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.

Robustness and relevance of predictive score in sudden cardiac death for patients with Brugada syndrome.

AIMS: Risk stratification of sudden cardiac arrest (SCA) in Brugada syndrome (Brs) remains the main challenge for physicians. Several scores have been suggested to improve risk stratification but never replicated. We aim to investigate the accuracy of the Brs risk scores. METHODS AND RESULTS: A total of 1613 patients [mean age 45 ± 15 years, 69% male, 323 (20%) symptomatic] were prospectively enrolled from 1993 to 2016 in a multicentric database. All data described in the risk score were double reviewed for the study. Among them, all patients were evaluated with Shanghai score and 461 (29%) with Sieira score. After a mean follow-up of 6.5 ± 4.7 years, an arrhythmic event occurred in 75 (5%) patients including 16 SCA, 11 symptomatic ventricular arrhythmia, and 48 appropriate therapies. Predictive capacity of the Shanghai score (n = 1613) and the Sieira (n = 461) score was, respectively, estimated by an area under the curve of 0.73 (0.67-0.79) and 0.71 (0.61-0.81). Considering Sieira score, the event rate at 10 years was significantly higher with a score of 5 (26.4%) than with a score of 0 (0.9%) or 1 (1.1%) (P < 0.01). No statistical difference was found in intermediate-risk patients (score 2-4). The Shanghai score does not allow to better stratify the risk of SCA. CONCLUSIONS: In the largest cohort of Brs patient ever described, risk scores do not allow stratifying the risk of arrhythmic event in intermediate-risk patient.

Long-Term Follow-Up of Patients With Tetralogy of Fallot and Implantable Cardioverter Defibrillator: The DAI-T4F Nationwide Registry.

BACKGROUND: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease, and sudden cardiac death represents an important mode of death in these patients. Data evaluating the implantable cardioverter defibrillator (ICD) in this patient population remain scarce. METHODS: A Nationwide French Registry including all patients with tetralogy of Fallot with an ICD was initiated in 2010 by the French Institute of Health and Medical Research. The primary time to event end point was the time from ICD implantation to first appropriate ICD therapy. Secondary outcomes included ICD-related complications, heart transplantation, and death. Clinical events were centrally adjudicated by a blinded committee. RESULTS: A total of 165 patients (mean age, 42.2±13.3 years, 70.1% males) were included from 40 centers, including 104 (63.0%) in secondary prevention. During a median (interquartile range) follow-up of 6.8 (2.5-11.4) years, 78 (47.3%) patients received at least 1 appropriate ICD therapy. The annual incidence of the primary outcome was 10.5% (7.1% and 12.5% in primary and secondary prevention, respectively; P=0.03). Overall, 71 (43.0%) patients presented with at least 1 ICD complication, including inappropriate shocks in 42 (25.5%) patients and lead dysfunction in 36 (21.8%) patients. Among 61 (37.0%) patients in primary prevention, the annual rate of appropriate ICD therapies was 4.1%, 5.3%, 9.5%, and 13.3% in patients with, respectively, 0, 1, 2, or ≥3 guidelines-recommended risk factors. QRS fragmentation was the only independent predictor of appropriate ICD therapies (hazard ratio, 3.47 [95% CI, 1.19-10.11]), and its integration in a model with current criteria increased the 5-year time-dependent area under the curve from 0.68 to 0.81 (P=0.006). Patients with congestive heart failure or reduced left ventricular ejection fraction had a higher risk of nonarrhythmic death or heart transplantation (hazard ratio, 11.01 [95% CI, 2.96-40.95]). CONCLUSIONS: Patients with tetralogy of Fallot and an ICD experience high rates of appropriate therapies, including those implanted in primary prevention. The considerable long-term burden of ICD-related complications, however, underlines the need for careful candidate selection. A combination of easy-to-use criteria including QRS fragmentation might improve risk stratification. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03837574.

Age at diagnosis of Brugada syndrome: Influence on clinical characteristics and risk of arrhythmia.

BACKGROUND: Despite a strong genetic background, Brugada syndrome (BrS) mainly affects middle-age patients. Data are scarce in the youngest and oldest age groups. OBJECTIVE: The purpose of this study was to describe the clinical characteristics and variations in rhythmic risk in BrS patients according to age. METHODS: Consecutive BrS patients diagnosed in 15 French tertiary centers in France were enrolled from 1993 to 2016 and followed up prospectively. All of the clinical and ECG data were double reviewed. RESULTS: Among the 1613 patients enrolled (age 45 ± 15 years; 69% male), 3 groups were defined according to age (52 patients <17 years; 1285 between 17 and 59 years; and 276 >60 years). In the youngest patients, we identified more female gender (42%), diagnosis by familial screening (63%), previous sudden cardiac death (15%), SCN5A mutation (62%) sinus dysfunction (8%) and aVR sign (37%) (P <.001). The oldest patients had the same clinical characteristics except for gender (40% women; P <.001). During median follow-up of 5.5 [2.1, 10.0] years, 91 patients experienced an arrhythmic event, including 7 (13%) in the youngest patients, 80 (6%) in middle-age patients, and 4 (1%) in the oldest patients. Annual event rates were 2.1%, 1%, and 0.3%, respectively (P <.01). CONCLUSION: Age on diagnosis changes the clinical presentation of BrS. Although children are identified more during familial screening, they present the highest risk of sudden cardiac death, which is an argument for early and extensive familial screening. The oldest patients present the lowest risk of SCD.

Radiation exposure during cardiac device implantation: Lessons learned from a multicenter registry.

BACKGROUND: Little data are available about radiation exposure during cardiac electrical device implantation, and no dose reference levels have been published. This multicenter, prospective, observational study assesses patient and staff radiation exposure during cardiac device implantations, and aims at defining dose reference levels. METHODS: Patient demographic, procedural, and radiation data were obtained for 657 procedures from nine institutions. Physician and staff exposure were measured using real-time dosimeters worn beneath and above lead apron. Statistical analysis included fluoroscopy time (FT), dose-area product (DAP), and DAP adjusted for FT and body mass index. RESULTS: Pacemakers and cardioverter defibrillators were implanted in 481 and 176 patients, respectively. Of these, 152 were treated with cardiac resynchronization therapy (CRT). Median FTs were 837s (interquartile range [IQR]: 480-1323), 117s (IQR: 69-209), and 101s (IQR: 58-162), and median DAPs were 1410 (IQR: 807-2601), 150 (IQR: 72-338), and 129 (IQR: 72-332) cGy.cm² for biventricular, dual chamber, and ventricular device implantation, respectively. Dose reference levels correspond to the third quartile values. During CRT, higher exposure was observed with four X-ray systems than with the two newer and customizable ones (adjusted DAP of 0.90 [IQR: 0.26-1.01] and 0.29 [IQR: 0.23-0.39], respectively; P < .001). CONCLUSION: Based on real-life measurements, this multicenter registry provides dose reference levels and may help centers assess radiation exposure. Although biventricular device implantation was responsible for the highest radiation exposure, FT was meaningfully shortened compared to previously reported values. For a same FT, the use of new generators and custom settings has significantly reduced DAP.

Number of electrocardiogram leads in the diagnosis of spontaneous Brugada syndrome.

BACKGROUND: The recently recommended single lead-based criterion for the diagnosis of Brugada syndrome may lead to overdiagnosis of this disorder and overestimation of the risk of sudden cardiac death. AIM: To investigate the value of a single-lead diagnosis in patients with Brugada syndrome and a spontaneous type 1 electrocardiogram. METHODS: Consecutive patients with Brugada syndrome were included in a multicentre prospective registry; only those with a spontaneous type 1 electrocardiogram were enrolled. Clinical and electrocardiogram data were reviewed by two physicians blinded to the patients' clinical and genetic status. RESULTS: Among 1613 patients, 505 (31%) were enrolled (79% male; mean age 46±15 years). A spontaneous type 1 electrocardiogram pattern was found in one lead in 250 patients (group 1), in two leads in 227 patients (group 2) and in three leads in 27 patients (group 3). Groups were similar except for individuals in group 3, who presented more frequently a fragmented QRS complex, an early repolarization pattern and a prolonged Tpeak-Tend interval. After a mean follow-up of 6.4±4.7 years, ventricular arrhythmia, sudden cardiac death or implantable cardiac defibrillator shock occurred in 46 (9%) patients, without differences between groups. CONCLUSION: The prognosis of Brugada syndrome with a spontaneous type 1 electrocardiogram pattern does not appear to be affected by the number of leads required for the diagnosis.

The European Society of Cardiology Cardiac Resynchronization Therapy Survey II: A comparison of cardiac resynchronization therapy implantation practice in Europe and France.

BACKGROUND: The first European Cardiac Resynchronization Therapy (CRT) Survey, conducted in 2008-2009, showed considerable variations in guideline adherence and implantation practice. A second prospective survey (CRT Survey II) was then performed to describe contemporary clinical practice regarding CRT among 42 European countries. AIM: To compare the characteristics of French CRT recipients with the overall European population of CRT Survey II. METHODS: Demographic and procedural data from French centres recruiting all consecutive patients undergoing either de novo CRT implantation or an upgrade to a CRT system were collected and compared with data from the European population. RESULTS: A total of 11,088 patients were enrolled in CRT Survey II, 754 of whom were recruited in France. French patients were older (44.7% aged≥75 years vs 31.1% in the European group), had less severe heart failure symptoms, a higher baseline left ventricular ejection fraction and fewer co-morbidities. Additionally, French patients had a shorter intrinsic QRS duration (19.1% had a QRS<130ms vs 12.3% in the European cohort). Successful implantation rates were similar, but procedural and fluoroscopy times were shorter in France. French patients were more likely to receive a CRT pacemaker than European patients overall. Of note, antibiotic prophylaxis was reported to be administered less frequently in France, and a higher rate of early device-related infection was observed. Importantly, French patients were less likely to receive optimal drugs for treating heart failure at hospital discharge. CONCLUSION: This study highlights contemporary clinical practice in France, and describes substantial differences in patient selection, implantation procedure and outcomes compared with the other European countries participating in CRT Survey II.

Clinical presentation and follow-up of women affected by Brugada syndrome.

BACKGROUND: Studies in Brugada syndrome (BrS) have mainly consisted of men. OBJECTIVE: The purpose of this study was to describe the clinical characteristics and arrhythmic risk factors in BrS women. METHODS: Consecutive BrS patients were enrolled from 1993 and followed prospectively. RESULTS: Among 1613 patients, 494 were women (mean age 47 ± 16 years). Women were more frequently asymptomatic than men (423 [86%] vs 867 [77%], respectively; P = .001) and less frequently had a spontaneous ECG pattern (107 [22%] vs 398 [36%], respectively; P <.001). During median [25th, 75th percentile] follow-up of 57 [23, 118] vs 62 [22, 113] months (P = .65), arrhythmic events occurred in 12 women (2%) vs 79 men (7%) (P = .0005). Mean age at the first event was 48.6 ± 17.8 years for women vs 43 ± 14.2 years for men (P <.001). Gender was significantly related to cardiac events (hazard ratio [HR] 2.96; 95% confidence interval [CI] 1.6-5.4; P = .0005). In multivariate analysis, event predictors in women were index patient status (HR 10.15; 95% CI 1.7-61.4; P = .01), previous sudden cardiac death (HR 69.4; 95% CI 15-312.5; P <.0001), syncope (HR 6.8; 95% CI 1.4-34.5; P = .02), fragmented QRS (HR 20.2; 95% CI 1.8-228.9; P = .02), and QRS duration >120 ms (HR 4.7; 95% CI 1.2-19.5; P = .03). CONCLUSION: Women represent a lower-risk group than men among individuals with BrS. In asymptomatic women, fragmented QRS and QRS >120 ms seem to be the only event predictors.

Heart rate variability and repolarization characteristics in symptomatic and asymptomatic Brugada syndrome.

AIM: Modulation of ST-segment elevation (STE) and tachyarrhythmic events by the autonomic nervous system (ANS) has been reported in patients with Brugada syndrome (BS). This study examined and compared the autonomic characteristics and STE in symptomatic vs. asymptomatic patients with BS. METHODS AND RESULT: We studied 40 symptomatic and 78 asymptomatic patients (mean age = 46.1 ± 13.7 years; 88 men) who underwent 24 h, 12-lead electrocardiograms, and exercise and a head-up tilt tests. Heart rate variability was examined and STE was measured at 5 points between 100 and 140 ms after the onset of 1 min averaged QRS complexes, and the type 1 Brugada pattern was automatically identified. 'Type 1 Brugada burden' was the percentage of averaged type 1 complexes. All measurements were made over 24 h, and during day and night times. During daytime, the variation coefficients of standard deviation of normal-to-normal intervals were 39.0 ± 12.3 vs. 34.1 ± 14.5 ms (P< 0.05) and high frequency normalized units were 39.9 ± 16.9 vs. 33.9 ± 16.2% (P< 0.05) in symptomatic vs. asymptomatic patients, respectively. ST-segment elevation was similar in symptomatic and asymptomatic patients at all time points. The type 1 Brugada burden in V2 was 38.7 ± 33.6% in the symptomatic vs. 24.3 ± 35.2% in the asymptomatic sample, a statistically non-significant difference. CONCLUSION: This analysis of ANS did not identify sensitive predictors of arrhythmic events in patients with BS. We observed, however, greater fluctuations in sinus node response to ANS in symptomatic patients. The type 1 Brugada electrocardiographic pattern was not as reliable a predictor of arrhythmic risk as previously reported.

Early use of an implantable loop recorder in syncope evaluation: a randomized study in the context of the French healthcare system (FRESH study).

BACKGROUND: The role of implantable loop recorders (ILRs) in the evaluation strategy for recurrent syncope in France is limited by lack of knowledge of the cost. AIM: To compare a conventional evaluation strategy for syncope with the early use of an ILR in low-risk patients, in terms of diagnostic yield, cost and impact on quality of life (QoL). METHODS: National prospective randomized open-label multicenter study of patients with a single syncope (if severe and recent) or at least two syncopes in the past year. RESULTS: Seventy-eight patients (32 men) were randomized to the ILR strategy (ILR group, n=39) or the conventional evaluation strategy (CONV group, n=39): mean age 66.2±14.8 years; 4.3±6.4 previous syncopes. After 14 months of follow-up, a certain cause of syncope was established in 18 (46.2%) patients in the ILR group and two (5%) patients in the CONV group (P<0.001). Advanced cardiological tests were performed less frequently in the ILR group than in the CONV group (0.03±0.2 vs. 0.2±0.5 tests per patient; P=0.05). Patients in the ILR group were hospitalized for a non-significantly shorter period than patients in the CONV group (5.7±3.2 vs. 8.0±1.4 days). There was no difference between the two groups in terms of QoL main composite score. CONCLUSION: In patients with unexplained syncope, the early use of an ILR has a superior diagnostic yield compared with the conventional evaluation strategy, with lower healthcare-related costs.

A pacemaker transthoracic impedance sensor with an advanced algorithm to identify severe sleep apnea: the DREAM European study.

BACKGROUND: Sleep apnea (SA) is associated with cardiovascular diseases and is highly prevalent in patients with pacemakers (PMs). OBJECTIVE: To validate a transthoracic impedance sensor with an advanced algorithm (sleep apnea monitoring) for identifying severe SA. METHODS: Patients with indications for PM (VVI/DDD) were enrolled regardless of symptoms suggesting SA. Severe SA diagnosis was acknowledged when the full polysomnography gave an apnea-hypopnea index (PSG-AHI) of ≥30 events/h. The PSG-AHI was compared with the respiratory disturbance index evaluated by the SAM algorithm (SAM-RDI) compiled from the device during the same diagnosis night, and the performance of the device and the SAM algorithm was calculated to identify patients with severe SA. The agreement between methods was assessed by using Bland and Altman statistics. RESULTS: Forty patients (mean age 73.8 ± 19.1 years; 67.5% men; body mass index 27.7 ± 4.4 kg/m(2)) were included. Severe SA was diagnosed by PSG in 56% of the patients. We did not retrieve SAM-RDI data in 14% of the patients. An optimal cutoff value for the SAM-RDI at 20 events/h was obtained by a receiver operator characteristic curve analysis, which yielded a sensitivity of 88.9% (95% confidence interval [CI] 65.3%-98.6%), a positive predictive value of 88.9% (95% CI 65.3%-98.6%), and a specificity of 84.6% (95% CI 54.6%-98.1%) (n = 31). The Bland-Altman limits of agreement for PSG-AHI (in events per hour) were [-14.1 to 32.4]. CONCLUSION: The results suggest that an advanced algorithm using PM transthoracic impedance could be used to identify SA in patients with PMs outside the clinic or at home.

Are women with severely symptomatic brugada syndrome different from men?

UNLABELLED: Women with Brugada Syndrome. INTRODUCTION: Spontaneous type-1 ECG has been recognized as a risk factor for sudden cardiac death (SCD) in Brugada syndrome (BrS), but studied populations predominantly consisted of men. We sought to investigate whether a spontaneous type-1 ECG pattern was also associated in women with severely symptomatic BrS. Other known risk factors were also examined for gender specificity. METHODS: Patients with severely symptomatic BrS, defined as resuscitated SCD and/or appropriate implantable cardioverter-defibrillator (ICD) shock, were included from 11 European centers. Clinical data, investigation of family history, 12-lead ECG, and results of electrophysiological study (EPS) were collected. The average follow-up was 4 +/- 3 years. RESULTS: Fifty-eight patients fulfilled the inclusion criteria (mean age 47 +/- 11 years, 8 women). Thirty-six men (72%) but only two women (25%) had a spontaneous type-1 ECG at baseline (P = 0.02). Maximal ST elevation before or after drug challenge was 3.7 +/- 1.3 mm in men versus 2.4 +/- 0.7 mm in women (P = 0.007). The proportion of patients with a family history of SCD or an SCN5A mutation was not significantly different between both groups. Of those patients with high-risk BrS who underwent EPS, 76%(12/25) of men and 50%(2/4) of women had a positive study. CONCLUSION: In contrast to men, most women with BrS and resuscitated SCD or appropriate ICD shock do not have a spontaneous type-1 ECG pattern. In addition, the degree of ST elevation is less pronounced in women than men. While women represent a lower-risk group overall, risk factors established from a predominantly male population may not be helpful in identifying high-risk females.