Reliable focal and rotational activations in CARTOFINDER mapping using the OctaRay catheter.

INTRODUCTION: The aim of the current study was to elucidated the reliable atrial fibrillation (AF) drivers identified by CARTOFINDER using OctaRay catheter. METHODS AND RESULTS: The reliability of focal and rotational activations identified by CARTOFINDER using OctaRay catheter was assessed by the sequential recordings in each site of both atrium before and after pulmonary vein isolation (PVI) in 10 persistent AF patients. The outcome measures were the reproducibility rate during the sequential recordings and the stability rate between pre- and post-PVI as reliable focal and rotational activations. The study results were compared with those under use of PentaRay catheter (N = 18). Total 68928 points of 360 sites in OctaRay group and 24 177 points of 311 sites in PentaRay were assessed. More focal activation sites were identified in OctaRay group than PentaRay group (7.9% vs. 5.7%, p < .001), although the reproducibility rate and the stability rate were significantly lower in OctaRay group (45.3% vs. 58.9%, p < .001; 11.2% vs. 28.4%, p < .001). Meanwhile, the prevalence of reproducible focal activation sites among overall points was comparable (3.6% vs. 3.3%, p = .08). Regarding rotational activation, more rotational activation sites were identified in OctaRay group (5.1% vs. 0.2%, p < .001), and the reproducibility rate and the stability rate were significantly higher in OctaRay group (45.2% and 12.5% vs. 0.0%, p < .001). Both reliable focal and rotational activation sites were characterized by significantly shorter AF-cycle length (CL) and higher repetition of focal and rotational activations during the recordings compared with the sites of non or unreliable focal and rotational activations. CONCLUSION: In CARTOFINDER, OctaRay catheter could identify reliable focal activation with high resolution and reliable rotational activation compared with PentaRay catheter. The repetitive focal and rotational activations with short AF-CL could be the potential target during ablation.

Prevalence and characteristics of atrioventricular nodal reentrant tachycardia with a bystander concealed nodoventricular/nodofascicular pathway.

BACKGROUND: The concealed nodoventricular/nodofascicular (NV/NF) pathway is mostly a bystander, retrograde bypass tract connecting the right ventricle/right bundle branch (RBB) and slow pathway that is observed in patients with atrioventricular nodal reentrant tachycardia (AVNRT). However, its prevalence and characteristics in response to pacing maneuvers have not been fully evaluated. OBJECTIVE: This study investigated the prevalence and characteristics of AVNRT with a bystander NV/NF pathway. METHODS: We retrospectively reviewed 153 consecutive patients undergoing catheter ablation of AVNRT. After exclusion of 52 patients with inadequate electrophysiologic data, 101 patients composed the study population. RESULTS: Three patients (3.0%) had bystander concealed NV/NF pathways, all of which were connected to the slow pathway. The tachycardia was typical slow pathway/fast pathway AVNRT in 2 patients and atypical fast pathway/slow pathway AVNRT in 1 patient. In all cases, His-refractory ventricular extra-stimuli (VES) reset the AVNRTs with delay through the NV/NF pathways. Ventricular overdrive pacing (VOP) in the early phase also reset the AVNRT with delay. Earlier VES and middle phase of VOP did not reset the tachycardia, and further earlier VES and late phase of VOP reset the tachycardia with advance through the RBB-His conduction. CONCLUSION: A bystander NV/NF pathway was not rare in patients with AVNRT. The VES and VOP for the AVNRTs with the bystander NV/NF pathways were characterized by the 2-phase resetting phenomenon: initial transient resetting with delay through the NV/NF pathway, and late resetting with advance through the RBB-His conduction.

Efficacy and safety of Saireito (TJ-114) in patients with atrial fibrillation undergoing catheter ablation procedures: A randomized pilot study.

BACKGROUND: Early arrhythmia recurrences commonly occur after atrial fibrillation (AF) ablation because of irritability and inflammation of left atrium. We hypothesized that short-term use of Saireito would be effective in reducing frequent atrial tachyarrhythmias in the early-phase post-ablation. METHODS: One hundred patients undergoing catheter ablation for symptomatic AF were randomly assigned to either a 30-day use of Saireito or control group. The primary endpoint was total number of episodes of frequent atrial tachyarrhythmias including definite recurrent AF and frequent premature atrial contractions during the 30-day treatment period post-ablation. RESULTS: Three (6.0%) out of 50 patients treated with Saireito discontinued the drug because of adverse symptoms. The Saireito group was associated with a numerically lower number of episodes of frequent atrial tachyarrhythmias than the control group (3.1 versus 5.2 times, P = 0.17). The mean daily episodes of frequent atrial tachyarrhythmias were significantly fewer in the Saireito group during Day-6 to Day-10 (0.12/day versus 0.27/day, P = 0.03), and during Day-11 to Day-15 (0.08/day versus 0.24/day, P = 0.001). The prevalence of adverse symptoms during the 30-day treatment period was significantly higher in the Saireito group (18.0% versus 2.0%, P = 0.005). CONCLUSIONS: Thirty-day use of Saireito following AF ablation was associated with a tendency toward reduced number of episodes of frequent atrial tachyarrhythmias during the treatment period, with more pronounced effect in the first two weeks.

Auxiliary roles of nardilysin in the early diagnosis of acute coronary syndrome: a prospective cohort study, the Nardi-ACS study.

Acute coronary syndrome (ACS) includes myocardial infarction (MI) and unstable angina (UA). MI is defined by elevated necrosis markers, preferably high-sensitivity cardiac troponins (hs-cTn). However, it takes hours for cTn to become elevated after coronary occlusion; therefore, difficulties are associated with diagnosing early post-onset MI or UA. The aim of this prospective cohort study was to examine the diagnostic ability of serum nardilysin (NRDC) for the early detection of ACS. This study consisted of two sequential cohorts, the Phase I cohort, 435 patients presenting to the emergency room (ER) with chest pain, and the Phase II cohort, 486 patients with chest pain who underwent coronary angiography. The final diagnosis was ACS in 155 out of 435 patients (35.6%) in the phase I and 418 out of 486 (86.0%) in the phase II cohort. Among 680 patients who presented within 24 h of onset, 466 patients (68.5%) were diagnosed with ACS. Serum NRDC levels were significantly higher in patients with ACS than in those without ACS. The sensitivity of NRDC in patients who presented within 6 h after the onset was higher than that of hsTnI, and the AUC of NRDC within 1 h of the onset was higher than that of hsTnI (0.718 versus 0.633). Among hsTnI-negative patients (300 of 680 patients: 44.1%), 136 of whom (45.3%) were diagnosed with ACS, the sensitivity and the NPV of NRDC were 73.5 and 65.7%, respectively. When measured in combination with hsTnI, NRDC plays auxiliary roles in the early diagnosis of ACS.

TAD boundary deletion causes PITX2-related cardiac electrical and structural defects.

While 3D chromatin organization in topologically associating domains (TADs) and loops mediating regulatory element-promoter interactions is crucial for tissue-specific gene regulation, the extent of their involvement in human Mendelian disease is largely unknown. Here, we identify 7 families presenting a new cardiac entity associated with a heterozygous deletion of 2 CTCF binding sites on 4q25, inducing TAD fusion and chromatin conformation remodeling. The CTCF binding sites are located in a gene desert at 1 Mb from the Paired-like homeodomain transcription factor 2 gene (PITX2). By introducing the ortholog of the human deletion in the mouse genome, we recapitulate the patient phenotype and characterize an opposite dysregulation of PITX2 expression in the sinoatrial node (ectopic activation) and ventricle (reduction), respectively. Chromatin conformation assay performed in human induced pluripotent stem cell-derived cardiomyocytes harboring the minimal deletion identified in family#1 reveals a conformation remodeling and fusion of TADs. We conclude that TAD remodeling mediated by deletion of CTCF binding sites causes a new autosomal dominant Mendelian cardiac disorder.

Multiplexed Assays of Variant Effect and Automated Patch-clamping Improve KCNH2-LQTS Variant Classification and Cardiac Event Risk Stratification.

Background: Long QT syndrome (LQTS) is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by KCNH2. Variant classification is difficult, often owing to lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance. Here, we sought to test whether variant-specific information, primarily from high-throughput functional assays, could improve both classification and cardiac event risk stratification in a large, harmonized cohort of KCNH2 missense variant heterozygotes. Methods: We quantified cell-surface trafficking of 18,796 variants in KCNH2 using a Multiplexed Assay of Variant Effect (MAVE). We recorded KCNH2 current density for 533 variants by automated patch clamping (APC). We calibrated the strength of evidence of MAVE data according to ClinGen guidelines. We deeply phenotyped 1,458 patients with KCNH2 missense variants, including QTc, cardiac event history, and mortality. We correlated variant functional data and Bayesian LQTS penetrance estimates with cohort phenotypes and assessed hazard ratios for cardiac events. Results: Variant MAVE trafficking scores and APC peak tail currents were highly correlated (Spearman Rank-order ρ = 0.69). The MAVE data were found to provide up to pathogenic very strong evidence for severe loss-of-function variants. In the cohort, both functional assays and Bayesian LQTS penetrance estimates were significantly predictive of cardiac events when independently modeled with patient sex and adjusted QT interval (QTc); however, MAVE data became non-significant when peak-tail current and penetrance estimates were also available. The area under the ROC for 20-year event outcomes based on patient-specific sex and QTc (AUC 0.80 [0.76-0.83]) was improved with prospectively available penetrance scores conditioned on MAVE (AUC 0.86 [0.83-0.89]) or attainable APC peak tail current data (AUC 0.84 [0.81-0.88]). Conclusion: High throughput KCNH2 variant MAVE data meaningfully contribute to variant classification at scale while LQTS penetrance estimates and APC peak tail current measurements meaningfully contribute to risk stratification of cardiac events in patients with heterozygous KCNH2 missense variants.