Evaluation of five algorithms in predicting the sublocalisation of right ventricular outflow tract arrhythmia (RVOTA) when compared to 3D electroanatomical mapping origin

Purpose To compare the predictive accuracy of five different algorithms as verified by successful ablation site using 3D electroanatomical non-contact mapping in patients with symptomatic and asymptomatic but high ventricular burden RVOT tachycardias. Methods 28 Consecutive patients admitted for radiofrequency catheter ablation for symptomatic and asymptomatic, but high ventricular burden idiopathic VPC were recruited for this study. All patients had previous failed or intolerant to beta-blocker and/or at least one class IC anti-arrhythmic agents, and they had normal left ventricular ejection fraction. All patients had documented monomorphic VPC with left bundle branch block morphology and an inferior axis. Concordance of the arrhythmia origin based on ECG algorithm and 3D mapping system site were further evaluated. Of the five algorithms, two algorithms with easy‐applicability and having a memorable design (Dixit and Joshi) and three algorithms with more complex and detailed design (Ito, Zhang, Pytkowski) were selected for comparisons. Results Assessment of the diagnostic accuracy showed that each of the five algorithms had only moderate accuracy, and the greatest accuracy was observed in the algorithm proposed by Pytkowski algorithm when assessed by a general cardiologist and Dixit algorithm when evaluated by the electrophysiologist. However, when the algorithms were compared for their accuracy, specificity, sensitivity, no significant differences were found (p = 0.99). Conclusions The ECG based algorithms for precise localising RVOTA origin simplify the mapping process, reduce the procedural and fluoroscopic time, and improve clinical outcomes, resulting in greater clinical utility. All the five published 12-lead ECG algorithms for ROTVA differentiation were similar in terms of the diagnostic accuracy, specificity, sensitivity and LRs.

Neuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansions

Regulatory mechanisms associated with repeat-rich sequences and chromosomal conformations in mature neurons remain unexplored. Here, we map cell-type specific chromatin domain organization in adult mouse cerebral cortex and report strong enrichment of Endogenous Retrovirus 2 (ERV2) repeat sequences in the neuron-specific heterochromatic B2NeuN+ megabase-scaling subcompartment. Single molecule long-read sequencing and comparative Hi-C chromosomal contact mapping in wild-derived SPRET/EiJ (Mus spretus) and laboratory inbred C57BL/6J (Mus musculus) reveal neuronal reconfigurations tracking recent ERV2 expansions in the murine germline, with significantly higher B2NeuN+ contact frequencies at sites with ongoing insertions in Mus musculus. Neuronal ablation of the retrotransposon silencer Kmt1e/Setdb1 triggers B2NeuN+ disintegration and rewiring with open chromatin domains enriched for cellular stress response genes, along with severe neuroinflammation and proviral assembly with infiltration of dendrites . We conclude that neuronal megabase-scale chromosomal architectures include an evolutionarily adaptive heterochromatic organization which, upon perturbation, results in transcriptional dysregulation and unleashes ERV2 proviruses with strong neuronal tropism.

Structural Insights on the SARS-CoV-2 Variants of Concern Spike Glycoprotein: A Computational Study With Possible Clinical Implications

Coronavirus disease 2019 (COVID-19) pandemic has been attributed to SARS-CoV-2 (SARS2) and, consequently, SARS2 has evolved into multiple SARS2 variants driving subsequent waves of infections. In particular, variants of concern (VOC) were identified to have both increased transmissibility and virulence ascribable to mutational changes occurring within the spike protein resulting to modifications in the protein structural orientation which in-turn may affect viral pathogenesis. However, this was never fully elucidated. Here, we generated spike models of endemic HCoVs (HCoV 229E, HCoV OC43, HCoV NL63, HCoV HKU1, SARS CoV, MERS CoV), original SARS2, and VOC (alpha, beta, gamma, delta). Model quality check, structural superimposition, and structural comparison based on RMSD values, TM scores, and contact mapping were all performed. We found that: 1) structural comparison between the original SARS2 and VOC whole spike protein model have minor structural differences (TM > 0.98); 2) the whole VOC spike models putatively have higher structural similarity (TM > 0.70) to spike models from endemic HCoVs coming from the same phylogenetic cluster; 3) original SARS2 S1-CTD and S1-NTD models are structurally comparable to VOC S1-CTD (TM = 1.0) and S1-NTD (TM > 0.96); and 4) endemic HCoV S1-CTD and S1-NTD models are structurally comparable to VOC S1-CTD (TM > 0.70) and S1-NTD (TM > 0.70) models belonging to the same phylogenetic cluster. Overall, we propose that structural similarities (possibly ascribable to similar conformational epitopes) may help determine immune cross-reactivity, whereas, structural differences (possibly associated with varying conformational epitopes) may lead to viral infection (either reinfection or breakthrough infection).

Time-Averaged Wavefront Analysis Demonstrates Preferential Pathways of Atrial Fibrillation, Predicting Pulmonary Vein Isolation Acute Response

Electrical activation during atrial fibrillation (AF) appears chaotic and disorganised, which impedes characterisation of the underlying substrate and treatment planning. While globally chaotic, there may be local preferential activation pathways that represent potential ablation targets. This study aimed to identify preferential activation pathways during AF and predict the acute ablation response when these are targeted by pulmonary vein isolation (PVI). In patients with persistent AF (n = 14), simultaneous biatrial contact mapping with basket catheters was performed pre-ablation and following each ablation strategy (PVI, roof, and mitral lines). Unipolar wavefront activation directions were averaged over 10 s to identify preferential activation pathways. Clinical cases were classified as responders or non-responders to PVI during the procedure. Clinical data were augmented with a virtual cohort of 100 models. In AF pre-ablation, pathways originated from the pulmonary vein (PV) antra in PVI responders (7/7) but not in PVI non-responders (6/6). We proposed a novel index that measured activation waves from the PV antra into the atrial body. This index was significantly higher in PVI responders than non-responders (clinical: 16.3 vs. 3.7%, p = 0.04; simulated: 21.1 vs. 14.1%, p = 0.02). Overall, this novel technique and proof of concept study demonstrated that preferential activation pathways exist during AF. Targeting patient-specific activation pathways that flowed from the PV antra to the left atrial body using PVI resulted in AF termination during the procedure. These PV activation flow pathways may correspond to the presence of drivers in the PV regions.

Echocardiographic diagnosis of atrial cardiomyopathy allows outcome prediction following pulmonary vein isolation

Background Relevant atrial cardiomyopathy (ACM), defined as a left atrial (LA) low-voltage area ≥ 2 cm2 at 0.5 mV threshold on endocardial contact mapping, is associated with new-onset atrial fibrillation (AF), higher arrhythmia recurrence rates after pulmonary vein isolation (PVI), and an increased risk of stroke. The current study aimed to assess two non-invasive echocardiographic parameters, LA emptying fraction (EF) and LA longitudinal strain (LAS, during reservoir (LASr), conduit (LAScd) and contraction phase (LASct)) for the diagnosis of ACM and prediction of arrhythmia outcome after PVI. Methods We prospectively enrolled 60 consecutive, ablation-naive patients (age 66 ± 9 years, 80% males) with persistent AF. In 30 patients (derivation cohort), LA-EF and LAS cut-off values for the presence of relevant ACM (high-density endocardial contact mapping in sinus rhythm prior to PVI at 3000 ± 1249 sites) were established in sinus rhythm and tested in a validation cohort (n = 30). Arrhythmia recurrence within 12 months was documented using 72-h Holter electrocardiograms. Results An LA-EF of < 34% predicted ACM with an area under the curve (AUC) of 0.846 (sensitivity 69.2%, specificity 76.5%) similar to a LASr < 23.5% (AUC 0.878, sensitivity 92.3%, specificity 82.4%). In the validation cohort, these cut-offs established the correct diagnosis of ACM in 76% of patients (positive predictive values 87%/93% and negative predictive values 73%/75%, respectively). Arrhythmia recurrence in the entire cohort was significantly more frequent in patients with LA-EF < 34% and LASr < 23.5% (56% vs. 29% and 55% vs. 26%, both p < 0.05). Conclusion The echocardiographic parameters LA-EF and LAS allow accurate, non-invasive diagnosis of ACM and prediction of arrhythmia recurrence after PVI. Graphic abstract

Automatic Extraction of Recurrent Patterns of High Dominant Frequency Mapping During Human Persistent Atrial Fibrillation

Purpose: Identifying targets for catheter ablation remains challenging in persistent atrial fibrillation (persAF). The dominant frequency (DF) of atrial electrograms during atrial fibrillation (AF) is believed to primarily reflect local activation. Highest DF (HDF) might be responsible for the initiation and perpetuation of persAF. However, the spatiotemporal behavior of DF remains not fully understood. Some DFs during persAF were shown to lack spatiotemporal stability, while others exhibit recurrent behavior. We sought to develop a tool to automatically detect recurrent DF patterns in persAF patients.Methods: Non-contact mapping of the left atrium (LA) was performed in 10 patients undergoing persAF HDF ablation. 2,048 virtual electrograms (vEGMs, EnSite Array, Abbott Laboratories, USA) were collected for up to 5 min before and after ablation. Frequency spectrum was estimated using fast Fourier transform and DF was identified as the peak between 4 and 10 Hz and organization index (OI) was calculated. The HDF maps were identified per 4-s window and an automated pattern recognition algorithm was used to find recurring HDF spatial patterns. Dominant patterns (DPs) were defined as the HDF pattern with the highest recurrence.Results: DPs were found in all patients. Patients in atrial flutter after ablation had a single DP over the recorded time period. The time interval (median [IQR]) of DP recurrence for the patients in AF after ablation (7 patients) decreased from 21.1 s [11.8 49.7 s] to 15.7 s [6.5 18.2 s]. The DF inside the DPs presented lower temporal standard deviation (0.18 ± 0.06 Hz vs. 0.29 ± 0.12 Hz, p &lt; 0.05) and higher OI (0.35 ± 0.03 vs. 0.31 ± 0.04, p &lt; 0.05). The atrial regions with the highest proportion of HDF region were the septum and the left upper pulmonary vein.Conclusion: Multiple recurrent spatiotemporal HDF patterns exist during persAF. The proposed method can identify and quantify the spatiotemporal repetition of the HDFs, where the high recurrences of DP may suggest a more organized rhythm. DPs presented a more consistent DF and higher organization compared with non-DPs, suggesting that DF with higher OI might be more likely to recur. Recurring patterns offer a more comprehensive dynamic insight of persAF behavior, and ablation targeting such regions may be beneficial.

Inhibition of Small-Conductance Calcium-Activated Potassium Current (IK,Ca) Leads to Differential Atrial Electrophysiological Effects in a Horse Model of Persistent Atrial Fibrillation

BackgroundSmall-conductance Ca2+-activated K+ (KCa2) channels have been proposed as a possible atrial-selective target to pharmacologically terminate atrial fibrillation (AF) and to maintain sinus rhythm. However, it has been hypothesized that the importance of the KCa2 current—and thereby the efficacy of small-conductance Ca2+-activated K+ current (IK,Ca) inhibition—might be negatively related to AF duration and the extent of AF-induced remodeling.Experimental Approach and MethodsTo address the hypothesis of the efficacy of IK,Ca inhibition being dependent on AF duration, the anti-arrhythmic properties of the IK,Ca inhibitor NS8593 (5 mg/kg) and its influence on atrial conduction were studied using epicardial high-density contact mapping in horses with persistent AF. Eleven Standardbred mares with tachypacing-induced persistent AF (42 ± 5 days of AF) were studied in an open-chest experiment. Unipolar AF electrograms were recorded and isochronal high-density maps analyzed to allow for the reconstruction of wave patterns and changes in electrophysiological parameters, such as atrial conduction velocity and AF cycle length. Atrial anti-arrhythmic properties and adverse effects of NS8593 on ventricular electrophysiology were evaluated by continuous surface ECG monitoring.ResultsIK,Ca inhibition by NS8593 administered intravenously had divergent effects on right and left AF complexity and propagation properties in this equine model of persistent AF. Despite global prolongation of AF cycle length, a slowing of conduction in the right atrium led to increased anisotropy and electrical dissociation, thus increasing AF complexity. In contrast, there was no significant change in AF complexity in the LA, and cardioversion of AF was not achieved.ConclusionsIntra-atrial heterogeneity in response to IK,Ca inhibition by NS8593 was observed. The investigated dose of NS8593 increased the AF cycle length but was not sufficient to induce cardioversion. In terms of propagation properties during AF, IK,Ca inhibition by NS8593 led to divergent effects in the right and left atrium. This divergent behavior may have impeded the cardioversion success.

Structural Comparison of the SARS CoV 2 Spike Protein Relative to Other Human-Infecting Coronaviruses

Coronaviruses (CoV) are enveloped positive-stranded RNA viruses and, historically, there are seven known human-infecting CoVs with varying degrees of virulence. CoV attachment to the host is the first step of viral pathogenesis and mainly relies on the spike glycoprotein located on the viral surface. Among the human-infecting CoVs, only the infection of SARS CoV 2 (SARS2) among humans resulted to a pandemic which would suggest that the protein structural conformation of SARS2 spike protein is distinct as compared to other human-infecting CoVs. Surprisingly, the possible differences and similarities in the protein structural conformation between the various human-infecting CoV spike proteins have not been fully elucidated. In this study, we utilized a computational approach to generate models and analyze the seven human-infecting CoV spike proteins, namely: HCoV 229E, HCoV OC43, HCoV NL63, HCoV HKU1, SARS CoV, MERS CoV, and SARS2. Model quality assessment of all CoV models generated, structural superimposition of the whole protein model and selected S1 domains (S1-CTD and S1-NTD), and structural comparison based on RMSD values, Tm scores, and contact mapping were all performed. We found that the structural orientation of S1-CTD is a potential structural feature associated to both the CoV phylogenetic cluster and lineage. Moreover, we observed that spike models in the same phylogenetic cluster or lineage could potentially have similar protein structure. Additionally, we established that there are potentially three distinct S1-CTD orientation (Pattern I, Pattern II, Pattern III) among the human-infecting CoVs. Furthermore, we postulate that human-infecting CoVs in the same phylogenetic cluster may have similar S1-CTD and S1-NTD structural orientation. Taken together, we propose that the SARS2 spike S1-CTD follows a Pattern III orientation which has a higher degree of similarity with SARS1 and some degree of similarity with both OC43 and HKU1 which coincidentally are in the same phylogenetic cluster and lineage, whereas, the SARS2 spike S1-NTD has some degree of similarity among human-infecting CoVs that are either in the same phylogenetic cluster or lineage.