Epicardial Activation Research Articles

Research Progress on Epicardial Repair After Myocardial Injury.

Myocardial Injuries, such as myocardial infarction, trigger complex biological responses. The epicardium, known for its regenerative capabilities, plays a pivotal role in cardiac repair by undergoing activation and subsequent cellular transformations. This review examines the mechanisms of epicardial activation after myocardial injury, focusing on epithelial-mesenchymal transition, cell proliferation, and cell migration. It underscores the significance of the epicardium in heart repair processes and discusses potential implications for developing novel cardiac therapies. These insights may pave the way for leveraging epicardial cell dynamics to enhance cardiac regeneration, ultimately reducing the morbidity associated with heart disease.

Variant patterns of electrical activation and recovery in normal human hearts revealed by noninvasive electrocardiographic imaging.

Although electrical activity of the normal human heart is well characterized by the electrocardiogram, detailed insights into within-subject and between-subject variations of ventricular activation and recovery by noninvasive electroanatomic mapping are lacking. We characterized human epicardial activation and recovery within and between normal subjects using non-invasive electrocardiographic imaging (ECGI) as a basis to better understand pathology. Epicardial activation and recovery were assessed by ECGI in 22 normal subjects, 4 subjects with bundle branch block (BBB) and 4 with long-QT syndrome (LQTS). We compared characteristics between the ventricles [left ventricle (LV) and right ventricle (RV)], sexes, and age groups (<50/≥50years). Pearson's correlation coefficient (CC) was used for within-subject and between-subject comparisons. Age of normal subjects averaged 49 ± 14 years, 6/22 were male, and no structural/electrical heart disease was present. The average activation time was longer in LV than in RV, but not different by sex or age. Electrical recovery was similar for the ventricles, but started earlier and was on average shorter in males. Median CCs of between-subject comparisons of the ECG signals, activation, and recovery patterns were 0.61, 0.32, and 0.19, respectively. Within-subject beat-to-beat comparisons yielded higher CCs (0.98, 0.89, and 0.82, respectively). Activation and/or recovery patterns of patients with BBB or LQTS contrasted significantly with those found in the normal population. Activation and recovery patterns vary profoundly between normal subjects, but are stable individually beat to beat, with a male preponderance to shorter recovery. Individual characterization by ECGI at baseline serves as reference to better understand the emergence, progression, and treatment of electrical heart disease.

Utility of noninvasive electrocardiographic imaging in the localization of nonpulmonary vein triggers of atrial fibrillation determined by pacing common trigger sites.

Identifying the origin of nonpulmonary vein atrial fibrillation (AF) triggers (NPVTs) after pulmonary vein isolation (PVI) can be challenging. We aimed to determine if noninvasive electrocardiographic imaging (ECGi) could localize pacing from common NPVT sites. ECGi combines measured body surface potentials with heart-torso geometry acquired from computed tomography (CT) to generate an activation map. In 12 patients with AF undergoing first time ablation, the ECGi vest was fitted for preprocedural CT scan and worn during the procedure. After PVI, we performed steady-state pacing from 15 typical anatomic NPVT sites at a cycle length of 700-800 ms. We co-registered the invasive anatomic map with the CT-based ECGi epicardial activation map to compare ECGi predicted to true pacing origin. In the study cohort (67% male, 58% persistent AF, and 67% with left atrial dilation), 148 (82%) pacing sites had both capture and adequate anatomy acquired from the three-dimensional mapping system to co-register with ECGi activation map. Median distance between true pacing sites and point of earliest epicardial activation derived from the ECGi maps for all sites was 17 mm (interquartile range, 10-22 mm). Assuming paced sites treated as regions with a radius of 2.5 cm, the earliest activation site on ECGi map falls within the region with 94% accuracy. ECGi can approximate the origin of paced beats from common NPVT sites to within a median distance of 17 mm. A rapidly identified region may then be the focus of more detailed catheter-based mapping techniques to facilitate successful localization and ablation of NPVTs.

Single-cell RNA sequencing analysis of the human fetal epicardium reveals several new genes involved in regulation of epicardial activation

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation Background The outside mesothelial layer of the heart, the epicardium, is essential for cardiac development. Cells from this layer undergo epithelial-to-mesenchymal transition (EMT), migrate into the tissue and partake in cardiogenesis by contributing cells and by secreting growth factors. In the adult heart, the epicardium is quiescent but upon ischemic injury it is activated and conveys a partial regenerative response. This activation step is important for repair, but suboptimal compared to the cardiogenic potential during development. Understanding the processes and cells that underlie developmental epicardial activation could contribute to enhancing the adult post-injury response, but little is known about the human developing epicardium. Purpose to determine the cellular composition of the human fetal epicardial layer and to identify the processes that regulate the activation of the epicardium. Methods An epicardial-cell enriched dataset was obtained by specifically dissecting the epicardial layers from 4 fetal human hearts (14-15 weeks gestation, obtained under informed consent and according to local ethical approval). Single live cells were sorted into 384-wells plates and sequenced. Data analysis was performed on 2073 cells using R-packages RaceID3 and StemID2. Findings were validated using qPCR and immunohistochemistry on tissue sections and cell culture models. Results Sequencing analysis revealed a distinct clustering of epicardial (epithelial, pre-EMT) and epicardial-derived mesenchymal (post-EMT) cell populations. Besides the identification of novel markers for epicardial cell states, the regulation of epicardial cell activation and EMT was investigated by applying pseudo-time analysis. We selected genes that were highly regulated (&amp;gt;2 fold change) in this trajectory for further analysis in vitro. We identified several genes including CRIP1, SULF1 and others that are expressed in epithelial cells in vitro and in vivo and are rapidly downregulated upon EMT. The expression profiles positively correlated with epithelial cell related genes and negatively with mesenchymal cell genes. Based on GO-terms, and protein expression within the epicardial layers in fetal and adult epicardium, we anticipated a role for these genes in maintaining the epithelial-state. Indeed, siRNA experiments in vitro with cultured primary human epicardial cells confirmed an essential role in EMT regulation. We continue to evaluate other genes identified in our sequencing dataset, resulting in several other potent and previously unknown pathways involved in regulation of epicardial activation. Conclusions We shed light on the composition of the human fetal epicardium using a highly enriched scRNA dataset. We identify specific markers for different cell-states, and reveal novel regulators of activation that in the future may be influenced to optimize the post-injury response.

Neural control of ventricular electrophysiology: the role of the posterior descending ganglionated plexus

Abstract Background The autonomic nervous system plays an integral role in cardiac physiology. While the atrially located ganglionated plexus have been studied in several species, there is limited knowledge regarding the functional characterization of ventricular ganglionated plexus. Purpose The aim of the present study was to assess the role of the posterior descending ganglionated plexus (PD-GP) for neural control of ventricular electrophysiology. Methods First, to investigate whether the mouse may be useful as an animal model, a review of whole-mount immunohistological stained murine hearts (n=43) was conducted. Second, functional studies were performed in an ex-vivo retrograde-perfused porcine model (n=3) at baseline (pacing with a cycle length of 600 ms), during PD-GP high-frequency and local nicotine stimulation (Figure 1A). Wave propagation characteristics were determined by epicardial activation mapping. Activation recovery intervals (ARIs) were analyzed with a multi-electrode sock placed around the epicardium (Figure 1B). Finally, morphological analysis of explanted human hearts was conducted to determine the potential of translation into clinical practice. Results In murine hearts, ventricular ganglionated plexus were present in only 10% of hearts. In porcine hearts, dispersion of conduction velocity was increased during PD-GP high-frequency (8.52±2.24 radian vs. 2.79±0.89 radian; p=0.018) and nicotine stimulation (19.79±6.49 radian vs. 2.79±0.89 radian; p=0.044) compared to paced rhythm (Figure 1C). High-frequency stimulation prolonged ARIs in the posterior (257.8±6.7 ms vs. 244.8±1.9 ms; p=0.044) and basal (258.1±4.2 ms vs. 244.8±1.9 ms; p=0.039) right ventricle compared to the posterior left ventricle, while nicotine did not affect ARIs (right ventricle: 255.7±29.0 ms vs. left ventricle: 245.0±29.3 ms; p=0.677) (Figure 1D). Analysis of explanted human hearts confirmed the presence of the PD-GP in close relationship to the posterior descending coronary artery within epicardial adipose tissue (Figure 2). Conclusions While we demonstrate functional relevance of the PD-GP in explanted porcine hearts, important species-related differences might exist.Ex-vivo retrograde-perfused swine modelAnalysis of explanted human hearts

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.

Trends Favoring an Anatomical Approach to Radiofrequency Catheter Ablation of Idiopathic Ventricular Arrhythmias Originating From the Left Ventricular Summit.

Epicardial radiofrequency catheter ablation (RFCA) of idiopathic ventricular arrhythmias (VAs) originating from the left ventricular summit (LVS) is challenging because of the anatomic barriers. On the other hand, RFCA at the endocardial sites near the earliest epicardial activation site of LVS-VAs (anatomic approach) has proven successful. The evolving trends in the approaches and outcomes of RFCA of LVS-VAs at a single center were evaluated. We studied 88 consecutive patients with idiopathic LVS-VAs at our institute from 2009 to 2019. These patients were divided into 3 periods: 2009 to 2012 (early), 2013 to 2015 (middle), and 2016 to 2019 (recent). The data were compared among the 3 periods. The RFCA success rate did not significantly change from the early to middle period but significantly increased from the middle to recent period (P=0.0315). The transpericardial approach usage significantly decreased over the 3 periods. The anatomic approach usage significantly increased over the 3 periods. The use of the transpericardial approach did not affect the RFCA outcomes over the 3 periods. The success rate of the anatomic RFCA tended to increase from the early to middle period and significantly increased from the middle to recent period (P=0.0412). The number of endocardial locations where RFCA was successful increased over the 3 periods. Over the 10-year period, the transpericardial approach became decreasingly performed, whereas the anatomic approach became increasingly performed with a satisfactory improvement in the RFCA outcomes of LVS-VAs. The anatomic RFCA became more successful by identifying more and various endocardial locations as target sites.

Pilot study to evaluate left-to-right ventricular offset in biventricular pacing-comparison of electrocardiographic imaging and ECG.

Biventricular pacing (BiVp) improves outcomes in systolic heart failure patients with electrical dyssynchrony. BiVp is delivered from epicardial left ventricular (LV) and endocardial right ventricular (RV) electrodes. Acute electrical activation changes with different LV-RV stimulation offsets can help guide individually optimized BiVp programming. We sought to study the BiVp ventricular activation with different LV-RV offsets and compare with 12-lead ECG. In five patients with BiVp (63 ± 17-year-old, 80% male, LV ejection fraction 27 ± 6%), we evaluated acute ventricular epicardial activation, varying LV-RV offsets in 20 ms increments from -40 to 80 ms, using electrocardiographic imaging (ECGI) to obtain absolute ventricular electrical uncoupling (VEUabs, absolute difference in average LV and average RV activation time) and total activation time (TAT). For each patient, we calculated the correlation between ECGI and corresponding ECG (3D-QRS-area and QRS duration) with different LV-RV offsets. The LV-RV offset to attain minimum VEUabs in individual patients ranged 20-60 ms. In all patients, a larger LV-RV offset was required to achieve minimum VEUabs (36 ± 17 ms) or 3D-QRS-area (40 ± 14 ms) than that for minimum TAT (-4 ± 9 ms) or QRS duration (-8 ± 11 ms). In individual patients, 3D-QRS-area correlated with VEUabs (r 0.65 ± 0.24) and QRS duration correlated with TAT (r 0.95 ± 0.02). Minimum VEUabs and minimum 3D-QRS-area were obtained by LV-RV offset within 20 ms of each other in all five patients. LV-RV electrical uncoupling, as assessed by ECGI, can be minimized by optimizing LV-RV stimulation offset. 3D-QRS-area is a surrogate to identify LV-RV offset that minimizes LV-RV uncoupling.

Ultra-high-frequency ECG volumetric and negative derivative epicardial ventricular electrical activation pattern

From precordial ECG leads, the conventional determination of the negative derivative of the QRS complex (ND-ECG) assesses epicardial activation. Recently we showed that ultra-high-frequency electrocardiography (UHF-ECG) determines the activation of a larger volume of the ventricular wall. We aimed to combine these two methods to investigate the potential of volumetric and epicardial ventricular activation assessment and thereby determine the transmural activation sequence. We retrospectively analyzed 390 ECG records divided into three groups-healthy subjects with normal ECG, left bundle branch block (LBBB), and right bundle branch block (RBBB) patients. Then we created UHF-ECG and ND-ECG-derived depolarization maps and computed interventricular electrical dyssynchrony. Characteristic spatio-temporal differences were found between the volumetric UHF-ECG activation patterns and epicardial ND-ECG in the Normal, LBBB, and RBBB groups, despite the overall high correlations between both methods. Interventricular electrical dyssynchrony values assessed by the ND-ECG were consistently larger than values computed by the UHF-ECG method. Noninvasively obtained UHF-ECG and ND-ECG analyses describe different ventricular dyssynchrony and the general course of ventricular depolarization. Combining both methods based on standard 12-lead ECG electrode positions allows for a more detailed analysis of volumetric and epicardial ventricular electrical activation, including the assessment of the depolarization wave direction propagation in ventricles.

Uncertainty Quantification of Fiber Orientation and Epicardial Activation.

Predictive models and simulations of cardiac function require accurate representations of anatomy, often to the scale of local myocardial fiber structure. However, acquiring this information in a patient-specific manner is challenging. Moreover, the impact of physiological variability in fiber orientation on simulations of cardiac activation is poorly understood. To explore these effects, we implemented bi-ventricular activation simulations using rule-based fiber algorithms and robust uncertainty quantification techniques to generate detailed maps of model variability. Specifically, we utilized polynomial chaos expansion, enabling efficient exploration with reduced computational demand through an emulator function approximating the underlying forward model. Our study focused on examining the epicardial activation sequences of the heart in response to six stimuli locations and five metrics of activation. Our findings revealed that physiological variability in fiber orientation does not significantly affect the location of activation features, but it does impact the overall spread of activation. We observed low variability near the earliest activation sites, but high variability across the rest of the epicardial surface. We conclude that the level of accuracy of myocardial fiber orientation required for simulation depends on the specific goals of the model and the related research or clinical goals.

Single-cell RNA sequencing analysis of the human fetal epicardium results in novel epicardial-specific markers and reveals a role for CRIP1 in epicardial EMT

Abstract Background The outside mesothelial layer of the heart, the epicardium, is essential during cardiac development. Cells from this layer undergo epithelial-to-mesenchymal transition (EMT), migrate into the tissue and partake in cardiogenesis by contributing cells and by secretion of growth factors. In the adult heart, the epicardium is quiescent but upon ischemic injury it is activated and conveys a regenerative response. This activation is important for repair, but suboptimal compared to the cardiogenic potential during development. Understanding the processes and cells that underlie developmental epicardial activation could contribute to enhancing the adult post-injury response, but little is known about the human developing epicardium. The Purpose of this study is to unravel the cellular composition of the human fetal epicardial layer and to identify novel processes that regulate the activation of the epicardium. Methods An epicardial-cell enriched dataset was obtained by specifically dissecting the epicardial layers from 4 fetal human hearts (14-15 weeks gestation, obtained under informed consent and according to local ethical approval). Single live cells were sorted into 384-wells plates and sequenced. Data analysis was performed using R-packages RaceID3 and StemID2. Findings were validated using qPCR and immunohistochemistry on tissue sections and cell culture models. Results Analysis of 2073 cells revealed a clustering of epicardial (epithelial, pre-EMT) and epicardial-derived (mesenchymal, post-EMT) cell populations. Since classical markers for the epicardium such as Wilms’ Tumor 1 and T-box transcription factor 18 were unable to specifically demarcate the epithelial state, we identified and validated several new markers (e.g. C3, NRK) that allow robust classification of epicardium-associated populations. To establish the regulation of epicardial activation and EMT, we applied pseudo-time analysis. We selected genes that were highly regulated (&amp;gt;2 fold change) in this trajectory for further analysis in vitro. qPCR indicated that CRIP1 is expressed in epithelial cells and rapidly downregulated upon EMT (3x reduction, n=3, *p=0.0104). The expression profile of CRIP1 positively correlates with UPK3B (R2:0.98) and negatively with mesenchymal TCF21 (R2: 0.99), together with GO-terms a role for CRIP in maintaining the epithelial-state is likely. Indeed, siRNA experiments in vitro with cultured epicardial cells confirmed an essential role for CRIP1 in EMT regulation. Together with its confirmed protein expression within the epicardial layer in fetal and adult tissue, this protein is of interest for regulating activation of the epicardium. Conclusions We shed light on the composition of the human fetal epicardium using a highly enriched scRNA dataset. We identify specific markers for different cell-states, and reveal novel regulators of activation that in the future may be influenced to optimise the post-injury response.

Abstract 17335: Novel Functional Genomic Studies in Scn1bb Variant Associated With Brugada Syndrome and the Ameliorative Effect of Acacetin

Background: Brugada syndrome (BrS) is a channelopathy associated with the development of life-threatening ventricular tachycardia and fibrillation (VT/VF). At present, pharmacological approaches to therapy are very limited. Objective: To evaluate the effect of an SCN1Bb variant and the effects of acacetin in experimental models of BrS. Methods: We evaluated the effect of acacetin in: 1) HEK293 cells expressing Kv4.3+ KChIP2 and Nav1.5+ SCN1B using patch clamp techniques (22 O C), 2) canine ventricular epicardial myocytes 3) coronary-perfused canine right (RV) preparations and 4) Langendorff-perfused canine whole-heart models of BrS in which the sodium channel blocker ajmaline or the calcium channel blocker verapamil, together with the transient outward current agonist NS5806 were used to provoke the arrhythmic phenotype. Results: Co-expression of SCN5A -WT+ KCND3-WT with KChIP2 + SCN1Bb -R214Q (variant associated with 3 cases of BrS and 1 case of sudden infant death (SIDS)), resulted in a 210% increase in total charge of the transient outward potassium current (I to ) as well as a 56.5% reduction in sodium channel current (I Na ) when compared to SCN1Bb-WT . In the absence of the mutation, acacetin inhibited I to with an IC 50 of 7.2±1.0 μM (n=3) in HEK cells, similar to the value obtained in native epicardial myocytes (6 μM). In the presence of the SCB1Bb mutant, IC 50 was dramatically reduced to 2.6±1 μM (n=5, p&lt;0.05) Mean ±SEM. In the wedge and whole-heart models of BrS, acacetin dose-dependently reduced the epicardial action potential notch recorded from the RV or RVOT. Acacetin (5-10 μM) totally suppressed the electrocardiographic and arrhythmic manifestation of BrS, regardless of the pharmacologic model used to induce the arrhythmic phenotype. All repolarization defects were reversed, resulting in marked diminution of J waves leading to total suppression of VT/VF. Conclusions: Our findings demonstrate the ability of an SCN1Bb variant to dramatically shift the balance of current in the early phases of the RV epicardial action potential by reducing I Na as well as augmenting I to , thus predisposing to the development of the BrS phenotype. Our observations also hold promise for acacetin as a safe and effective pharmacologic treatment for BrS and some cases of SIDS.

Abstract 17749: Regionalization of Non-Pulmonary Vein Triggers for Atrial Fibrillation When the P Wave is Obscured Using Non-Invasive Electrocardiographic Imaging QRS-T Subtraction Algorithm

Introduction: Ablation of non-pulmonary vein triggers (NPVTs) after pulmonary vein isolation (PVI) may reduce atrial fibrillation (AF) recurrence. Localizing a trigger which initiates AF after a single atrial ectopic beat is challenging, especially in the scenario when the trigger P wave is obscured by preceding QRS-T complex. Aim: To evaluate the potential for noninvasive electrocardiographic imaging (ECGi) to localize NPVTs when the P wave morphology is superimposed on the T wave of the previous beat. Methods: We developed an algorithm which overlays and subtracts the preceding QRS-T wave complex from the QRS-T wave complex which is obscuring the P wave of interest, thus revealing the P wave morphology (Figure 1A). Resultant unobscured P waves (from multiple body surface electrodes) are then used for ECGi computation. In five patients undergoing AF ablation, after PVI, we paced from 15 atrial sites where NPVTs commonly arise, and evaluated the epicardial activation maps generated by ECGi both when pacing was timed to ensure an unobscured P wave and when timed to coincide with preceding QRS-T complex. Co-registration of CT-based ECGi activation maps with invasive electroanatomic map (EAM) allowed comparison of the earliest activation site on ECGi map from both the obscured P waves after QRS-T subtraction and unobscured P waves with true pacing locations on EAM (Figure 1B). Results: From 146 pacing sites in our patient cohort, for the unobscured P waves, median distance between earliest site on ECGi map and EAM pacing location was 16 mm (10-21 mm), and for obscured P waves after QRS-T subtraction, median distance was also 16 mm (12-23 mm) (Figure 1C). Conclusion: Using a QRS-T subtraction algorithm, ECGi can approximate origin of paced P waves whether P wave is unobscured or obscured by the preceding QRS-T complex. Spontaneous NPVT P waves are commonly obscured by the QRS-T wave and the ability to rapidly localize an early coupled P wave may facilitate NPVT mapping and ablation.

Site-specific prolongation of repolarization prevents postmyocardial infarction tachycardia.

Site-specific prolongation of repolarization prevents postmyocardial infarction tachycardia.

A novel workflow for advanced mapping of repolarization dispersion from endocardial unipolar electrograms in patients with coved-type brugada syndrome

Abstract Funding Acknowledgements Type of funding sources: None. Background Accentuation of the action potential notch in the epicardium causes the prolongation of the epicardial action potentials in the right ventricular outflow tract (RVOT) and is the basis for arrhythmogenesis in patients affected by Brugada syndrome (BrS). Activation-recovery interval (ARI) approximates the action potential duration and may be used to study repolarization dispersion in BrS. Purpose Our aim was to investigate repolarization dispersion within the RVOT in spontaneous coved-type ECG BrS patients and in controls, evaluating also the relation between repolarization dispersion and conduction abnormalities to better define the electro-anatomical substrate of the disease. Methods BrS probands (n=13) and control subjects (n=4) underwent endocardial mapping of RV with the CARTO 3 system. BrS patients were also studied with programmed ventricular stimulation (PVS). Data was exported from the CARTO system and converted into MatLab format using OpenEP. A specific region of interest (ROI) including the sub-pulmonary RVOT and entire RV free wall was then selected using Paraview. With an automated algorithm, we measured ARI and ARIc (corrected using the "Bazett formula") for each point of the ROI, which were then interpolated to obtain ARI maps. We also acquired right ventricular activation time (RVAT) and maps for the assessment of slow conduction zones. By dividing RVAT color scale in 5 ms steps (isoSteps), isochronal activation areas were identified in the ROI. Results Out of the 13 BrS subjects, 4 had VT or VF inducible during PVS (PVS+) while 9 did not (PVS-). One patient had appropriate ICD shocks during follow-up. BrS patients had higher mean ARI and ARIc compared to controls (288.5±22.2 vs 251.5±8.4 ms, p&amp;lt;0.001; 312.0±30.4 vs 281.8±10.3 ms, p=0.023). ARI was found to be higher in PVS+ than in PVS- patients (294.8±27.1 vs 285.8±20.1 ms, p=0.5), as well as ARIc (327.7±49.9 vs 304.6±16.4 ms, p=0.49) although these differences were not significant. BrS patients showed a longer RVAT (106.0±21.4 vs 74.5±5.5 ms, p=0.003), and increased zones of crowding, as expressed by isochronal steps (13.85±2.94 vs 9.25±1.26, p=0.01). Notably, a strong correlation was found between ARIc and RVAT (Pearson R coefficient = 0.83, p&amp;lt;0.05), independently from the results of PVS (PVS+ R=0.99, p=0.01; PVS- R=0.83, p=0.06). Conclusions We introduced a novel workflow for the electrical substrate characterisation of subjects with BrS phenotype. Our preliminary data show the presence of repolarization dispersion along with conduction slowing in the RVOT of BrS patients compared to controls. In our population, repolarization dispersion and impairment of RVOT conduction were strongly related especially in inducible BrS patients.

Clinical evaluation of the new 12-lead ECG noninvasive epi-endocardial mapping technology

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): XSpline S.p.a. Aim Noninvasive electrocardiographic mapping systems may require multichannel (150-250) ECG body surface recordings which is a huge limitation for the adoption into clinical practice. However, most of the currently available noninvasive mapping systems accurately represent epicardial activation. Over the last few years, various technical solutions have been implemented to increase the accuracy of ECG forward-inverse calculations including machine learning algorithms. We developed a novel 12-lead ECG-based, fully automated system for noninvasive full transmural (epi-endocardial) mapping. The aim of this study was to evaluate accuracy of this system in heart failure patients with typical LBBB. Methods Eight consecutive patients (median age: 65; 25-75% range 59-64; 5 male) with typical LBBB QRS morphology (QRS duration 146–224 ms), scheduled for CRT implantation underwent a cardiac CT scan and 12-lead ECG recording, followed by detailed bi-ventricular endocardial electroanatomical contact mapping (EAM). A median of 258 (181-576) local electrograms in LV and 86 (70-139) in RV were collected during EAM. Cardiac CT data were semiautomatically processed using a Unet-like neural network to obtain meshes containing the heart (each chamber with both endocardial and epicardial contour as well as coronary sinus and its branches), lungs and torso using different segmentation module. Noninvasive epi-endocardial activation maps were calculated using state-of-the-art mathematical models including machine learning methods. These data were compared with EAM from the invasive mapping system using Spearman correlation (r), mean absolute error (MAE) and relative distance metrics. Results All early and latest activation patterns were correctly identified (see figure). The average correlation (r) of endocardial activation maps was 0.92 for all cases (min-max: 0.82-0.96). MAE was rather small (9-15 mm) when the non-invasive late activation zone nearly matches the CARTO data (average distance error 14 mm). Overall, the QRS complex was correctly reproduced by our method in all cases (r = 0.96). Conclusions This study shows that new mapping technique can accurately reconstruct endocardial electrical activation maps based on 12-lead ECG and cardiac CT scan. The approach may be very useful in pre-procedural planning of device implantation and catheter ablation. Larger validation studies are however needed for confirming method accuracy at epicardial site.

Delayed ventricular conduction alters ventricular repolarization in patients with heart failure: an electrocardiographic imaging study

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Personal grant from the Dutch Heart Foundation. Background In the normal human heart, the polarity of the T-wave is concordant with the QRS complex. This phenomenon is often explained by longer repolarization of earlier activated regions. Patients with delayed ventricular conduction often have discordant T-waves, but the link to regional repolarization is unknown. Aim To compare epicardial repolarization-activation (RT-AT) relations in patients with heart failure and reduced ejection fraction (HFrEF) with those having a structural normal heart. Methods 14 patients with HFrEF and delayed ventricular conduction and 11 patients no history of structural heart disease and a normal surface ECG (nQRS) were analyzed using electrocardiographic imaging (ECGI). HFrEF patients were subcategorized as left bundle branch block (LBBB, n=6) or non-specified intraventricular conduction disturbance (IVCD, n=8). Noninvasive ECGI was used to assess epicardial activation (ATs) and repolarization times (RTs). RT-AT relationships were evaluated for 24 epicardial segments using linear regression analysis. Interventricular repolarization dispersion (inter-RTD) was defined as the difference between average left-ventricular (LV) and right-ventricular RT, while total epicardial repolarization dispersion (total-RTD) was defined as the standard deviation of all epicardial RTs. The maximum of the local RT gradients (RTG) was defined as their 95th percentile. RT parameters were described as median±IQR and Kruskal Wallis tests were used to evaluate the differences between the groups. Results An HFrEF patient’s representative 24-segment AT and RT bullseyes with a positive RT-AT relation (~depolarize last, repolarize last) is provided in Figure1A. A positive RT-AT slope was present in the majority of HFrEF patients (1.14±0.17 for LBBB and 1.16±0.55 for IVCD), whereas the nQRS group (-0.25±2.16) demonstrated an overall slightly negative slope with high variability (Figure 1B and 1C). Individual (thin lines) and group-averaged (thick lines) RT-AT slopes normalized for the earliest AT and earliest RT (in case of a positive RT-AT slope) or latest RT (in case of a negative slope) are visualized in Figure 1C. Both inter-RTD (41±25 for LBBB, 32±13 ms for IVCD, and 8±20 ms for nQRS) as well as total-RTD (34±9for LBBB, 34±12 ms for IVCD, and 24±8 ms for nQRS) was significantly higher in the LBBB and IVCD group compared to the nQRS group, whereas RTG did not differ between the groups (Figure 1B). RT-AT slopes, inter-RTD, total-RTD, and RTG did not significant differ between the LBBB and IVCD subgroup. Conclusion This ECGI study shows that in patients with HFrEF, later activated regions also have a later completion of repolarization, regardless of conduction delay, whereas a variable RT-AT relation is present in subjects with structural normal hearts. HFrEF additionally initiates a higher degree of interventricular and total repolarization dispersion.

PO-01-181 DELAYED VENTRICULAR CONDUCTION ALTERS VENTRICULAR REPOLARIZATION IN PATIENTS WITH HEART FAILURE: AN ELECTROCARDIOGRAPHIC IMAGING STUDY

In the normal human heart, the polarity of the T-wave is concordant with the QRS complex. This phenomenon is explained by longer repolarization of earlier activated regions. Patients with delayed ventricular conduction have discordant T-waves, but the link to regional repolarization is unknown. To compare epicardial repolarization-activation (RT-AT) relations in patients with heart failure and reduced ejection fraction (HFrEF) with those having a structural normal heart. 14 patients with HFrEF and delayed ventricular conduction and 11 patients no history of structural heart disease and a normal surface ECG (nQRS) were analyzed using ECG imaging (ECGI). HFrEF patients were categorized as left bundle branch block (LBBB, n=6) or non-specified intraventricular conduction disturbance (IVCD, n=8). ECGI was used to assess epicardial activation (ATs) and repolarization times (RTs). RT-AT relationships were evaluated for 24 segments using linear regression analysis. Interventricular repolarization dispersion (inter-RTD) was defined as the difference between average left-ventricular (LV) and right-ventricular RT, while total epicardial repolarization dispersion (total-RTD) was defined as the standard deviation of all epicardial RTs. The maximum of the local RT gradients (RTG) was defined as their 95th percentile. Kruskal Wallis tests were used to evaluate the differences between the groups. An HFrEF patient’s representative AT and RT bullseyes with a positive RT-AT relation (∼depolarize last, repolarize last) is provided in Figure1A. A positive RT-AT slope was present in the majority of HFrEF patients (1.14±0.17 for LBBB and 1.16±0.55 for IVCD), whereas the nQRS group (-0.25±2.16) demonstrated an overall slightly negative slope with high variability (Figure 1B and 1C). Individual (thin lines) and group-averaged (thick lines) RT-AT normalized slopes are visualized in Figure 1C. Both inter-RTD as well as total-RTD was significantly higher in the LBBB and IVCD group compared to the nQRS group, whereas RTG did not differ between the groups (Figure 1B). None of the RT parameters significantly differed between the LBBB and IVCD subgroup. This ECGI study shows that in patients with HFrEF, later activated regions also have a later completion of repolarization, regardless of conduction delay, whereas a variable RT-AT relation is present in subjects with structural normal hearts. HFrEF additionally initiates a higher degree of interventricular and total repolarization dispersion.

Catheter ablation of intramural outflow tract premature ventricular complexes: a multicentre study.

Ablation of outflow tract ventricular arrhythmias may be limited by a deep intramural location of the arrhythmogenic source. This study evaluates the acute and long-term outcomes of patients undergoing ablation of intramural outflow tract premature ventricular complexes (PVCs). This multicenter series included patients with structurally normal heart or nonischemic cardiomyopathy and intramural outflow tract PVCs defined by: (a) ≥ 2 of the following criteria: (1) earliest endocardial or epicardial activation < 20ms pre-QRS; (2) Similar activation in different chambers; (3) no/transient PVC suppression with ablation at earliest endocardial/epicardial site; or (b) earliest ventricular activation recorded in a septal coronary vein. Ninety-two patients were included, with a mean PVC burden of 21.5±10.9%. Twenty-six patients had had previous ablations. All PVCs had inferior axis, with LBBB pattern in 68%. In 29 patients (32%) direct mapping of the intramural septum was performed using an insulated wire or multielectrode catheter, and in 13 of these cases the earliest activation was recorded within a septal vein. Most patients required special ablation techniques (one or more), including sequential unipolar ablation in 73%, low-ionic irrigation in 26%, bipolar ablation in 15% and ethanol ablation in 1%. Acute PVC suppression was achieved in 75% of patients. Following the procedure, the PVC burden was reduced to 5.8±8.4%. The mean follow-up was 15±14 months and 16 patients underwent a repeat ablation. Ablation of intramural PVCs is challenging; acute arrhythmia elimination is achieved in 3/4 patients, and non-conventional approaches are often necessary for success.

Attenuation of stretch-induced arrhythmias following chemical ablation of Purkinje fibres, in isolated rabbit hearts.

Purkinje fibres (PFs) play an important role in some ventricular arrhythmias and acute ventricular stretch can evoke mechanically-induced arrhythmias. We tested whether Purkinje fibres, play a role in these arrhythmias. Pseudo-ECGs were recorded in isolated, Langendorff-perfused, rabbit hearts in which the left ventricular endocardial surface was also irrigated with Tyrode, via an indwelling catheter placed in the left ventricular lumen. The number and period of ectopic activations was measured during left ventricular lumen inflation via an indwelling fluid-filled balloon (500μL added over 2s and maintained for 15s in total). Mechanically-induced arrhythmias occurred in 70% of balloon inflations: they were maximal in the first 5s and ceased within 15s. Brief, (10s) irrigation of the left ventricular lumen with Lugol solution (IK/I2), via the indwelling catheter, reduced inflation-induced ectopics by 98% (p < 0.05). Ablation of endocardial PFs by Lugol was confirmed by Triphenyltetrazolium Chloride staining. Optical mapping revealed the left ventricular epicardial activation patterns of ectopics could have PF-mediated and focal sources. In silico modelling predicted ectopic sources originating in the endocardial region propagate to and through the Purkinje fibres network. Acute distention-induced ectopics are multi-focal, their attenuation by Lugol, their activation patterns and in silico modelling indicate a participation of Purkinje fibres in these arrhythmias.