Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome.

Mutations in the N-terminal WD40 domain of coatomer protein complex subunit α (COPA) cause a type I interferonopathy, typically characterized by alveolar hemorrhage, arthritis, and nephritis. We described 3 heterozygous mutations in the C-terminal domain (CTD) of COPA (p.C1013S, p.R1058C, and p.R1142X) in 6 children from 3 unrelated families with a similar syndrome of autoinflammation and autoimmunity. We showed that these CTD COPA mutations disrupt the integrity and the function of coat protein complex I (COPI). In COPAR1142X and COPAR1058C fibroblasts, we demonstrated that COPI dysfunction causes both an anterograde ER-to-Golgi and a retrograde Golgi-to-ER trafficking defect. The disturbed intracellular trafficking resulted in a cGAS/STING-dependent upregulation of the type I IFN signaling in patients and patient-derived cell lines, albeit through a distinct molecular mechanism in comparison with mutations in the WD40 domain of COPA. We showed that CTD COPA mutations induce an activation of ER stress and NF-κB signaling in patient-derived primary cell lines. These results demonstrate the importance of the integrity of the CTD of COPA for COPI function and homeostatic intracellular trafficking, essential to ER homeostasis. CTD COPA mutations result in disease by increased ER stress, disturbed intracellular transport, and increased proinflammatory signaling.

Atrial fibrillation cycle-length (AF-CL) inside the pulmonary veins predicts paroxysmal AF ablation success- the INDUCE-AF study.

BACKGROUND: A novel method to measure atrial fibrillation cycle length (AF-CL) was recently described, based on the average of 10 consecutive signals (FARS10). FARS10 accurately identified pulmonary vein isolation (PVI)-responders among patients with persistent AF. Whether this method is applicable to patients with paroxysmal AF is unknown. OBJECTIVE: The aim of this study is to evaluate the prognostic value of FARS10 measurements in patients with paroxysmal AF. METHODS AND RESULTS: We enrolled paroxysmal AF patients undergoing PVI in a prospective multicenter study. After AF induction with a standardized protocol, the AF-CL was measured using FARS-10 method. The primary endpoint was AF/AT-recurrence. One-hundred and four patients were included (61 ± 14 years, 25% females). After a mean follow-up of 12 ± 4 months, AF/AT recurrence rate was 20%. The fastest PV CL (fPV-CL) was independently associated with the primary endpoint at multivariate analysis (HR 1.02, p < 0.001). Every 10 ms increase in fPV-CL, AF recurrences increased by 20%. The value of 160 ms was found to be the optimal cut-off (specificity 81%, sensitivity 76%). Patients with fPV-CL < 160 ms experienced lower AF recurrences as compared to patients with fPV-CL > 160 ms (8% vs. 32% at 1 year; HR = 0.17, p < 0.001). Progression to persistent AF was observed in 13% of patients with fPV-CL > 160 ms. CONCLUSION: fPV-CL measured with the FARS-10 method accurately predicts PVI success in paroxysmal AF patients undergoing PVI. Patients with slow PV activity (fPV-CL > 160 ms) experience higher AF recurrence rate after PVI and more frequent progression to persistent AF. In 104 patients with paroxysmal atrial fibrillation (AF) undergoing AF ablation, AF was induced at the beginning of the procedure. Pulmonary vein activity was measured using FARS10 measurement (10 consecutive fastest atrial repetitive similar morphology signals). The value of 160 ms was found to be the best cut-off to discriminate outcomes. At 1-year follow-up, patients with fast veins (< 160 ms) experienced significantly fewer AF recurrences as compared to patients with slow veins (> 160 ms). PV activity measured with FARS10 method accurately discriminates pulmonary vein isolation responders, in patients with paroxysmal AF. ABBREVIATIONS: AF atrial fibrillation, AT atrial tachycardia, CL cycle length, FARS10: 10 consecutive fastest atrial repetitive similar morphology signal, fPV fastest pulmonary vein, HR hazard ratio, ms milliseconds.

Dynamic changes of left atrial substrate over time following pulmonary vein isolation: the Progress-AF study.

AIMS: Little is known about dynamic changes of the left atrial (LA) substrate over time in patients with atrial fibrillation (AF). This study aims to evaluate substrate changes following pulmonary vein isolation (PVI). METHODS AND RESULTS: In our prospective observational study, consecutive patients undergoing first PVI-only and redo ablation were included. High-density maps of the two procedures were compared. Progression or regression was diagnosed if a significant concordant decrease or increase in bipolar voltages in ≥2 segments was observed, respectively. In 28 patients (61.2 ± 9.5 years, 39% female, 53.5% persistent AF), 111.013 voltage points from 56 high-density LA maps (1.982 points/patient) were analysed. Comparing the high-density maps of the first and second procedures, in the progression group (17 patients, 61%), there was a decrease in global (-35%, P < 0.001) and all regional voltages. In the regression group (11 patients, 39%), there was an increase in global (+43%, P < 0.001) and regional voltages. Comparing the progression with the regression group, the area of low-voltage zone (LVZ) increased (+3.5 vs. -4.5 cm2, P < 0.001) and LA activation time prolonged (+8.0 vs. -9.1 ms, P = 0.005). Baseline clinical parameters did not predict progression or regression. In patients with substrate progression, pulmonary veins (PVs) were more frequently isolated (P = 0.02) and the AF pattern at recurrence was more frequently persistent (P = 0.005). CONCLUSION: Our study describes bidirectional dynamic properties of the LA substrate with concordant either progressive or regressive changes. Regression occurs with reduced AF burden after the first procedure, while progression is associated with persistent AF recurrence despite durable PV isolation. The dynamic nature of LA substrate poses questions about LVZ-based ablation strategies.

Gender-Related Differences in Atrial Substrate in Patients with Atrial Fibrillation.

Gender-related differences have been reported in patients who underwent pulmonary vein isolation (PVI). Atrial substrate plays a role in the outcomes after ablation but gender-related differences in atrial substrate have never been described in detail. We sought to analyze gender-related differences in atrial remodeling (spontaneous low-voltage zones [LVZs]) and their clinical relevance after PVI. We conducted a prospective multicenter study, including consecutive patients who underwent first PVI-only atrial fibrillation (AF) ablation. LVZs were analyzed on high-density electroanatomical maps collected with multipolar catheter, before PVI. In total, 262 patients (61 ± 11 years, 31% female, 50% persistent AF) were followed for 28 months. In women, LVZs were larger (10% vs 4% of left atrial surface [p <0.001]) and female gender was independently associated with fourfold higher risk of having advanced (LVZ > 15%) atrial remodeling (odds ratio 4.56, p <0.001). AF recurrence-free survival was not different between men and women (log-rank p = 0.2). Although LVZs were independently associated higher AF recurrences at multivariate analysis (hazard ratio [HR] 1.2, p = 0.038), female gender was not (HR 1.4, p = 0.211). Specifically, the LVZ cutoff to predict outcomes was different in men and women: >5% in men (HR 3.0, p <0.001), >15% in women (HR 2.7, p = 0.02). In conclusion, women have more widespread LVZ in all left atrial regions. Despite more extensive atrial remodeling, the AF recurrence rate is similar in men and women, and LVZs become prognostic in women only at high burden (>15%). LVZs seem to have a different prognostic role in men and women.

Inactivating TDP2 missense mutation in siblings with congenital abnormalities reminiscent of fanconi anemia.

Mutations in TDP2, encoding tyrosyl-DNA phosphodiesterase 2, have been associated with a syndromal form of autosomal recessive spinocerebellar ataxia, type 23 (SCAR23). This is a very rare and progressive neurodegenerative disorder described in only nine patients to date, and caused by splice site or nonsense mutations that result in greatly reduced or absent TDP2 protein. TDP2 is required for the rapid repair of DNA double-strand breaks induced by abortive DNA topoisomerase II (TOP2) activity, important for genetic stability in post-mitotic cells such as neurons. Here, we describe a sibship that is homozygous for the first TDP2 missense mutation (p.Glu152Lys) and which presents with clinical features overlapping both SCAR23 and Fanconi anemia (FA). We show that in contrast to previously reported SCAR23 patients, fibroblasts derived from the current patient retain significant levels of TDP2 protein. However, this protein is catalytically inactive, resulting in reduced rates of repair of TOP2-induced DNA double-strand breaks and cellular hypersensitivity to the TOP2 poison, etoposide. The TDP2-mutated patient-derived fibroblasts do not display increased chromosome breakage following treatment with DNA crosslinking agents, but both TDP2-mutated and FA cells exhibit increased chromosome breakage in response to etoposide. This suggests that the FA pathway is required in response to TOP2-induced DNA lesions, providing a possible explanation for the clinical overlap between FA and the current TDP2-mutated patients. When reviewing the relatively small number of patients with SCAR23 that have been reported, it is clear that the phenotype of such patients can extend beyond neurological features, indicating that the TDP2 protein influences not only neural homeostasis but also other tissues as well.

Left Bundle Branch Area Defibrillator (LBBAD): A First-in-Human Feasibility Study.

BACKGROUND: Left bundle branch area (LBBA) pacing is a promising pacing technique. LBBA implantable cardioverter-defibrillator (ICD) lead implantation reduces the number of leads in patients with both pacing and ICD indications, reducing cost and potentially increasing safety. LBBA positioning of ICD leads has not previously been described. OBJECTIVES: The goal of this study was to evaluate the safety and feasibility of implanting an LBBA ICD lead. METHODS: This prospective, single-center, feasibility study was conducted in patients with an ICD indication. LBBA ICD lead implantation was attempted. Acute pacing parameters and paced electrocardiography data were collected, and defibrillation testing was performed. RESULTS: LBBA defibrillator (LBBAD) implantation was attempted in 5 patients (mean age 57 ± 16.5 years; 20% female) and achieved in 3 (60%). Mean procedural and fluoroscopy duration were 170.0 ± 17.3 minutes and 28.8 ± 16.1 minutes, respectively. Left bundle capture was achieved in 2 patients (66%) and left septal capture in 1 patient. LBBA pacing exhibited a mean QRS duration and V6 R-wave peak time of 121.3 ± 8.3 milliseconds and 86.1 ± 10.0 milliseconds. In all 3 patients, defibrillation testing was successful with mean time to adequate shock delivery of 8.6 ± 2.6 seconds. Acute LBBA pacing threshold and R-wave amplitudes were 0.80 ± 0.60 V at 0.4 milliseconds and 7.0 ± 2.7 mV. No LBBA lead-related complications occurred. CONCLUSIONS: This first-in-human evaluation showed the feasibility of LBBAD implantation in a small cohort of patients. With current tools, implantation remains complex and time-consuming. Considering the feasibility reported and the potential benefits, further technological development in this field is warranted with evaluation of long-term safety and performance.

Conduction system pacing, a European survey: insights from clinical practice.

AIMS: The field of conduction system pacing (CSP) is evolving, and our aim was to obtain a contemporary picture of European CSP practice. METHODS AND RESULTS: A survey was devised by a European CSP Expert Group and sent electronically to cardiologists utilizing CSP. A total of 284 physicians were invited to contribute of which 171 physicians (60.2%; 85% electrophysiologists) responded. Most (77%) had experience with both His-bundle pacing (HBP) and left bundle branch area pacing (LBBAP). Pacing indications ranked highest for CSP were atrioventricular block (irrespective of left ventricular ejection fraction) and when coronary sinus lead implantation failed. For patients with left bundle branch block (LBBB) and heart failure (HF), conventional biventricular pacing remained first-line treatment. For most indications, operators preferred LBBAP over HBP as a first-line approach. When HBP was attempted as an initial approach, reasons reported for transitioning to utilizing LBBAP were: (i) high threshold (reported as >2 V at 1 ms), (ii) failure to reverse bundle branch block, or (iii) > 30 min attempting to implant at His-bundle sites. Backup right ventricular lead use for HBP was low (median 20%) and predominated in pace-and-ablate scenarios. Twelve-lead electrocardiogram assessment was deemed highly important during follow-up. This, coupled with limitations from current capture management algorithms, limits remote monitoring for CSP patients. CONCLUSIONS: This survey provides a snapshot of CSP implementation in Europe. Currently, CSP is predominantly used for bradycardia indications. For HF patients with LBBB, most operators reserve CSP for biventricular implant failures. Left bundle branch area pacing ostensibly has practical advantages over HBP and is therefore preferred by many operators. Practical limitations remain, and large randomized clinical trial data are currently lacking.

Anterior mitral line in patients with persistent atrial fibrillation and anterior scar: A multicenter matched comparison-The MiLine study.

BACKGROUND: The benefit of an anterior mitral line (AML) in patients with persistent atrial fibrillation (AF) and anterior atrial scar undergoing ablation has never been investigated. OBJECTIVE: The purpose of this study was to evaluate the outcomes of AML in addition to standard treatment compared to standard treatment alone (no AML) in this subset of patients. METHODS: Patients with persistent AF and anterior low-voltage zone (LVZ) treated with AML in 3 centers were retrospectively enrolled. The patients were matched in 1:1 fashion with patients having persistent AF and anterior LVZ who underwent conventional ablation in the same centers. Matching parameters were age, LVZ burden, and repeated ablation. Primary endpoint was AF/atrial tachycardia (AT) recurrence. RESULTS: One hundred eight-six patients (age 66 ± 9 years; 34% women) were selected and divided into 2 matched groups. Bidirectional conduction block was achieved in 95% of AML. After median follow-up of 2 years, AF/AT recurrence occurred in 29% of the patients in the AML group vs 48% in the no AML group (log-rank P = .024). On Cox regression multivariate analysis, left atrial volume (hazard ratio [HR] 1.03; P = .006) and AML (HR 0.46; P = .003) were significantly associated with the primary endpoint. On univariate logistic regression, lower body mass index, older age, extensive anterior LVZ, and position of the left atrial activation breakthrough away from the AML were associated with first-pass AML block. CONCLUSION: In this retrospective matched analysis of patients with persistent AF and anterior scar, AML in addition to standard treatment was associated with improved AF/AT-free survival compared to standard treatment alone.

Characterization of Atrial Substrate to Predict the Success of Pulmonary Vein Isolation: The Prospective, Multicenter MASH-AF II (Multipolar Atrial Substrate High Density Mapping in Atrial Fibrillation) Study.

Background Left atrial substrate may have mechanistic relevance for ablation of atrial fibrillation (AF). We sought to analyze the relationship between low-voltage zones (LVZs), transition zones, and AF recurrence in patients undergoing pulmonary vein isolation. Methods and Results We conducted a prospective multicenter study on consecutive patients undergoing pulmonary vein isolation-only approach. LVZs and transition zones (0.5-1 mV) were analyzed offline on high-density electroanatomical maps collected before pulmonary vein isolation. Overall, 262 patients (61±11 years, 31% female) with paroxysmal (130 pts) or persistent (132 pts) AF were included. After 28 months of follow-up, 73 (28%) patients experienced recurrence. An extension of more than 5% LVZ in paroxysmal AF and more than 15% in persistent AF was associated with recurrence (hazard ratio [HR], 4.4 [95% CI, 2.0-9.8], P<0.001 and HR, 1.9 [95% CI, 1.1-3.7], P=0.04, respectively). Significant association was found between LVZs and transition zones and between LVZs and left atrial volume index (LAVI) (both P<0.001). Thirty percent of patients had significantly increased LAVI without LVZs. Eight percent of patients had LVZs despite normal LAVI. Older age, female sex, oncological history, and increased AF recurrence characterized the latter subgroup. Conclusions In patients undergoing first pulmonary vein isolation, the impact of LVZs on outcomes occurs with lower burden in paroxysmal than persistent AF, suggesting that not all LVZs have equal prognostic implications. A proportional area of moderately decreased voltages accompanies LVZs, suggesting a continuous substrate instead of the dichotomous division of healthy or diseased tissue. LAVI generally correlates with LVZs, but a small subgroup of patients may present with disproportionate atrial remodeling, despite normal LAVI.

Electrocardiographic phenotype of exercise-induced arrhythmogenic cardiomyopathy: A retrospective observational study.

Introduction: The right ventricle can be susceptible to pathologic alterations with exercise. This can cause changes to the ECG. Our aim was to identify the electrocardiographic phenotype of exercise induced (ExI) arrhythmogenic cardiomyopathy (ACM). Methods: A retrospective analysis of ECGs at rest, peak exercise and 1 min of recovery in four groups of individuals was performed: Arrhythmogenic Cardiomyopathy with genetic confirmation (Gen-ACM; n = 16), (genetically negative) ExI-ACM (n = 15), control endurance athletes (End; n = 16) and sedentary individuals (Sed; n = 16). The occurrence of ventricular arrhythmias (VA) and, at each stage, QRS duration, Terminal Activation Delay (TAD), the ratio of the sum of the QRS durations in the right precordials (V1-V3) over that in the left precordials (V4-V6; R/L duration ratio), the presence of complete RBBB and T-wave inversion (TWI) beyond lead V2 were evaluated. Results: At rest, complete RBBB was exclusively found in Gen-ACM (6%) and ExI-ACM (13%). No epsilon waves were identified. TWI beyond V2 was uniquely present in Gen-ACM (73%) and ExI-ACM (38%; p < 0.001). VA was present in Gen-ACM (88%); ExI-ACM (80%), End (25%) and Sed (19%; p < 0.001). The presence of R/L duration ratio of >1.2 and TAD ≥ 55 ms were not significantly different over the four groups (p = 0.584 and p = 0.218, respectively). At peak exercise the most striking finding was a significant decrease of the R/L duration ratio in individuals with ACM, which was the result of lateral precordial QRS prolongation. Conclusion: ExI-ACM shares important ECG-features with Gen-ACM, suggesting a similar underlying pathogenesis regardless of the presence or absence of desmosomal mutations.

Left bundle branch area pacing outcomes: the multicentre European MELOS study.

AIMS: Permanent transseptal left bundle branch area pacing (LBBAP) is a promising new pacing method for both bradyarrhythmia and heart failure indications. However, data regarding safety, feasibility and capture type are limited to relatively small, usually single centre studies. In this large multicentre international collaboration, outcomes of LBBAP were evaluated. METHODS AND RESULTS: This is a registry-based observational study that included patients in whom LBBAP device implantation was attempted at 14 European centres, for any indication. The study comprised 2533 patients (mean age 73.9 years, female 57.6%, heart failure 27.5%). LBBAP lead implantation success rate for bradyarrhythmia and heart failure indications was 92.4% and 82.2%, respectively. The learning curve was steepest for the initial 110 cases and plateaued after 250 cases. Independent predictors of LBBAP lead implantation failure were heart failure, broad baseline QRS and left ventricular end-diastolic diameter. The predominant LBBAP capture type was left bundle fascicular capture (69.5%), followed by left ventricular septal capture (21.5%) and proximal left bundle branch capture (9%). Capture threshold (0.77 V) and sensing (10.6 mV) were stable during mean follow-up of 6.4 months. The complication rate was 11.7%. Complications specific to the ventricular transseptal route of the pacing lead occurred in 209 patients (8.3%). CONCLUSIONS: LBBAP is feasible as a primary pacing technique for both bradyarrhythmia and heart failure indications. Success rate in heart failure patients and safety need to be improved. For wider use of LBBAP, randomized trials are necessary to assess clinical outcomes.

Rescue left bundle branch area pacing in coronary venous lead failure or nonresponse to biventricular pacing: Results from International LBBAP Collaborative Study Group.

BACKGROUND: Cardiac resynchronization therapy (CRT) using biventricular pacing (BVP) is effective in patients with heart failure, left bundle branch block (LBBB), and reduced left ventricular function. Left bundle branch area pacing (LBBAP) has been reported as an alternative option for CRT. OBJECTIVE: The purpose of this study was to assess the feasibility and outcomes of LBBAP in patients who failed conventional BVP because of coronary venous (CV) lead complications or who were nonresponders to BVP. METHODS: At 16 international centers, LBBAP was attempted in patients with conventional CRT indication who failed BVP because of CV lead complications or lack of therapeutic response to BVP. Heart failure hospitalization (HFH) and death, echocardiographic outcomes, procedural data, pacing parameters, and lead complications including CV lead failure are reported. RESULTS: LBBAP was successfully performed in 200 patients (CV lead failures 156; nonresponders 44) (age 68 ± 11 years; female 35%; LBBB 55%; right ventricular pacing 23%; ischemic cardiomyopathy 28%; nonischemic cardiomyopathy 63%; left ventricular ejection fraction [LVEF] ≤35% in 80%). Procedural duration was 119.5 ± 59.6 minutes, and fluoroscopy duration was 25.7 ± 18.5 minutes. LBBAP threshold and R-wave amplitudes were 0.68 ± 0.35 V @ 0.45 ms and 10.4 ± 5 mV at implant, respectively, and remained stable during mean follow-up of 12 ± 10.1 months. LBBAP resulted in significant QRS narrowing from 170 ± 28 ms to 139 ± 25 ms (P <.001) with V6 R-wave peak times of 85 ± 17 ms. LVEF improved from 29% ± 10% at baseline to 40% ± 12% (P <.001) during follow-up. The risk of death or HFH was lower in those with CV lead failure than in nonresponders (hazard ratio 0.357; 95% confidence interval 0.168-0.756; P = .007) CONCLUSION: LBBAP is a viable alternative to CRT in patients who failed conventional BVP due to CV lead failure or who were nonresponders.

A new prediction model for left ventricular systolic function recovery after catheter ablation of atrial fibrillation in patients with heart failure: The ANTWOORD Study.

BACKGROUND: in patients with heart failure (HF) and atrial fibrillation (AF), AF ablation improves left ventricular ejection fraction (LVEF), along with prognosis, in a variable percentage of patients. We aimed to investigate the predictors of LVEF recovery after AF ablation and to develop a prediction model for individualized assessment. METHODS: we conducted an observational, retrospective, single-centre study on 111 consecutive patients with AF and HF with impaired LVEF (<50%) undergoing ablation. Patients were divided into Responder vs. Non-Responder according to the "Universal definition of HF". Clinical predictors were evaluated by multivariate logistic regression analysis and cross-validation technique. Independent predictors were used to build an internally validated prediction model. RESULTS: Responders (54%) had significantly shorter QRS duration and less dilated left atrium. Persistent AF and absence of a known etiology were more frequent among Responders. AF recurrence was similar between the two groups (p = 0.2), but the percentage of patient with persistent AF after ablation was significantly lower among Responders (p < 0.001). Absence of known etiology, presence of persistent AF, left atrial volume index<50 mL/m2, and QRS < 120 msec were independent predictors of LVEF recovery and composed the Score (AUC 0.93;95%CI 0.88-0.98-p < 0.001). Patients with Score ≤ 1 had 90% likelihood of LVEF recovery, compared to 5% in patients with 3-6. CONCLUSIONS: Patients with wide QRS, known HF etiology, dilated left atrium, and paroxysmal AF were less likely to recover LVEF after AF ablation. A new score system based on the above-mentioned parameters adequately predicts LVEF recovery after AF ablation. These results warrant confirmation and prospective validation.

Reproducibility and predictive value of a simple novel method to measure atrial fibrillation cycle length in persistent atrial fibrillation - FARS-AF study.

INTRODUCTION: Different methods are used for atrial fibrillation (AF) cycle length (CL) measurement with variable results. Previous studies of pulmonary vein (PV) CL measurement showed contradictory results on predicting PV isolation (PVI) efficacy. A novel simple method of measuring the average of 10 consecutive Fastest Atrial Repetitive Similar morphology signal (FARS10 )-CL to characterize local atrial activity rate was evaluated prospectively. METHODS: The intra-observer reproducibility of FARS10 -CL and traditional AF-CL measurement of continuously fragmented coronary sinus (CS) signals were tested. We prospectively enrolled 100 consecutive patients (62 ± 10 years, 72% male) undergoing wide antral PVI only ablation for persistent AF, measured PV-FARS10 -CLs, and evaluated long-term outcome. RESULTS: The Kendall area correlation between repeated traditional AF-CL measurements was -0.006 and between repeated FARS10 -CL measurements in the right and left atrial appendages, CS and PVs were 0.944, 0.859, 0.882, 0.675-0.955, respectively. Patients with recurrent atrial tachyarrhythmia had significantly longer fastest PV-FARS10 -CL (172 ± 41 vs. 156 ± 41 ms, p = .047). Patients with high burden of spontaneous low-voltage zone (LVZ) had significantly longer fastest PV-FARS10 -CL. Freedom from recurrent tachyarrhythmia at 24 months was 85% versus 59% in patients with fastest PV-FARS10 -CL ≤ 140 versus >140 ms, p = .0018, respectively. In multivariable analysis fastest PV-FARS10 -CL ≤ 140 ms was the only significant predictor of freedom from recurrent tachyarrhythmia. CONCLUSIONS: FARS10 -CL measurements have a high reproducibility in contrast to traditional AF-CL measurement of continuously fragmented CS signals. Patients with high burden of LVZ have longer fastest PV-FARS10 -CLs. Fastest PV-FARS10 -CL ≤ 140 ms is associated with a high success of wide antral PVI-only ablation approach in persistent AF.

Left bundle branch-optimized cardiac resynchronization therapy (LOT-CRT): Results from an international LBBAP collaborative study group.

BACKGROUND: Cardiac resynchronization therapy (CRT) based on the conventional biventricular pacing (BiV-CRT) technique sometimes results in broad QRS complex and suboptimal response. OBJECTIVE: We aimed to assess the feasibility and outcomes of CRT based on left bundle branch area pacing (LBBAP, in lieu of the right ventricular lead) combined with coronary venous left ventricular pacing in an international multicenter study. METHODS: LBBAP-optimized CRT (LOT-CRT) was attempted in nonconsecutive patients with CRT indications. Addition of the LBBA (or coronary venous) lead was at the discretion of the implanting physician, who was guided by suboptimal paced QRS complex, and/or on clinical grounds. RESULTS: LOT-CRT was successful in 91 of 112 patients (81%). The baseline characteristics were as follows: mean age 70 ± 11 years, female 22 (20%), left ventricular ejection fraction 28.7% ± 9.8%, left ventricular end-diastolic diameter 62 ± 9 mm, N-terminal pro-B-type natriuretic peptide level 5821 ± 8193 pg/mL, left bundle branch block 47 (42%), nonspecific intraventricular conduction delay 25 (22%), right ventricular pacing 26 (23%), and right bundle branch block 14 (12%). The procedure characteristics were as follows: mean fluoroscopy time 27.3 ± 22 minutes, LBBAP capture threshold 0.8 ± 0.5 V @ 0.5 ms, and R-wave amplitude 10 mV. LOT-CRT resulted in significantly greater narrowing of QRS complex from 182 ± 25 ms at baseline to 144 ± 22 ms (P < .0001) than did BiV-CRT (170 ± 30 ms; P < .0001) and LBBAP (162 ± 23 ms; P < .0001). At follow-up of ≥3 months, the ejection fraction improved to 37% ± 12%, left ventricular end-diastolic diameter decreased to 59 ± 9 mm, N-terminal pro-B-type natriuretic peptide level decreased to 2514 ± 3537 pg/mL, pacing parameters were stable, and clinical improvement was noted in 76% of patients (New York Heart Association class 2.9 vs 1.9). CONCLUSION: LOT-CRT is feasible and safe and provides greater electrical resynchronization as compared with BiV-CRT and could be an alternative, especially when only suboptimal electrical resynchronization is obtained with BiV-CRT. Randomized controlled trials comparing LOT-CRT and BiV-CRT are needed.

Etiology and Outcome of Catheter Ablation in Patients With Onset of Atrial Fibrillation <45 Years of Age.

Etiologic factors and long-term outcomes of catheter ablation of atrial fibrillation (AF) in young patients have not been well characterized. This study aimed to analyze the etiologic factors and outcomes of pulmonary vein isolation (PVI) in patients with young-onset AF (young-AF, defined as having first documented episode <45 years). Consecutive patients with young-AF undergoing PVI (n = 197) in 2 academic centers were enrolled and followed for 36.1 ± 24.5 months. A control group of patients with AF onset ≥45 years (n = 554) was included. The most frequent risk factors in young-AF were intensive exercise (25%), moderate-to-heavy alcohol consumption (23%), and familial AF (22%). Compared with patients with AF onset ≥45-year, patients with young-AF were more often men (82% vs 66%, p <0.001), had more frequently paroxysmal AF (81% vs 60%, p <0.001), had less left atrial dilatation (40.9 ± 6.2 mm vs 44.2 ± 7.2 mm, p <0.001), and had lower 4-year recurrence rate after last PVI procedure (22% vs 45%, p <0.001). In young-AF, structural heart disease (SHD) was the only independent predictor of recurrence. Patients with young-AF selected to undergo cryoballoon (CB) ablation were younger (35.0 ± 7.7 vs 36.6 ± 6.7 years, p = 0.035) and had less persistent AF (6% vs 24%, p = 0.004) and coronary artery disease (2% vs 7%, p = 0.02) compared with radiofrequency ablation. After excluding patients with persistent AF and SHD, there was no difference in single procedural success between radiofrequency or CB PVI (27% vs 17%, p = 0.11). In conclusion, patients with young-AF have diverse etiologies and high single and multiprocedural PVI successes. SHD is the only independent predictor of recurrence. In patients with young-AF, there is a selection bias for CB ablation.

Intensive recreational athletes in the prospective multinational ICD Sports Safety Registry: Results from the European cohort.

BACKGROUND: In the ICD Sports Safety Registry, death, arrhythmia- or shock-related physical injury did not occur in athletes who continue competitive sports after implantable cardioverter-defibrillator (ICD) implantation. However, data from non-competitive ICD recipients is lacking. This report describes arrhythmic events and lead performance in intensive recreational athletes with ICDs enrolled in the European recreational arm of the Registry, and compares their outcome with those of the competitive athletes in the Registry. METHODS: The Registry recruited 317 competitive athletes ≥ 18 years old, receiving an ICD for primary or secondary prevention (234 US; 83 non-US). In Europe, Israel and Australia only, an additional cohort of 80 'auto-competitive' recreational athletes was also included, engaged in intense physical activity on a regular basis (≥2×/week and/or ≥ 2 h/week) with the explicit aim to improve their physical performance limits. Athletes were followed for a median of 44 and 49 months, respectively. ICD shock data and clinical outcomes were adjudicated by three electrophysiologists. RESULTS: Compared with competitive athletes, recreational athletes were older (median 44 vs. 37 years; p = 0.0004), more frequently men (79% vs. 68%; p = 0.06), with less idiopathic ventricular fibrillation or catecholaminergic polymorphic ventricular tachycardia (1.3% vs. 15.4%), less congenital heart disease (1.3% vs. 6.9%) and more arrhythmogenic right ventricular cardiomyopathy (23.8% vs. 13.6%) ( p < 0.001). They more often had a prophylactic ICD implant (51.4% vs. 26.9%; p < 0.0001) or were given a beta-blocker (95% vs. 65%; p < 0.0001). Left ventricular ejection fraction, ICD rate cut-off and time from implant were similar. Recreational athletes performed fewer hours of sports per week (median 4.5 vs. 6 h; p = 0.0004) and fewer participated in sports with burst-performances ( vs. endurance) as their main sports: 4% vs. 65% ( p < 0.0001). None of the athletes in either group died, required external resuscitation or was injured due to arrhythmia or shock. Freedom from definite or probable lead malfunction was similar (5-year 97% vs. 96%; 10-year 93% vs. 91%). Recreational athletes received fewer total shocks (13.8% vs. 26.5%, p = 0.01) due to fewer inappropriate shocks (2.5% vs. 12%; p = 0.01). The proportion receiving appropriate shocks was similar (12.5% vs. 15.5%, p = 0.51). Recreational athletes received fewer total (6.3% vs. 20.2%; p = 0.003), appropriate (3.8% vs. 11.4%; p = 0.06) and inappropriate (2.5% vs. 9.5%; p = 0.04) shocks during physical activity. Ventricular tachycardia/fibrillation storms during physical activity occurred in 0/80 recreational vs. 7/317 competitive athletes. Appropriate shocks during physical activity were related to underlying disease ( p = 0.004) and competitive versus recreational sports ( p = 0.004), but there was no relation with age, gender, type of indication, beta-blocker use or burst/endurance sports. The proportion of athletes who stopped sports due to shocks was similar (3.8% vs. 7.5%, p = 0.32). CONCLUSIONS: Participants in recreational sports had less frequent appropriate and inappropriate shocks during physical activity than participants in competitive sports. Shocks did not cause death or injury. Recreational athletes with ICDs can engage in sports without severe adverse outcomes unless other reasons preclude continuation.

Differential presentation of atrioventricular nodal re-entrant tachycardia in athletes and non-athletes.

AIMS: Prolonged participation in exercise results in structural and electrical cardiac remodelling. The development of an athlete's heart is recognized as a risk factor for atrial arrhythmias. This study aims to evaluate the impact of athlete heart remodelling on the presentation of atrioventricular nodal re-entrant tachycardia (AVNRT). METHODS AND RESULTS: A retrospective analysis of an ablation database selecting all patients with an electrophysiologically confirmed diagnosis of AVNRT. Athletes (individuals participating in moderate to intensive sports for ≥3 h per week having done so for ≥5 years) were compared with healthy non-athletes. Atrioventricular nodal re-entrant tachycardia subforms were classified according the methods described by Katritsis and Josephson in 2013 and by Heidbuchel and Jackman in 2014. A total of 504 AVNRT patients were fully characterized, of whom 85 (17%) were athletes. Almost half of the athletes presented with atypical forms of AVNRT, where in non-athletes this frequency was about 20%. There was no difference in acute procedural success among the two groups, but the procedures in athletes were more complex, as reflected by an almost two-fold increase in the use of a long sheath to reach the slow pathway ablation area and a higher recurrence rate in athletes (10% vs. 4%). CONCLUSION: Athletes present more frequently with atypical subforms of AVNRT. This is possibly related to cardiac remodelling with dilatation of the cardiac cavities leading to changed conduction properties in the septal area. Ablation outcome is equally safe in athletes as in non-athletes with similar acute success rates. Athletes experience a higher longer-term recurrence rate.

Less Pulmonary Vein Reconnection at Redo Procedures Following Radiofrequency Point-by-Point Antral Pulmonary Vein Isolation With the Use of Contemporary Catheter Ablation Technologies.

OBJECTIVES: This study investigated whether real-world use of contemporary technologies changed pulmonary vein (PV) reconnection and redo pulmonary vein isolation (PVI) procedure frequencies. BACKGROUND: Previous studies consistently reported that following PVI recurrence of PV conduction is observed in >80% of patients. METHODS: Consecutive patients undergoing 529 first and/or redo radiofrequency point-by-point PVI between January 2013 and December 2016 were included. RESULTS: Between 2013 and 2016, redo PVI rate in atrial fibrillation significantly decreased (p < 0.001); in ≤12 months, first redo PVI rate decreased from 19% to 4%. The percentage of patients having PV reconnection at second PVI significantly decreased from 90% to 29% (p = 0.001). One PVI was performed in 393 and >1 in 79 patients. Female sex was associated with >1 PVI (hazard ratio [HR]: 1.86; 95% confidence interval [CI]: 1.10 to 3.13; p = 0.02). Sixty patients underwent first and second PVI in the study period. Female sex (HR: 2.79; 95% CI: 1.67 to 4.64; p < 0.001) and left atrial diameter (HR: 1.05; 95% CI: 1.01 to 1.08; p = 0.01) were associated with more and use of automatic ablation annotation algorithm during first PVI with fewer (HR: 0.54; 95% CI: 0.32 to 0.92; p = 0.02) redo PVI procedures. In 31 of 60 patients, ≥1 PV was reconnected at second PVI. The need for "touch-up" applications at the first PVI was the only predictor of PV reconnection. CONCLUSIONS: Redo rate in atrial fibrillation and PV reconnection at redo PVI significantly decreased in recent years. Male sex, left atrial diameter, and use of automatic ablation annotation algorithm at first PVI were associated with fewer redo procedures. First-pass isolation was associated with lower PV reconnection rate at second procedure. Female sex was associated with more redo procedures but not higher PV reconnection frequencies.

Undersensing of ventricular fibrillation due to interference between a pacemaker and defibrillator in the same patient.

Sensing in pacemakers (PMs) and implantable cardioverter defibrillators (ICDs) is crucial to normal device behaviour. Since both devices treat different arrhythmias, the technical approach to signal detection is also completely different. A PM has a fixed threshold of sensing, above which events are sensed and therapy of the device withheld. On the other hand, the defibrillator has a variable threshold of sensing to detect tachyarrhythmias, with sometimes very small and changing electrogram amplitudes. In this case report, we describe interference between a PM and an ICD caused by these differences in the detection of cardiac events, leading to undersensing of ventricular fibrillation at defibrillation threshold testing.