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.

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.

Enlarged right atrium predicts pacemaker implantation after atrial fibrillation ablation in patients with tachycardia-bradycardia syndrome.

Introduction: Although catheter ablation (CA) of tachycardia-bradycardia syndrome (TBS) in patients with atrial fibrillation (AF) is considered to be an effective treatment strategy, pacemaker implantations (PMIs) are often required even after a successful CA. This study aimed to elucidate the clinical predictors of a PMI after CA. Methods: From 2011 to 2020, 103 consecutive patients diagnosed with TBS were retrospectively enrolled in the study. Among the 103 patients, 54 underwent a PMI and 49 CA of AF. During 47.4 ± 35.4 months after 1.4 ± 0.6 CA sessions, 37 (75.5%) of 49 patients were free from atrial arrhythmia recurrences. PMIs were performed in 11 patients (PMI group) and the remaining 38 did not receive a PMI (non-PMI group). Results: When comparing the PMI and non-PMI groups, there were no differences in the basic mean heart rate (P = 0.36), maximum pauses detected by 24-hour Holter-monitoring (P = 0.61), and other clinical parameters between the two groups while the right atrial area index was larger (42.1 ± 24.0 vs. 21.8 ± 8.4 cm2/m2 P = 0.002) in the PMI group than non-PMI group. The ROC curve analysis showed that the optimal cutoff point of the ratio of the right atrial area index to the left atrial area index for predicting a PMI following CA was 0.812 (Sensitivity 72.7%, specificity 71.1%, positive predictive value 42.1%, negative predictive value 90.0%, diagnostic accuracy 71.4%, AUC = 0.81). Conclusion: Right atrial enlargement prior to CA was considered to be one of the risk factors for a PMI after CA of AF.

Surgery for ventricular tachycardia originating from the left ventricular summit.

OBJECTIVES: Ventricular tachycardia (VT) originating from the left ventricular summit region, the most superior region of the left ventricle surrounded by the major coronary arteries and veins, is frequently refractory to pharmacological therapies and endocardial and epicardial catheter ablation. METHODS: Eleven patients with an age from 31 to 79 (median 56) years old, underwent map-guided surgery for left ventricular summit VT. All patients had undergone 1-5 unsuccessful sessions of catheter ablation for incessant VT, preoperatively. Five patients had suffered VT storm and 1 had a history of cardiopulmonary resuscitation. Four patients had implanted with a defibrillator. Epicardium to endocardium transmural cryothermia was applied at the VT origin determined by intraoperative epicardial mapping with electro-anatomical mapping system. Harmonic scalpel was used to remove the epicardial fat and cryothermia was applied directly to the myocardium, avoiding thermal or mechanical injuries to the coronary vessels. Additional endocardial cryothermia at the VT origin was performed by a cryoprobe introduced into the left ventricular cavity through an aortotomy. RESULTS: There was no surgical mortality or long-term mortality related to VT during a median follow-up period of 60 months (interquartile range: 34-82). Five-year freedom from preoperatively documented left ventricular summit VT and non-documented VT was 91% and 73%, respectively. All the patients with postoperative VT underwent successful catheter ablation. Other patients were free from VT during the follow-up period. CONCLUSIONS: Epicardial to endocardial transmural cryothermia at the VT origin guided by intraoperative electro-anatomical mapping with a close collaboration with electrophysiologists was crucial in successful surgery for left ventricular summit VT.

External Validation of the Kumamoto Criteria in Transthyretin Amyloid Cardiomyopathy Screening　- A Retrospective Cohort Study.

Background: The Kumamoto criteria have been proposed as a non-invasive screen for transthyretin amyloid cardiomyopathy. This study assessed the validity of the Kumamoto criteria externally. Methods and Results: The study included 138 patients (median age 73 years; 65% male) who underwent 99 mTc-pyrophosphate (PYP) scintigraphy. Patients were divided into 4 groups according to total scores on the Kumamoto criteria (i.e., 0-3) for the following 3 factors: high-sensitivity cardiac troponin T ≥0.0308 ng/mL, wide (≥120 ms) QRS, and left ventricular posterior wall thickness ≥13.6 mm. The diagnostic performance and positive predictive value (PPV) of the Kumamoto criteria for positive 99 mTc-PYP scintigraphy were validated. Eighteen (13%) patients were positive on 99 mTc-PYP scintigraphy. The Kumamoto criteria had a favorable diagnostic performance (area under the curve 0.808). The PPV for groups with scores of 0, 1, 2, and 3 was 0% (n=0/42), 11% (n=6/57), 21% (n=7/33), and 83% (n=5/6), respectively, which is lower, particularly for those with a score of 2, than in the original Kumamoto cohort. However, the PPV increased after combining the Kumamoto criteria with a history of orthopedic diseases (spinal canal stenosis and/or carpal tunnel syndrome). Conclusions: This study suggests that the Kumamoto criteria have a favorable diagnostic performance; however, the PPV may decrease depending on the study population. Combining the Kumamoto criteria with the presence of orthopedic disease may improve the PPV.

Improvement in Quality of Life via Catheter Ablation for Atrial Fibrillation in Patients Undergoing Hemodialysis Therapy.

Background: Atrial fibrillation (AF) is the most common arrhythmia in patients undergoing hemodialysis (HD); AF lowers quality of life (QoL) and increases the risk of dialysis-related complications. The present study aimed to evaluate the effectiveness of AF ablation on the QoL in patients undergoing HD. Methods: Nineteen patients undergoing HD (14 men, age 68 ± 8 years; 15 with paroxysmal AF) who underwent catheter ablation (CA) of AF were enrolled in the study. The Kidney Disease Quality of Life Short Form (KDQOL-SF) was assessed to evaluate the QoL of the HD patients at baseline and 6 months after the ablation. Ablation outcomes and procedural complications were evaluated and compared to those of 1053 consecutive non-HD patients who underwent AF ablation. Results: The KDQOL-SF of the HD patients 6 months after the ablation showed an improvement in physical functioning (54 ± 23 to 68 ± 28, P < 0.01), general health perceptions (38 ± 17 to 48 ± 15, P < 0.01), and symptoms/problems (75 ± 21 to 84 ± 13, P = 0.02), compared to baseline. For intradialytic symptoms, dyspnea during HD significantly improved after the CA in the HD patients without AF recurrence (43% to 7%, P = 0.04), whereas the atrial tachyarrhythmias and hypotension during HD remained unchanged. During the follow-up period of 17 ± 13 months after the last procedure, the incidence of being arrhythmia-free was similar (HD patients, 79% vs non-HD patients, 86%, log-rank P = 0.82). No life-threatening complications occurred in any of the patients. Conclusions: CA of AF improves QoL in patients undergoing chronic HD therapy.

Contexte: La fibrillation auriculaire (FA), la forme d'arythmie la plus fréquente chez les patients sous hémodialyse (HD), entraîne une diminution de la qualité de vie (QdV) et une augmentation des risques de complications liées à la dialyse. La présente étude visait à évaluer l'effet de l'ablation de la FA sur la QdV des patients sous HD. Méthodologie: Dix-neuf patients sous HD (âgés de 68 ± 8 ans, dont 14 étaient des hommes et 15 étaient atteints de FA paroxystique) ayant subi une ablation par cathéter de la FA ont été admis dans l'étude. Le questionnaire KDQOL-SF (Kidney Disease Quality of Life Short Form) a été utilisé pour évaluer la QdV des patients sous HD avant l'intervention et six mois après l'ablation. L'issue de l'ablation et les complications liées à l'intervention ont été évaluées et comparées à celles de 1 053 patients consécutifs n'étant pas hémodialysés et ayant subi une ablation de la FA. Résultats: La comparaison des résultats initiaux au KDQOL-SF des patients hémodialysés avec les résultats obtenus six mois après l'ablation a montré des améliorations de la fonction physique (de 54 ± 23 à 68 ± 28, p < 0,01), de la perception de l'état de santé global (de 38 ± 17 à 48 ± 15, p < 0,01), et des symptômes/problèmes de santé (de 75 ± 21 à 84 ± 13, p = 0,02). En ce qui concerne les symptômes survenant lors des séances d'HD, une amélioration significative de la dyspnée a été observée après l'ablation par cathéter chez les patients sous HD sans récurrence de la FA (de 43 % à 7 %, p = 0,04), alors qu'aucun changement n'a été constaté pour les tachyarythmies auriculaires et l'hypotension. Durant la période de suivi de 17 ± 13 mois après la dernière intervention, le nombre de patients sans arythmie était comparable dans les deux groupes (79 % chez les patients hémodialysés et 86 % chez les patients non hémodialysés, test du log-rank = 0,82). Aucun patient n'a subi de complication menaçant le pronostic vital. Conclusions: L'ablation par cathéter de la FA permet d'améliorer la QdV des patients qui subissent un traitement par HD de longue durée.

Possibility of steroid therapy without pacemaker implantation in patients with sarcoidosis presenting atrioventricular block.

Atrioventricular Block (AVB) is one of the common manifestations in cardiac sarcoidosis (CS). Although pacemaker implantation is generally recommended in patients with CS complicated by symptomatic AVB, some case reports have shown that they can be managed by steroid therapy without pacemaker implantation. The aim of this study was to evaluate the feasibility and effectiveness of steroid therapy without pacemaker implantation in patients with CS complicated by symptomatic AVB. We performed medical record review of consecutive ten CS patients who admitted Nippon Medical School Hospital for symptomatic second or third degree AVB between April 2015 and March 2021. Of the studied population, steroid therapy before pacemaker implantation was feasible in three patients with second degree AVB. Two of them showed subsequent recovery of atrioventricular conduction to 1:1, and they were managed by steroid therapy without pacemaker. The remaining one patient showed no improvement of atrioventricular conduction and required pacemaker implantation. Seven patients with third degree AVB required device implantation (pacemaker; n = 7, cardiac resynchronization therapy defibrillator; n = 1) before steroid therapy mainly because of hemodynamic instability. Steroid therapy without pacemaker implantation might be feasible, and possibly be effective in patients with CS presenting second degree AVB. However, the feasibility is limited in patients with third degree AVB.

Protective Effect of Catheter Ablation of Atrial Fibrillation on the Renal Function in Patients With Hypertrophic Cardiomyopathy.

Atrial fibrillation (AF) is a common arrhythmia in patients with hypertrophic cardiomyopathy (HCM) and is associated with renal function deterioration. The protective effects of catheter ablation (CA) of AF on renal function in patients with HCM remain unsolved. From 2009 to 2020, a total of 169 consecutive patients with HCM and AF (age 70 ± 12, 87 males) were retrospectively evaluated. The estimated glomerular filtration rate (eGFR) was evaluated at the study enrollment or 1 month before the CA and reevaluated 3 and 12 months later. In the 169 patients, 63 underwent CA of AF (ablation group), and the remaining 106 did not (control group). After propensity score matching, 45 pairs were matched. The baseline eGFR was similar between the 2 groups (p = 0.83). During a mean follow-up period of 34 ± 27 months, sinus rhythm was maintained in 36 patients (80%) after 1.7 ± 0.8 ablation procedures. The eGFR significantly decreased from baseline to 3 months (p <0.01) and from baseline to 1 year (p <0.01) in the control group, whereas the eGFR in the ablation group was maintained both from baseline to 3 months (p = 0.94) and from baseline to 1 year (p = 1.00) after the CA. The change in the eGFR between baseline and 12 months was significantly smaller in the ablation group than in the control group (p <0.01). After logistic regression analysis, CA of AF was the independent predictor of an improvement of eGFR (odds ratio 2.81, 95% confidence interval 1.08 to 7.36, p = 0.04). In conclusion, CA of AF had a protective effect on renal function in patients with HCM.

Localization of Late Gadolinium Enhancement and Its Association with Ventricular Tachycardia in Patients with Cardiac Sarcoidosis.

Sustained ventricular tachycardia (sVT), leading to sudden cardiac death, is one of the common manifestations in cardiac sarcoidosis (CS). Although late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) has been reported to be associated with sVT, the relationships of its localization to sVT have not been fully evaluated.To evaluate the localization of LGE and its relationships to sVT in patients with CS, we reviewed medical record of consecutive 31 patients with CS who underwent CMR. The localization of LGE was divided into four categories: Left ventricular (LV) septum, LV free wall, right ventricular (RV) septum, and RV free wall. We investigated the association of sVT with localization of LGE and other parameters including serum biomarkers LV ejection fraction on echocardiography and Fluorine-18-fluorodeoxyglucose (FDG) accumulation on positron emission tomography (PET) -CT.Of the studied population, 8 patients (25.8%) were known to present with sVT among 31 CS patients. LGE was observed in the RV free wall in 6 patients with sVT, whereas it was in 5 patients without sVT (75.0% versus 21.7%, P = 0.022). Univariate analysis showed that only LGE in the RV free wall was associated with sVT (odds ratio [OR]: 10.80; 95% confidence interval [CI]: 1.64-70.93, P = 0.013).LGE in the RV free wall was associated with sVT in patients with CS.

Feasibility and safety of CT-aided pericardiocentesis from a subxiphoid anterior approach by using fluoroscopy in patients with chronic pericardial effusions.

BACKGROUND: Pericardiocentesis is an essential procedure for the diagnosis and treatment of pericardial effusions. The purpose of this study was to evaluate the feasibility and safety of a subxiphoid anterior approach using fluoroscopy aided by a sagittal axis chest computed tomography (CT) view in comparison with an ultrasound-guided apical approach in patients with chronic pericardial effusion. METHODS: Among 72 consecutive patients (68.8 ± 14.4 years old, 52 males) with hemodynamically stable chronic pericardial effusions, a total of 85 procedures were retrospectively analyzed. We divided them into two groups according to the site of the approach for the pericardiocentesis. RESULTS: A subxiphoid anterior approach (n = 53) was performed guided by fluoroscopy. The sagittal axis view of the chest CT was constructed to determine the puncture angle and direction for the subxiphoid anterior approach. An apical approach (n = 32) was performed by ultrasound guidance. The success rates of the anterior and apical approaches were 98.1% and 93.8%, respectively. There were two cases with cardiac perforations in the apical approach group, while no cases developed perforations in the subxiphoid anterior approach group. CONCLUSION: The subxiphoid anterior approach for pericardiocentesis was feasible and safe for managing chronic pericardial effusions. A reconstruction of the sagittal axis view of the chest CT imaging was helpful to identify the direction and depth to access the pericardial space from the subxiphoid puncture site before the pericardiocentesis using the lateral fluoroscopic view.

Long-Term Electrocardiographic Follow-Up of a Patient with Light-Chain Cardiac Amyloidosis.

Amyloid light-chain (AL) cardiac amyloidosis can cause restrictive cardiomyopathy, which has a poor prognosis. Although electrocardiography (ECG) is useful for its diagnosis and management, there are few reports on the long-term follow-up of electrocardiographic changes in affected patients. The present patient was a 62-year-old woman who visited our hospital for assessment of palpitations and lower leg edema. A chest radiograph showed cardiac enlargement, and ECG revealed sinus rhythm, first-degree atrioventricular block, low QRS voltage in the limb leads and a pseudo-myocardial infarction pattern in the precordial leads. Echocardiography revealed left ventricular hypertrophy with systolic and diastolic dysfunction. Immunoelectrophoresis demonstrated M-protein (IgGλ), and bone marrow biopsy suggested IgGλ-type plasmacytoma. Myocardial biopsy findings were compatible with cardiac amyloidosis. On the basis of these findings, we diagnosed AL cardiac amyloidosis. Melphalan-prednisolone (MP) therapy was started in conjunction with treatment for non-sustained ventricular tachycardia and congestive heart failure. Two years and 4 months later, the sinus rhythm converted to atrial tachycardia. At a follow-up examination at 4 years and 8 months, right branch block appeared. After that, intraventricular conduction worsened, and the low voltage in the limb leads was not observed. Seven years after diagnosis, she was hospitalized for treatment of pneumonia and heart failure with tachycardia. On the seventh day of hospitalization, heart rhythm changed to atrial stand-still with escaped ventricular rhythm and she died of cardiac arrest. These ECG changes are valuable information regarding the pathophysiological changes that occur in AL cardiac amyloidosis.

Perioperative coronary artery spasms in patients undergoing catheter ablation of atrial fibrillation.

PURPOSE: Catheter ablation (CA) is an established treatment for atrial fibrillation (AF). Although coronary artery spasms (CAS) during or after ablation procedures have been described as a rare complication in some case reports, the incidence and characteristics of this complication have not been fully elucidated. The present observational study aimed to clarify the CAS in a large number of patients experiencing AF ablation. METHODS: A total of 2913 consecutive patients (male: 78%, mean 66 ± 10 years) who underwent catheter ablation of AF were enrolled. RESULTS: Nine patients (0.31%, mean 66 ± 10 years, 7 males) had transient ST-T elevation (STE). Eight out of the 9 patients had STE in the inferior leads. STE occurred after the transseptal puncture in 7 patients, after the sheath was pulled out of the left atrium in 1, and 2 h after the ablation procedure in 1. Six patients had definite angiographic CAS without any sign of an air embolization on the emergent coronary angiography. In the3 other patients, the STE improved either directly after an infusion of nitroglycerin or spontaneously before the CAG. The patients with CAS had a higher frequency of a smoking habit (89% vs. 53%; P = .04), smaller left atrial diameter (36 ± 6 vs. 40 ± 7; P = .07), and lower CHADS2 score (0.6 ± 0.5 vs. 1.3 ± 1.1; P = .004) than those without. CONCLUSIONS: Although the incidence was rare (0.31%), CAS should be kept in mind as a potentially life-threatening complication throughout an AF ablation procedure especially performed under conscious sedation.

Metal interference alert guided septal approach with 3 catheter positions on intracardiac echocardiography for a near-zero fluoroscopy catheter ablation of atrial fibrillation.

BACKGROUND: Attempting to minimize radiation exposure during catheter ablation of atrial fibrillation (AF) for patients, operators and medical staffs should be performed. This study aimed to investigate the feasibility and safety of a metal interference alert guided septal approach using 3 intracardiac echocardiography viewing positions for near-zero fluoroscopy AF ablation procedures. METHODS/RESULTS: A total of 668 procedures among 608 consecutive patients with AF (67.2 ± 7.3 years, 408 males) who underwent catheter ablation were retrospectively evaluated and divided into 2 groups, near-zero group (n = 42) and conventional group (n = 595). In the near-zero group, a metal interference alert guided septal approach with 3 different catheter intracardiac echocardiography positions to minimize the fluoroscopy time was applied, and a left atrial access with 2 long sheaths from a single septal puncture without fluoroscopy was successfully achieved in 41 out of 42 cases. The total fluoroscopy time was significantly shorter in the near-zero group than that in the conventional group (0.5 ± 2.0 vs. 21.4 ± 12.9 min p < 0.0001). The total procedure time and time to the septal puncture were both significantly longer in the near-zero group than those in the conventional group (131.4 ± 40.2 vs. 116.6 ± 46.4p = 0.0453, 31.6 ± 9.2 vs. 19.9 ± 10.2 min, p < 0.0001), The ablation time did not differ between the 2 groups (Near-zero: 99.8 ± 41.0 vs. Conventional: 96.8 ± 44.3 min, p = 0.6663). There were no significant differences in the complication rate between the 2 groups (Near-zero: 0 vs. Conventional 14 case, p = 0.6151). CONCLUSION: A metal interference alert guided septal approach using 3 intracardiac echocardiography viewing positions was feasible and safe for a near-zero fluoroscopy catheter ablation of AF.

Differential diagnosis between LQT1 and LQT2 by QT/RR relationships using 24-hour Holter monitoring: A multicenter cross-sectional study.

BACKGROUND: The clinical course and therapeutic strategies in the congenital long QT syndrome (LQTS) are genotype-specific. However, accurate estimation of LQTS genotype is often difficult from the standard 12-lead ECG. OBJECTIVES: This study aims to evaluate the utility of QT/RR slope analysis by the 24-hour Holter monitoring for differential diagnosis of LQTS genotype between LQT1 and LQT2. METHODS: This cross-sectional study enrolled 54 genetically identified LQTS patients (29 LQT1 and 25 LQT2) recruited from three medical institutions. The QT-apex (QTa) interval and the QT-end (QTe) interval at each 15-second were plotted against the RR intervals, and the linear regression (QTa/RR and QTe/RR slopes, respectively) was calculated from the entire 24-hour and separately during the day or night-time periods of the Holter recordings. RESULTS: The QTe/RR and QTa/RR slopes at the entire 24-hour were significantly steeper in LQT2 compared to those in LQT1 patients (0.262 ± 0.063 vs. 0.204 ± 0.055, p = .0007; 0.233 ± 0.052 vs. 0.181 ± 0.040, p = .0002, respectively). The QTe interval was significantly longer, and QTe/RR and QTa/RR slopes at daytime were significantly steeper in LQT2 than in LQT1 patients. The receiver operating curve analysis revealed that the QTa/RR slope of 0.211 at the entire 24-hour Holter was the best cutoff value for differential diagnosis between LQT1 and LQT2 (sensitivity: 80.0%, specificity: 75.0%, and area under curve: 0.804 [95%CI = 0.68-0.93]). CONCLUSION: The continuous 24-hour QT/RR analysis using the Holter monitoring may be useful to predict the genotype of congenital LQTS, particularly for LQT1 and LQT2.