Implantable loop recorders in patients with Brugada syndrome: the BruLoop study.

BACKGROUND AND AIMS: Available data on continuous rhythm monitoring by implantable loop recorders (ILRs) in patients with Brugada syndrome (BrS) are scarce. The aim of this multi-centre study was to evaluate the diagnostic yield and clinical implication of a continuous rhythm monitoring strategy by ILRs in a large cohort of BrS patients and to assess the precise arrhythmic cause of syncopal episodes. METHODS: A total of 370 patients with BrS and ILRs (mean age 43.5 ± 15.9, 33.8% female, 74.1% symptomatic) from 18 international centers were included. Patients were followed with continuous rhythm monitoring for a median follow-up of 3 years. RESULTS: During follow-up, an arrhythmic event was recorded in 30.7% of symptomatic patients [18.6% atrial arrhythmias (AAs), 10.2% bradyarrhythmias (BAs), and 7.3% ventricular arrhythmias (VAs)]. In patients with recurrent syncope, the aetiology was arrhythmic in 22.4% (59.3% BAs, 25.0% VAs, and 15.6% AAs). The ILR led to drug therapy initiation in 11.4%, ablation procedure in 10.9%, implantation of a pacemaker in 2.5%, and a cardioverter-defibrillator in 8%. At multivariate analysis, the presence of symptoms [hazard ratio (HR) 2.5, P = .001] and age >50 years (HR 1.7, P = .016) were independent predictors of arrhythmic events, while inducibility of ventricular fibrillation at the electrophysiological study (HR 9.0, P < .001) was a predictor of VAs. CONCLUSIONS: ILR detects arrhythmic events in nearly 30% of symptomatic BrS patients, leading to appropriate therapy in 70% of them. The most commonly detected arrhythmias are AAs and BAs, while VAs are detected only in 7% of cases. Symptom status can be used to guide ILR implantation.

A Clinical Diagnostic Test for Calcium Release Deficiency Syndrome.

Importance: Sudden death and cardiac arrest frequently occur without explanation, even after a thorough clinical evaluation. Calcium release deficiency syndrome (CRDS), a life-threatening genetic arrhythmia syndrome, is undetectable with standard testing and leads to unexplained cardiac arrest. Objective: To explore the cardiac repolarization response on an electrocardiogram after brief tachycardia and a pause as a clinical diagnostic test for CRDS. Design, Setting, and Participants: An international, multicenter, case-control study including individual cases of CRDS, 3 patient control groups (individuals with suspected supraventricular tachycardia; survivors of unexplained cardiac arrest [UCA]; and individuals with genotype-positive catecholaminergic polymorphic ventricular tachycardia [CPVT]), and genetic mouse models (CRDS, wild type, and CPVT were used to define the cellular mechanism) conducted at 10 centers in 7 countries. Patient tracings were recorded between June 2005 and December 2023, and the analyses were performed from April 2023 to December 2023. Intervention: Brief tachycardia and a subsequent pause (either spontaneous or mediated through cardiac pacing). Main Outcomes and Measures: Change in QT interval and change in T-wave amplitude (defined as the difference between their absolute values on the postpause sinus beat and the last beat prior to tachycardia). Results: Among 10 case patients with CRDS, 45 control patients with suspected supraventricular tachycardia, 10 control patients who experienced UCA, and 3 control patients with genotype-positive CPVT, the median change in T-wave amplitude on the postpause sinus beat (after brief ventricular tachycardia at ≥150 beats/min) was higher in patients with CRDS (P < .001). The smallest change in T-wave amplitude was 0.250 mV for a CRDS case patient compared with the largest change in T-wave amplitude of 0.160 mV for a control patient, indicating 100% discrimination. Although the median change in QT interval was longer in CRDS cases (P = .002), an overlap between the cases and controls was present. The genetic mouse models recapitulated the findings observed in humans and suggested the repolarization response was secondary to a pathologically large systolic release of calcium from the sarcoplasmic reticulum. Conclusions and Relevance: There is a unique repolarization response on an electrocardiogram after provocation with brief tachycardia and a subsequent pause in CRDS cases and mouse models, which is absent from the controls. If these findings are confirmed in larger studies, this easy to perform maneuver may serve as an effective clinical diagnostic test for CRDS and become an important part of the evaluation of cardiac arrest.

Microelectrode voltage mapping for substrate assessment in catheter ablation of ventricular tachycardia: A dual-center experience.

INTRODUCTION: The assessment of the ventricular myocardial substrate critically depends on the size of mapping electrodes, their orientation with respect to wavefront propagation, and interelectrode distance. We conducted a dual-center study to evaluate the impact of microelectrode mapping in patients undergoing catheter ablation (CA) of ventricular tachycardia (VT). METHODS: We included 21 consecutive patients (median age, 68 [12], 95% male) with structural heart disease undergoing CA for electrical storm (n = 14) or recurrent VT (n = 7) using the QDOT Micro catheter and a multipolar catheter (PentaRay, n = 9). The associations of peak-to-peak maximum standard bipolar (BVc ) and minibipolar (PentaRay, BVp ) with microbipolar (BVµMax ) voltages were respectively tested in sinus rhythm with mixed effect models. Furthermore, we compared the features of standard bipolar (BE) and microbipolar (µBE) electrograms in sinus rhythm at sites of termination with radiofrequency energy. RESULTS: BVµMax was moderately associated with both BVc (ß = .85, p < .01) and BVp (ß = .56, p < .01). BVµMax was 0.98 (95% CI: 0.93-1.04, p < .01) mV larger than corresponding BVc , and 0.27 (95% CI: 0.16-0.37, p < .01) mV larger than matching BVp in sinus rhythm, with higher percentage differences in low voltage regions, leading to smaller endocardial dense scar (2.3 [2.7] vs. 12.1 [17] cm2 , p < .01) and border zone (3.2 [7.4] vs. 4.8 [20.1] cm2 , p = .03) regions in microbipolar maps compared to standard bipolar maps. Late potentials areas were nonsignificantly greater in microelectrode maps, compared to standard electrode maps. At sites of VT termination (n = 14), µBE were of higher amplitude (0.9 [0.8] vs. 0.4 [0.2] mV, p < .01), longer duration (117 [66] vs. 74 [38] ms, p < .01), and with greater number of peaks (4 [2] vs. 2 [1], p < .01) in sinus rhythm compared to BE. CONCLUSION: microelectrode mapping is more sensitive than standard bipolar mapping in the identification of viable myocytes in SR, and may facilitate recognition of targets for CA.

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.

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.

Clinical characterization of the first Belgian SCN5A founder mutation cohort.

AIMS: We identified the first Belgian SCN5A founder mutation, c.4813 + 3_4813 + 6dupGGGT. To describe the clinical spectrum and disease severity associated with this mutation, clinical data of 101 SCN5A founder mutation carriers and 46 non-mutation carrying family members from 25 Belgian families were collected. METHODS AND RESULTS: The SCN5A founder mutation was confirmed by haplotype analysis. The clinical history and electrocardiographic parameters of the mutation carriers and their family members were gathered and compared. A cardiac electrical abnormality was observed in the majority (82%) of the mutation carriers. Cardiac conduction defects, defined as PR or QRS prolongation on electrocardiogram (ECG), were most frequent, occurring in 65% of the mutation carriers. Brugada syndrome (BrS) was the second most prevalent phenotype identified in 52%, followed by atrial dysrythmia in 11%. Overall, 33% of tested mutation carriers had a normal sodium channel blocker test. Negative tests were more common in family members distantly related to the proband. Overall, 23% of the mutation carriers were symptomatic, with 8% displaying major adverse events. As many as 13% of the patients tested with a sodium blocker developed ventricular arrhythmia. One family member who did not carry the founder mutation was diagnosed with BrS. CONCLUSION: The high prevalence of symptoms and sensitivity to sodium channel blockers in our founder population highlights the adverse effect of the founder mutation on cardiac conduction. The large phenotypical heterogeneity, variable penetrance, and even non-segregation suggest that other genetic (and environmental) factors modify the disease expression, severity, and outcome in these families.

Recommendations for participation in leisure-time physical activity and competitive sports of patients with arrhythmias and potentially arrhythmogenic conditions. Part 2: ventricular arrhythmias, channelopathies, and implantable defibrillators.

This paper belongs to a series of recommendation documents for participation in leisure-time physical activity and competitive sports by the European Association of Preventive Cardiology (EAPC). Together with an accompanying paper on supraventricular arrhythmias, this second text deals specifically with those participants in whom some form of ventricular rhythm disorder is documented, who are diagnosed with an inherited arrhythmogenic condition, and/or who have an implanted pacemaker or cardioverter defibrillator. A companion text on recommendations in athletes with supraventricular arrhythmias is published in the European Journal of Preventive Cardiology. Since both texts focus on arrhythmias, they are the result of a collaboration between EAPC and the European Heart Rhythm Association (EHRA). The documents provide a framework for evaluating eligibility to perform sports, based on three elements, i.e. the prognostic risk of the arrhythmias when performing sports, the symptomatic impact of arrhythmias while performing sports, and the potential progression of underlying structural problems as the result of sports.

iPSC-Cardiomyocyte Models of Brugada Syndrome-Achievements, Challenges and Future Perspectives.

Brugada syndrome (BrS) is an inherited cardiac arrhythmia that predisposes to ventricular fibrillation and sudden cardiac death. It originates from oligogenic alterations that affect cardiac ion channels or their accessory proteins. The main hurdle for the study of the functional effects of those variants is the need for a specific model that mimics the complex environment of human cardiomyocytes. Traditionally, animal models or transient heterologous expression systems are applied for electrophysiological investigations, each of these models having their limitations. The ability to create induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), providing a source of human patient-specific cells, offers new opportunities in the field of cardiac disease modelling. Contemporary iPSC-CMs constitute the best possible in vitro model to study complex cardiac arrhythmia syndromes such as BrS. To date, thirteen reports on iPSC-CM models for BrS have been published and with this review we provide an overview of the current findings, with a focus on the electrophysiological parameters. We also discuss the methods that are used for cell derivation and data acquisition. In the end, we critically evaluate the knowledge gained by the use of these iPSC-CM models and discuss challenges and future perspectives for iPSC-CMs in the study of BrS and other arrhythmias.

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.

Out-of-hospital cardiac arrest due to idiopathic ventricular fibrillation in patients with normal electrocardiograms: results from a multicentre long-term registry.

AIMS: To define the clinical characteristics and long-term clinical outcomes of a large cohort of patients with idiopathic ventricular fibrillation (IVF) and normal 12-lead electrocardiograms (ECGs). METHODS AND RESULTS: Patients with ventricular fibrillation as the presenting rhythm, normal baseline, and follow-up ECGs with no signs of cardiac channelopathy including early repolarization or atrioventricular conduction abnormalities, and without structural heart disease were included in a registry. A total of 245 patients (median age: 38 years; males 59%) were recruited from 25 centres. An implantable cardioverter-defibrillator (ICD) was implanted in 226 patients (92%), while 18 patients (8%) were treated with drug therapy only. Over a median follow-up of 63 months (interquartile range: 25-110 months), 12 patients died (5%); in four of them (1.6%) the lethal event was of cardiac origin. Patients treated with antiarrhythmic drugs only had a higher rate of cardiovascular death compared to patients who received an ICD (16% vs. 0.4%, P = 0.001). Fifty-two patients (21%) experienced an arrhythmic recurrence. Age ≤16 years at the time of the first ventricular arrhythmia was the only predictor of arrhythmic recurrence on multivariable analysis [hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.18-0.92; P = 0.03]. CONCLUSION: Patients with IVF and persistently normal ECGs frequently have arrhythmic recurrences, but a good prognosis when treated with an ICD. Children are a category of IVF patients at higher risk of arrhythmic recurrences.

Performant Mutation Identification Using Targeted Next-Generation Sequencing of 14 Thoracic Aortic Aneurysm Genes.

At least 14 causative genes have been identified for both syndromic and nonsyndromic forms of thoracic aortic aneurysm/dissection (TAA), an important cause of death in the industrialized world. Molecular confirmation of the diagnosis is increasingly important for gene-tailored patient management but consecutive, conventional molecular TAA gene screening is expensive and labor-intensive. To circumvent these problems, we developed a TAA gene panel for next-generation sequencing of 14 TAA genes. After validation, we applied the assay to 100 Marfan patients. We identified 90 FBN1 mutations, 44 of which were novel. In addition, Multiplex ligation-dependent probe amplification identified large deletions in six of the remaining samples, whereas false-negative results were excluded by Sanger sequencing of FBN1, TGFBR1, and TGFBR2 in the last four samples. Subsequently, we screened 55 syndromic and nonsyndromic TAA patients. We identified causal mutations in 15 patients (27%), one in each of the six following genes: ACTA2, COL3A1, TGFBR1, MYLK, SMAD3, SLC2A10 (homozygous), two in NOTCH1, and seven in FBN1. We conclude that our approach for TAA genetic testing overcomes the intrinsic hurdles of consecutive Sanger sequencing of all candidate genes and provides a powerful tool for the elaboration of clinical phenotypes assigned to different genes.

Phenotypic spectrum of the first Belgian MYBPC3 founder: a large multi-exon deletion with a varying phenotype.

Background: Variants in the MYBPC3 gene are a frequent cause of hypertrophic cardiomyopathy (HCM) but display a large phenotypic heterogeneity. Founder mutations are often believed to be more benign as they prevailed despite potential negative selection pressure. We detected a pathogenic variant in MYBPC3 (del exon 23-26) in several probands. We aimed to assess the presence of a common haplotype and to describe the cardiac characteristics, disease severity and long-term outcome of mutation carriers. Methods: Probands with HCM caused by a pathogenic deletion of exon 23-26 of MYBPC3 were identified through genetic screening using a gene panel encompassing 59 genes associated with cardiomyopathies in a single genetic center in Belgium. Cascade screening of first-degree relatives was performed, and genotype positive relatives were further phenotyped. Clinical characteristics were collected from probands and relatives. Cardiac outcomes included death, heart transplantation, life-threatening arrhythmia, heart failure hospitalization or septal reduction therapy. Haplotype analysis, using microsatellite markers surrounding MYBPC3, was performed in all index patients to identify a common haplotype. The age of the founder variant was estimated based on the size of the shared haplotype using a linkage-disequilibrium based approach. Results: We identified 24 probands with HCM harbouring the MYBPC3 exon 23-26 deletion. Probands were on average 51 ± 16 years old at time of clinical HCM diagnosis and 62 ± 10 years old at time of genetic diagnosis. A common haplotype of 1.19 Mb was identified in all 24 probands, with 19 of the probands sharing a 13.8 Mb haplotype. The founder event was estimated to have happened five generations, or 175-200 years ago, around the year 1830 in central Flanders. Through cascade screening, 59 first-degree relatives were genetically tested, of whom 37 (62.7%) were genotype positive (G+) and 22 (37.3%) genotype negative (G-). They were on average 38 ± 19 years old at time of genetic testing. Subsequent clinical assessment revealed a HCM phenotype in 19 (51.4%) G+ relatives. Probands were older (63 ± 10 vs. 42 ± 21 years; p < 0.001) and had more severe phenotypes than G+ family members, presenting with more symptoms (50% vs. 13.5%; p = 0.002), arrhythmia (41.7% vs. 12.9%, p = 0.014), more overt hypertrophy and left ventricular outflow tract obstruction (43.5% vs. 3.0%; p < 0.001). Male G+ relatives more often had a HCM phenotype (78.6% vs. 34.8%; p = 0.010) and were more severely affected than females. At the age of 50, a penetrance of 78.6% was observed, defined as the presence of HCM in 11 of 14 G+ relatives with age ≥50 years. Overall, 20.3% of all variant carriers developed one of the predefined cardiac outcomes after a median follow-up of 5.5 years with an average age of 50 (±21) years. Conclusion: A Belgian founder variant, an exon 23-26 deletion in MYBPC3, was identified in 24 probands and 37 family members. The variant is characterized by a high penetrance of 78.6% at the age of 50 years but has variable phenotypic expression. Adverse outcomes were observed in 20.3% of patients during follow-up.

Variants in structural cardiac genes in patients with cancer therapy-related cardiac dysfunction after anthracycline chemotherapy: a case control study.

BACKGROUND: Variants in cardiomyopathy genes have been identified in patients with cancer therapy-related cardiac dysfunction (CTRCD), suggesting a genetic predisposition for the development of CTRCD. The diagnostic yield of genetic testing in a CTRCD population compared to a cardiomyopathy patient cohort is not yet known and information on which genes should be assessed in this population is lacking. METHODS: We retrospectively included 46 cancer patients with a history of anthracycline induced CTRCD (defined as a decrease in left ventricular ejection fraction (LVEF) to < 50% and a ≥ 10% reduction from baseline by echocardiography). Genetic testing was performed for 59 established cardiomyopathy genes. Only variants of uncertain significance and (likely) pathogenic variants were included. Diagnostic yield of genetic testing was compared with a matched cohort of patients with dilated cardiomyopathy (DCM, n = 46) and a matched cohort of patients without cardiac disease (n = 111). RESULTS: Average LVEF at time of CTRCD diagnosis was 30.1 ± 11.0%. Patients were 52.9 ± 14.6 years old at time of diagnosis and 30 (65.2%) were female. Most patients were treated for breast cancer or lymphoma, with a median doxorubicin equivalent dose of 300 mg/m2 [112.5-540.0]. A genetic variant, either pathogenic, likely pathogenic or of uncertain significance, was identified in 29/46 (63.0%) of patients with CTRCD, which is similar to the DCM cohort (34/46, 73.9%, p = 0.262), but significantly higher than in the negative control cohort (47/111, 39.6%, p = 0.018). Variants in TTN were the most prevalent in the CTRCD cohort (43% of all variants). All (likely) pathogenic variants identified in the CTRCD cohort were truncating variants in TTN. There were no significant differences in severity of CTRCD and in recovery rate in variant-harbouring individuals versus non-variant harbouring individuals. CONCLUSIONS: In this case-control study, cancer patients with anthracycline-induced CTRCD have an increased burden of genetic variants in cardiomyopathy genes, similar to a DCM cohort. If validated in larger prospective studies, integration of genetic data in risk prediction models for CTRCD may guide cancer treatment. Moreover, genetic results have important clinical impact, both for the patient in the setting of precision medicine, as for the family members that will receive genetic counselling.

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.

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.

Clinical and functional characterisation of a recurrent KCNQ1 variant in the Belgian population.

BACKGROUND: The c.1124_1127delTTCA p.(Ile375Argfs*43) pathogenic variant is the most frequently identified molecular defect in the KCNQ1 gene in the cardiogenetics clinic of the Antwerp University Hospital. This variant was observed in nine families presenting with either Jervell-Lange-Nielsen syndrome or long QT syndrome (LQTS). Here, we report on the molecular, clinical and functional characterization of the KCNQ1 c.1124_1127delTTCA variant. RESULTS: Forty-one heterozygous variant harboring individuals demonstrated a predominantly mild clinical and electrophysiological phenotype, compared to individuals harboring other KCNQ1 pathogenic variants (5% symptomatic before 40 years of age, compared to 24% and 29% in p.(Tyr111Cys) and p.(Ala341Val) variant carriers, respectively, 33% with QTc ≤ 440 ms compared to 10% in p.(Tyr111Cys) and p.(Ala341Val) variant carriers). The LQTS phenotype was most comparable to that observed for the Swedish p.(Arg518*) founder mutation (7% symptomatic at any age, compared to 17% in p.(Arg518*) variant carriers, 33% with QTc ≤ 440 ms compared to 16% in p.(Arg518*) variant carriers). Surprisingly, short tandem repeat analysis did not reveal a common haplotype for all families. One KCNQ1 c.1124_1127delTTCA harboring patient was diagnosed with Brugada syndrome (BrS). The hypothesis of a LQTS/BrS overlap syndrome was supported by electrophysiological evidence for both loss-of-function and gain-of-function (acceleration of channel kinetics) in a heterologous expression system. However, BrS phenotypes were not identified in other affected individuals and allelic KCNQ1 expression testing in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) showed nonsense mediated decay of the c.1124_1127delTTCA allele. CONCLUSIONS: The c.1124_1127delTTCA frameshift variant shows a high prevalence in our region, despite not being confirmed as a founder mutation. This variant leads to a mild LQTS phenotype in the heterozygous state. Despite initial evidence for a gain-of-function effect based on in vitro electrophysiological assessment in CHO cells and expression of the KCNQ1 c.1124_1127delTTCA allele in patient blood cells, additional testing in iPSC-CMs showed lack of expression of the mutant allele. This suggests haploinsufficiency as the pathogenic mechanism. Nonetheless, as inter-individual differences in allele expression in (iPSC-) cardiomyocytes have not been assessed, a modifying effect on the BrS phenotype through potassium current modulation cannot be excluded.

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.

Variable clinical expression of a Belgian TGFB3 founder variant suggests the presence of a genetic modifier.

Background: TGFB3 variants cause Loeys-Dietz syndrome type 5, a syndromic form of thoracic aortic aneurysm and dissection. The exact disease phenotype is hard to delineate because of few identified cases and highly variable clinical representation. Methodology: We provide the results of a haplotype analysis and a medical record review of clinical features of 27 individuals from 5 different families, originating from the Campine region in Flanders, carrying the NM_003239.5(TGFB3):c.787G>C p.(Asp263His) likely pathogenic variant, dbSNP:rs796051886, ClinVar:203492. The Asp263 residue is essential for integrin binding to the Arg-Gly-Asp (RGD) motif of the TGFß3-cytokine. Results: The haplotype analysis revealed a shared haplotype of minimum 1.92 Mb and maximum 4.14 Mb, suggesting a common founder originating >400 years ago. Variable clinical features included connective tissue manifestations, non-aneurysmal cardiovascular problems such as hypertrophic cardiomyopathy, bicuspid aortic valve, mitral valve disease, and septal defects. Remarkably, only in 4 out of the 27 variant-harboring individuals, significant aortic involvement was observed. In one family, a 31-year-old male presented with type A dissection. In another family, the male proband (65 years) underwent a Bentall procedure because of bicuspid aortic valve insufficiency combined with sinus of Valsalva of 50 mm, while an 80-year-old male relative had an aortic diameter of 43 mm. In a third family, the father of the proband (75 years) presented with ascending aortic aneurysm (44 mm). Conclusion: The low penetrance (15%) of aortic aneurysm/dissection suggests that haploinsufficiency alone by the TGFB3 variant may not result in aneurysm development but that additional factors are required to provoke the aneurysm phenotype.