous repolarization compared to conventional BiVP. Purpose To compare time-dependent repolarization changes in patients with dyssynchronous heart failure receiving LBBAP versus BiVP. Methods Patients with dyssynchronous heart failure eligible for cardiac resynchronization therapy who underwent LBBAP (n=13) or BiVP (n=28) were retrospectively included. Standard 12-lead electrocardiograms (ECG) obtained prior to implantation [baseline], shortly following implantation (0-2 days,[acute]) and during follow-up (31-180 days, [FU]) were analyzed. The QT interval and Tpeak to Tend interval (Tpeak-Tend) were calculated using a semi-automatic approach in MATLAB. Repolarization differences between LBBAP and BiVP patients were determined using the Mann-Whitney U-test. Time-dependent changes within groups were determined using the Wilcoxon signed rank tests. Significance was defined as a p-value ≤0.05. Results The QT interval did not significantly change over time in BiVP patients, but it decreased immediately following implantation and during FU in LBBAP patients. At FU, QT interval was significantly lower in LBBAP than in BiVP patients (Figure 1, left panel). A slight increase in Tpeak-Tend interval over time in BiVP patients, while it tends to decrease over time in LBBAP patients can be seen in the right panel. Acutely and long term after implantation, Tpeak-Tend was significantly lower in LBBAP than in BiVP patients. Conclusion LBBAP is associated with lower QT and Tpeak-Tend intervals compared to BiVP during FU, suggesting that LBBAP leads to less heterogeneity of repolarization over time. These findings suggest a more physiological repolarization pattern in LBBAP compared to BiVP, which may decrease the risk of developing VTAs.

Heterogeneity of Repolarization and Cell-Cell Variability of Cardiomyocyte Remodeling Within the Myocardial Infarction Border Zone Contribute to Arrhythmia Susceptibility.

After myocardial infarction, the infarct border zone (BZ) is the dominant source of life-threatening arrhythmias, where fibrosis and abnormal repolarization create a substrate for reentry. We examined whether repolarization abnormalities are heterogeneous within the BZ in vivo and could be related to heterogeneous cardiomyocyte remodeling. Myocardial infarction was induced in domestic pigs by 120-minute ischemia-reperfusion injury. After 1 month, remodeling was assessed by magnetic resonance imaging, and electroanatomical mapping was performed to determine the spatial distribution of activation-recovery intervals. Cardiomyocytes were isolated and tissue samples collected from the BZ and remote regions. Optical recording allowed assessment of action potential duration (di-8-Anepps, stimulation at 1 Hz, 37 °C) of large cardiomyocyte populations while gene expression in cardiomyocytes was determined by single nuclear RNA sequencing. In vivo, activation-recovery intervals in the BZ tended to be longer than in remote with increased spatial heterogeneity evidenced by a greater local SD (3.5±1.3 ms versus remote: 2.0±0.5 ms, P=0.036, npigs=5). Increased activation-recovery interval heterogeneity correlated with enhanced arrhythmia susceptibility. Cellular population studies (ncells=635-862 cells per region) demonstrated greater heterogeneity of action potential duration in the BZ (SD, 105.9±17.0 ms versus remote: 73.9±8.6 ms; P=0.001; npigs=6), which correlated with heterogeneity of activation-recovery interval in vivo. Cell-cell gene expression heterogeneity in the BZ was evidenced by increased Euclidean distances between nuclei of the BZ (12.1 [9.2-15.0] versus 10.6 [7.5-11.6] in remote; P<0.0001). Differentially expressed genes characterizing BZ cardiomyocyte remodeling included hypertrophy-related and ion channel-related genes with high cell-cell variability of expression. These gene expression changes were driven by stress-responsive TFs (transcription factors). In addition, heterogeneity of left ventricular wall thickness was greater in the BZ than in remote. Heterogeneous cardiomyocyte remodeling in the BZ is driven by uniquely altered gene expression, related to heterogeneity in the local microenvironment, and translates to heterogeneous repolarization and arrhythmia vulnerability in vivo.

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.

Role of localized repolarization and conduction heterogeneities in ventricular arrhythmias and sudden cardiac death

Recent clinical studies have indicated the presence of localized tissue abnormalities in sudden cardiac death (SCD) survivors without apparent structural heart disease, including idiopathic ventricular fibrillation (VF) and J-wave Syndromes. The origin of these abnormalities, showing distinct electrical features on contact mapping, and mechanisms of associated arrhythmias are still a matter of debate. To determine the respective role of localized repolarization and conduction heterogeneities in vulnerability to arrhythmias and SCD, and to characterize their specific electrical signatures. Optical mapping was performed on porcine right ventricular models of either local (i) repolarization shortening, (ii) conduction slowing, or (iii) micro-structural heterogeneity which were created by locally perfusing (i) pinacidil (20 μM n = 13) or (ii) flecainide (2 μM n = 13) via an epicardial catheter (branch of right coronary artery), or (iii) by local epicardial tissue destruction through radiofrequency application (9 micro lesions 30W 1 sec n = 13). Pseudo-ECG were assessed and the number of induced and spontaneous arrhythmias were quantified and mapped in each preparation. An HD grid mapping catheter was used to record bipolar electrograms (n = 5 in each group). Electrograms were normal in model (i), but showed local fragmentation in 40% of preparations in model (ii) with greater effects observed at high pacing frequencies (3 Hz). In model (iii), the structural substrate alone increased the width and number of peaks in the electrograms, and addition of flecainide (2 μM) in this model induced pronounced fragmentation (≥ 3 peaks and ≥ 70ms duration) in 100% of the cases. Arrhythmogenicity was significantly increased in models (i) and (ii) which presented 82% and 45% more spontaneous arrhythmias (P < 0.0001 and 0.05 vs. baseline) and a reduced pacing frequency threshold to induce arrhythmias (−69% and −50%, P < 0.001 vs. baseline). In these models, the frequency of spontaneous activity was increased (+411% P < 0.01 and +181% P < 0.05 vs. baseline) and originated near the heterogeneous area. Microstructural substrates have the most pronounced impact on electrograms, especially when combined with sodium channel blockers, while repolarization heterogeneities do not lead to electrogram fragmentation but are associated with the highest prevalence of spontaneous arrhythmias. Both heterogeneities show increased ectopic activity.

PO-02-216 SEGMENTAL INCREASE IN HETEROGENEITY OF REPOLARIZATION CORRESPONDS TO REGIONS OF DECREASED INNERVATION AFTER MYOCARDIAL INFARCTION

Myocardial infarction (MI) results in a dense scar region surrounded by a heterogeneous remodeled border zone. In this region denervation and nerve regeneration during healing could be region dependent and contribute to segmental differences in the functional substrate for arrhythmias. To examine regional electrophysiological remodeling in relation to perfusion and innervation changes after myocardial infarction. Anterio-septal MI was induced in 6 domestic pigs by a 120-minute occlusion of the left anterior descending artery (LAD) followed by reperfusion. After one month, PET-MR imaging was performed to evaluate myocardial perfusion (13N-ammonia) and innervation (11C-epinephrine), together with late gadolinium enhanced MR imaging for scar quantification. The next day electro-anatomical mapping was performed. The BZ was defined using contact mapping as the region with bipolar voltage between 0.5 and 1.5 mV. A non-contact recording of a 64-electrode array was translated to 2048 non-contact electrograms distributed over the LV (EnSite PrecisionTM, St. Jude/Abbott Medical). In each of the 2048 points non-contact electrograms over 25 consecutive beats were processed to determine the beat-to-beat variability of repolarization (BVR). Spatial heterogeneity of repolarization was quantified in each point as the repolarization time variability within a 1cm radius neighborhood. MI size was 14.2±3.2% of the left ventricle on gadolinium enhanced MR imaging. The perfusion and innervation defects were significantly larger (22.3±3.2%, P<0.01 and 28.1±4.3%, P<0.01 respectively). The innervation defect was also significantly larger than the perfusion defect (P=0.03). Regional analysis revealed less innervation in the anterior versus the septal border zone (14.2±2.9 %/min vs 18.6+3.1 %/min, P<0.01). In one animal the electrophysiology study was unsuccessful due to a high baseline heart rate (>120 BPM). In the remaining animals, the average spatial heterogeneity was higher in the anterior than septal border zone (5.8±3.0 ms vs 3.8±2.6 ms, P<0.01). Additionally, the maximum BVR tended to be higher in the anterior than septal border zone (2.6±1.3 ms vs 2.02±0.77 ms, P=0.08). MI resulting from LAD occlusion/reperfusion leads to increased denervation on the anterior side of the infarct, correlating with increased repolarization heterogeneity in this region.

PO-01-180 MECHANISMS OF PULMONARY ARTERIAL HYPERTENSION-INDUCED ATRIAL FIBRILLATION IN THE RIGHT HEART: INSIGHTS FROM MULTI-SCALE MODELS OF THE HUMAN ATRIA

Pulmonary arterial hypertension (PAH) is one of the common conditions primarily affecting the right heart and promoting atrial fibrillation (AF), but the mechanisms are poorly understood. This study aimed to use multi-scale atrial models to investigate mechanisms by which right atrial (RA) remodeling facilitates and perpetuates atrial arrhythmias. We have developed single-cell-to-tissue-level computer models to mimic control and disease conditions by incorporating the most recent experimental data on PAH-induced electrical and structural remodeling (Hiram et al., JACC, 2019). The effects of PAH-induced remodeling in both RA and left atria (LA) on action potential duration (APD), calcium transient (CaT), conduction velocity (CV), and dynamics of re-entrant excitation waves were assessed using the multi-scale computer models. Our computer simulation results suggested that at the single cell level, although PAH-induced remodeling prolonged action potential (ΔAPD: 49.6 ms in the RA vs. 41.6 ms in the LA) and increased calcium transient (ΔCaT: 7.5e-2 μM in the RA vs. 0.9e-3 μM in the LA), heterogeneous remodeling increased susceptibility to afterdepolarizations only in the RA (Fig. A). At the tissue level, dramatically reduced CV (ΔCV: -0.5 m/s in the RA vs. -0.05 m/s in the LA) abbreviated wavelength inthe RA but not inthe LA. In addition, afterdepolarizations in the RA increased repolarization dispersion and promoted unidirectional conduction block (Fig B). Finally, the upregulated fibrosis increased the chance of breakdown of excitation waves and sustained reentries in in the RA (Fig C). These results demonstrated that PAH-induced AF is mainly in RA not LA, due to a higher degree of cardiac remodeling. RA remodeling increases arrhythmias risk due to elevated susceptibility to afterdepolarizations, reduced wavelength, increased repolarization heterogeneity and upregulation of fibrosis, which together facilitate initiation and maintenance of re-entrant circuits in the right heart.

Evaluation of frontal QRS-T angle values in electrocardiography in patients with chronic rhinosinusitis

BackgroundChronic Rhinosinusitis (CRS) refers to inflammation of the paranasal sinuses and nasal mucosa. Electrocardiographic indicators of ventricular repolarization have been shown to correlate with systemic inflammation parameters. Recently, the frontal QRS-T (fQRS-T) angle has been accepted as a new indicator of ventricular depolarization and repolarization heterogeneity. The (fQRS-T) angle is recommended in predicting the risk of malignant ventricular arrhythmia. In this study, we aimed to evaluate the ventricular arrhythmia potential in patients with chronic rhinosinusitis by examining the relationship between fQRS-T angle on ECG and inflammation markers.MethodsInflammatory markers as well as electrocardiographc (ECG) f(QRS-T) angle, QRS duration, QT interval and corrected QT interval were examined in 54 patients with CRS versus 56 healthy control subjects.ResultsThe f(QRS-T) angle was significantly higher in CRS patients than in healthy controls (p < .001). The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and monocyte-to-lymphocyte ratio (MLR) were significantly higher in CRS patients compared to healthy controls (p < .001, for all). Based on correlation analysis, NLR and f(QRS-T) angles were highly correlated (r = .845, p < .001), and according to the results of linear regression analysis, NLR was independently associated with the f(QRS-T) angle (t = 5.149, Beta = 0.595, p = < 0.001).ConclusionBoth f(QRS-T) angle and NLR are significantly increased in CRS patients compared to healthy controls, with increases in NLR also independently associating with increases in f(QRS-T) angle. While the increases in f(QRS-T) angle did not result in clinically alarming absolute values for f(QRS-T), CRS patients might nonetheless be at relatively higher risk for malignant cardiac arrhythmias.