Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci.

BACKGROUND AND AIMS: Brugada syndrome (BrS) is an inherited arrhythmia with a higher disease prevalence and more lethal arrhythmic events in Asians than in Europeans. Genome-wide association studies (GWAS) have revealed its polygenic architecture mainly in European populations. The aim of this study was to identify novel BrS-associated loci and to compare allelic effects across ancestries. METHODS: A GWAS was conducted in Japanese participants, involving 940 cases and 1634 controls, followed by a cross-ancestry meta-analysis of Japanese and European GWAS (total of 3760 cases and 11 635 controls). The novel loci were characterized by fine-mapping, gene expression, and splicing quantitative trait associations in the human heart. RESULTS: The Japanese-specific GWAS identified one novel locus near ZSCAN20 (P = 1.0 × 10-8), and the cross-ancestry meta-analysis identified 17 association signals, including six novel loci. The effect directions of the 17 lead variants were consistent (94.1%; P for sign test = 2.7 × 10-4), and their allelic effects were highly correlated across ancestries (Pearson's R = .91; P = 2.9 × 10-7). The genetic risk score derived from the BrS GWAS of European ancestry was significantly associated with the risk of BrS in the Japanese population [odds ratio 2.12 (95% confidence interval 1.94-2.31); P = 1.2 × 10-61], suggesting a shared genetic architecture across ancestries. Functional characterization revealed that a lead variant in CAMK2D promotes alternative splicing, resulting in an isoform switch of calmodulin kinase II-δ, favouring a pro-inflammatory/pro-death pathway. CONCLUSIONS: This study demonstrates novel susceptibility loci implicating potentially novel pathogenesis underlying BrS. Despite differences in clinical expressivity and epidemiology, the polygenic architecture of BrS was substantially shared across ancestries.

Optimal cardiac rhythm during substrate mapping in scar-related ventricular tachycardia: Significance of wavefront direction on identifying critical sites.

BACKGROUND: A rotational activation pattern (RAP) around the localized line of a conduction block often correlates with sites specific to the critical zones of ventricular tachycardia (VT). The wavefront direction during substrate mapping affects manifestation of the RAP and line of block. OBJECTIVE: The purpose of this study was to investigate the most optimal cardiac rhythm for identifying RAP and line of block in substrate mapping. METHODS: We retrospectively evaluated 71 maps (median 3205 points/map) in 46 patients (65 ± 15 years; 33% with ischemic cardiomyopathy) who underwent high-density substrate mapping and ablation of scar-related VT. Appearance of a RAP during sinus, right ventricular (RV)-paced, left ventricular (LV)-paced, and biventricular-paced rhythms was investigated. RESULTS: RAP was identified in 24 of 71 maps (34%) in the region where wavefronts from a single direction reached but not in the region where wavefronts from multiple directions centripetally collided. The probability of identifying the RAP depended on scar location; that is, anteroseptal and inferoseptal, inferior and apical, and basal lateral RAPs were likely to be identified during sinus/atrial, RV-paced, and LV-paced rhythms, respectively. In 13 patients, the RAP was not evident in the baseline map but became apparent during remapping in the other rhythm, in which the wavefront reached the site earlier within the entire activation time. CONCLUSION: The optimal rhythm for substrate mapping depends on the spatial distribution of the area of interest. A paced rhythm with pacing sites near the scar may facilitate the identification of critical VT zones.

Immediate pharmacotherapy intensification after cardiac resynchronization therapy: incidence, characteristics, and impact.

AIMS: Cardiac resynchronization therapy (CRT) is an established treatment for drug-refractory heart failure (HF) in patients with left bundle branch block (LBBB). Acute haemodynamic improvement after CRT implantation may enable the intensification of HF medication soon thereafter. Immediate pharmacotherapy intensification (IPI) after CRT implantation achieves a synergetic effect, possibly leading to a better prognosis. This study aimed to explore the incidence, characteristics, and impact of IPI on real-world outcomes among CRT recipients with a history of hospitalization for acute HF. METHODS AND RESULTS: This multicentre retrospective study enrolled CRT recipients with LBBB morphology, a QRS width ≥120 ms, a left ventricular ejection fraction ≤35%, and New York Heart Association II-IV HF symptoms. All patients had previous HF hospitalizations within the previous year and received guideline-directed medical therapy before CRT implantation. Patient baseline characteristics, including HF medication, were collected. IPI was defined as the intensification of beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists within 30 days of CRT implantation. The primary endpoint was all-cause death or first hospitalization for HF; the secondary endpoint was all-cause death. We enrolled 194 patients (75% male; mean age, 65 ± 13 years; 78% with non-ischaemic cardiomyopathy). One hundred five (54%) patients received IPI. Patients who received IPI exhibited a significantly shorter QRS duration (159 ± 26 vs. 171 ± 32 ms; P = 0.004), higher estimated glomerular filtration rate (55.2 ± 20.0 vs. 47.8 ± 24.7 mL/min/1.73 m2 ; P = 0.022), and more dilated cardiomyopathy. During a median follow-up period of 29 months, 70 (36%) patients reached the primary endpoint and 42 (22%) patients died. Patients with IPI showed significantly better outcomes for the primary and secondary endpoints than patients without IPI. The volumetric responder ratio at 6 months after implantation was not significantly different between patients with and without IPI; however, patients who received IPI had reduced mortality even at 6 months after implantation. In the multivariate analysis, IPI was an independent predictor of the primary endpoint (hazard ratio, 0.51; 95% confidence interval, 0.27-0.97; P = 0.043). CONCLUSIONS: Immediate intensification of HF medication was achieved in 54% of CRT recipients and was significantly higher in patients without excessive QRS prolongation, preserved renal function, and dilated cardiomyopathy than others. In patients with LBBB morphology and QRS ≥ 120 ms, IPI was associated with a significantly better prognosis and fewer HF hospitalizations after CRT implantation than others.

Electrophysiological and Histopathological Characteristics of Ventricular Tachycardia Associated With Primary Cardiac Tumors.

BACKGROUND: Ventricular tachycardia (VT) associated with primary cardiac tumors (PCTs) originating from the ventricles is rare, but lethal, in young patients. OBJECTIVES: This study aimed to clarify the mechanisms underlying primary cardiac tumor-related ventricular tachycardia (PCT-VT) and establish a therapeutic strategy for this form of VT. METHODS: Among 67 patients who underwent surgery for VT at our institute between 1981 and 2020, 4 patients aged 1 to 34 years, including 3 males, showed PCT-VT (fibroma, 2; lipoma, 1; and hamartoma, 1), which was investigated using a combination of intraoperative electroanatomical mapping and histopathological studies. RESULTS: All 4 patients developed electrical storms of sustained VTs refractory to multiple drugs and repetitive endocardial ablations. The VT mechanism was re-entry, and intraoperative electroanatomical mapping showed a centrifugal activation pattern originating from the border between the tumor and healthy myocardium, where fractionated potentials were detected during sinus rhythm. Histopathological studies of serial sections of specimens acquired from these areas revealed tumor infiltration into the surrounding myocardium with cell disorganization, exhibiting myocardial disarray. Several myocardia entrapped in the tumor edges contributed to the development and sustainment of re-entrant VT activation. In the 2 patients in whom complete resection was unfeasible, encircling cryoablation to entirely isolate the unresectable tumor was effective in suppressing VT occurrence. CONCLUSIONS: The mechanism underlying PCT-VT involves re-entry localized at the tumor edges. Myocardial disarray associated with tumor infiltration is a substrate for this form of VT. Cryoablation along the border between the tumor and myocardium is a promising therapeutic option for unresectable PCT-VT.

Triggers of Ventricular Fibrillation in Patients With Inferolateral J-Wave Syndrome.

BACKGROUND: There are few data on ventricular fibrillation (VF) initiation in patients with inferolateral J waves. OBJECTIVES: This multicenter study investigated the characteristics of triggers initiating spontaneous VF in inferolateral J-wave syndrome. METHODS: A total of 31 patients (age 37 ± 14 years, 24 male) with spontaneous VF episodes associated with inferolateral J waves were evaluated to determine the origin and characteristics of triggers. The J-wave pattern was recorded in inferior leads in 11 patients, lateral leads in 3, and inferolateral leads in 17. RESULTS: The VF triggers (n = 37) exhibited varying QRS durations (176 ± 21 milliseconds, range 119-219 milliseconds) and coupling intervals (339 ± 46 milliseconds, range 250-508 milliseconds) with a right (70%) or left (30%) bundle branch block (BBB) pattern. Trigger patterns were associated with J-wave location: left BBB triggers with inferior J waves and right BBB triggers with lateral J waves. Electrophysiologic study was performed for 22 VF triggers in 19 patients. They originated from the left or right Purkinje system in 6 and from the ventricular myocardium in 10 and were undetermined in 6. Purkinje vs myocardial triggers showed distinct electrocardiographic characteristics in coupling interval and QRS-complex duration and morphology. Abnormal epicardial substrate associated with fragmented electrograms was identified in 9 patients, with triggers originating from the same region in 7 patients. Catheter ablation resulted in VF suppression in 15 patients (79%). CONCLUSIONS: VF initiation in inferolateral J-wave syndrome is associated with significant individual heterogeneity in trigger characteristics. Myocardial triggers have electrocardiographic features distinct from Purkinje triggers, and their origin often colocalizes with an abnormal epicardial substrate.

Intractable Ventricular Tachycardia Prior to an Overt Cardiac Tumor Mass of Metastatic Cardiac Rhabdomyosarcoma (Spindle-cell Type).

We herein report a 37-year-old man who experienced recurrence of metastatic cardiac rhabdomyosarcoma along with intractable ventricular tachycardia (VT) 7 years after resection of rhabdomyosarcoma in his right elbow. At 36 years old, he developed VT unresponsive to radiofrequency catheter ablation (RFCA). Initially, the cardiac tumor was not detected, but it gradually grew in size at the RFCA site. A surgical biopsy confirmed the diagnosis of metastatic cardiac rhabdomyosarcoma. Despite radiation therapy, cardiac tumor progression and VT instability could not be prevented. Ultimately, the patient died 27 months after the initial documentation of VT.

Unidirectional conduction characterizing epicardial connections in patients with atrial tachyarrhythmias.

INTRODUCTION: Electrophysiological characteristics of epicardial connections (ECs) in atria and pulmonary veins (PVs) are unclear despite their important contributions to atrial fibrillation (AF). Unidirectional conduction associated with source-sink mismatch can occur in ECs due to their fine fibers with abrupt changes in orientation. We detailed the prevalence and electrophysiological characteristics of unidirectional conduction in the atria and investigated its association with the clinical manifestation of AF. METHODS: This study retrospectively reviewed electrophysiological studies and radiofrequency catheter ablation in 261 consecutive patients with AF. RESULTS: Unidirectional conduction was observed during ablation encircling the PVs in eight (3.1%) patients, and all occurred in the suspected (N = 4) or definitively (N = 4) recognized ECs. These ECs included three intercaval bundles, four septopulmonary bundles, and one Marshall bundle, and were first manifested in a second procedure in 6 (75%) patients. The unidirectional property was from PV to atrium (exit conduction) in all intercaval bundles and three septopulmonary bundles, and from atrium to PV (entrance conduction) in the remaining two bundles. Intercaval bundles acted as a limb of bi-atrial macro-reentrant tachycardia (50%, three of the six including previous cases). Ablation of the exit outside the PVs, including the right atrium, eliminated ECs in three (38%) patients. All patients remain free from arrhythmia recurrence after a mean 13-month follow-up. CONCLUSION: A unidirectional conduction property was closely associated with the EC, as estimated by histological findings. Recognition of this fact by electrophysiologists may help to clarify mechanisms for AF and atrial tachycardia and guide the creation of efficient and safe ablation lesion sets.

Purkinje-Related Ventricular Tachycardia and Ventricular Fibrillation: Solved and Unsolved Questions.

Of the monomorphic ventricular tachycardias, there are 4 specific tachycardias related to the Purkinje system: 1) idiopathic verapamil-sensitive fascicular ventricular tachycardia (FVT); 2) non-re-entrant FVT; 3) bundle branch re-entry and interfascicular re-entry; and 4) Purkinje-mediated VT in structural heart disease. Verapamil-sensitive FVT is classified into 4 types according to the location of the circuit: 1) left posterior type; 2) left anterior type; 3) left upper septal type;and 4) reverse type. And, in the left anterior and posterior types, there are septal and papillary muscle subtypes. Although macro-re-entry has been reported to be the mechanism underlying verapamil-sensitive FVT, recording the entire circuit is challenging. One possible reason is that the Purkinje-muscle junction may penetrate the myocardial layer as a part of the circuit. The Purkinje network may thus play an important role in the initiation and maintenance of ventricular fibrillation. Further, it has been reported that the development and the abnormalities of the Purkinje system are associated with the arrhythmogenesis of ventricular fibrillation. Furthermore, it has been reported that catheter ablation of trigger ventricular premature complexes, and/or "de-networking" of the Purkinje system, can be used as electrical bailout therapy. There is a hypothesis that the intramural Purkinje system is involved in the generation of J waves. Nevertheless, as there are still unresolved issues that must be debated and accurately analyzed, this review aims to discuss the solved and unsolved questions related to Purkinje-related arrhythmias.

Acute and mid-term outcomes of ablation for atrial fibrillation with VISITAG SURPOINT: the Japan MIYABI registry.

AIMS: The effectiveness of pulmonary vein isolation (PVI) guided by VISITAG SURPOINT (VS) has been demonstrated in Western populations. However, data for Asian populations are limited. VS settings may differ for Asians, given their smaller body size. This study aimed to describe outcomes of radiofrequency atrial fibrillation (AF) ablation guided by VS in a large Asian population. METHODS AND RESULTS: The prospective, observational, multicentre MIYABI registry collected real-world data from patients undergoing VS-guided AF ablation using ThermoCool SmartTouch and ThermoCool SmartTouch SF catheters from 50 Japanese centres. All patients had paroxysmal AF or persistent AF for <6 months. Primary adverse events (PAEs) were evaluated for safety. The primary efficacy endpoint was the proportion of patients with PVI at the end of the procedure. Mid-term effectiveness (up to 12 months) was evaluated by freedom from documented atrial arrhythmias. Of the 1011 patients enrolled, 1002 completed AF ablation. The mean number of VS values per procedure was 428.8 on the anterior wall and 400.4 on the posterior wall. Nine patients (0.9%) experienced PAEs. Upon procedure completion, 99.7% of patients had PVI. Twelve-month freedom from atrial arrhythmia recurrence was 88.5%; 5.7% of patients were re-ablated. At repeat ablation, 54% of RSPV, 73% of RIPV, 70% of LSPV, and 86% of LIPV evaluated remained durably isolated. CONCLUSION: Despite lower anterior wall VS values compared with the CLOSE protocol (≥550), the present study demonstrated comparable efficacy outcomes, indicating that a VS of ≥550 for the anterior wall may not be necessary for Asian patients.

The R Wave Amplitude in Lead aVL Could Predict Successful Catheter Ablation of Ventricular Arrhythmias Originating below the His Bundle Region of the Right Ventricle.

Radiofrequency catheter ablation (RFCA) to treat ventricular arrhythmias (VAs) originating below the His bundle (HB) region of the right ventricular (RV) septum could impair the atrioventricular node conduction. This study aimed to clarify the parameters of the 12-lead electrocardiography that predict successful RFCA of VAs originating from this region. This study included 20 consecutive patients (13 men; mean age, 68 ± 7 years) with monomorphic VAs in whom the earliest ventricular activation during the VA was below the HB region of the RV septum. According to the ablation results, the patients were divided into two groups: successful ablation (S-group; n = 10) and failed ablation groups (F-group; n = 10). The electrocardiographic parameters during the VAs and RFCA results were assessed. The R wave amplitudes in leads aVL (P = 0.001) and I (P = 0.010) in the S-group were both smaller than those in the F-group. In addition, the S-group had smaller negative deflection amplitudes in leads III (P = 0.002) and aVF (P = 0.003) than the F-group. According to the receiver operating characteristic curve analysis, the most useful electrocardiographic parameter for predicting successful ablation was the R wave amplitude in lead aVL (area under the curve, 0.895; P < 0.001); a cutoff value of < 1.3 mV predicted a successful RFCA with the highest accuracy (sensitivity, 90%; specificity, 80%; positive predictive value, 82%; negative predictive value, 89%). The R wave amplitude in lead aVL was the most useful parameter for predicting a successful RFCA to treat VAs originating below the HB region of the RV septum.

Reverse remodeling of the tricuspid valve complex by sinus rhythm restoration after catheter ablation.

BACKGROUND: Atrial fibrillation (AF) can cause right atrium enlargement and structural changes of the tricuspid valve annulus (TVA). The features of the structural changes and benefits obtained from rhythm-control therapy is unknown. OBJECTIVES: We investigated how the TVA changes and whether its size decreases after rhythm-control therapy. METHODS: Multi-detector row computed tomography (MDCT) was performed before and after catheter ablation for AF. TVA morphology and right atrium (RA) volume was evaluated by MDCT. The features of TVA morphology in patients with AF after rhythm-control therapy were analyzed. RESULTS: MDCT was performed in 89 patients with AF. The 3D perimeter was more correlated with diameter in the anteroseptal-posterolateral (AS-PL) direction than in the anterior-posterior direction. Seventy patients showed 3D perimeter reduction owing to rhythm-control therapy and the change was associated with the rate of change in the AS-PL diameter. Rate of change of the 3D perimeter was associated with that of the AS-PL diameter among TVA morphology and RA volume. We divided the subjects into three groups according to the tertiles of the TA perimeter. 3D perimeter in all groups was decreased after rhythm-control therapy. The AS-PL diameter in the 2nd and 3rd tertiles was decreased and increased TVA height in all groups. CONCLUSION: TVA in patients with AF was enlarged and flattened in the early phase, and rhythm-control therapy resulted in reverse remodeling of the TVA and in the reduction of right atrial volume. These results suggest that early AF intervention can lead to the restoration of the TVA structure.

Fascicular Ventricular Tachycardias: Potential Role of the Septal Fascicle.

Ventricular tachycardias involving the fascicular system are amongst the most challenging and intriguing arrhythmias for cardiac electrophysiologists. Although some of the more common forms have been recognized clinically for decades, other variants continue to be characterized. Moreover, considerable uncertainty persists to date with regards to the mechanisms underpinning these arrhythmias. In this state-of-the-art review, we discuss the seminal historical and contemporary observations that have collectively advanced our understanding of fascicular ventricular tachycardias. From this base, we canvas the basic and clinical evidence supporting a potential role for the septal fascicular network and propose a new schema hypothesizing involvement of this fascicle. Although we focus primarily on the most common left posterior fascicular ventricular tachycardia, our discussion and proposal have mechanistic and therapeutic implications for the spectrum of fascicular arrhythmias.

Impact of Interatrial Epicardial Connections on the Dominant Frequency of Atrial Fibrillation.

BACKGROUND: An epicardial connection (EC) between the right-sided pulmonary venous (RtPV) carina and right atrium (RA) may preclude PV isolation, but its electrophysiological role during atrial fibrillation (AF) remains unknown.Methods and Results: This prospective observational study included 98 consecutive patients undergoing catheter ablation for AF, subdivided into the EC group (n=17) and non-EC group (n=80) based on observation of RA posterior wall breakthrough during RtPV pacing. Mean left atrial (LA) dominant frequency (mean DFLA) was defined as the averaged DFs at the right and left PVs and LA appendage. The regional DF was higher in the EC group vs. the non-EC group except at the left PV antrum. The DF at the RA appendage (RAA) and mean DFLAwere equivocal (6.5±0.7 vs. 6.6±0.7 Hz) in the EC group, but the mean DFLAwas significantly higher than that at the RAA (5.8±0.6 vs. 6.1±0.5 Hz, P=0.001) in the non-EC group, suggesting an LA-to-RA DF gradient. A significant correlation of DF between the RtPV antrum and RAA was observed in the EC group (P<0.001, r=0.84) but not in the non-EC group. CONCLUSIONS: An electrophysiological link via interatrial ECs might attenuate the hierarchical nature of activation frequencies of AF, leading to advanced electrical remodeling of the atria.