Abstract Background The genetic bases of cardiac conduction-system disease (CCSD) range from ion channelopathies to mutations in many other genes. Genome-wide association studies have shown common variants in SCN10A influence cardiac conduction. However, it has not yet to be determined whether vulnerability to CCSD is associated with rare coding sequence variation in the SCN10A gene. Purpose We sought to determine the clinical impact of rare variants in SCN10A in patients with CCSD and classified the variants according to the 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines. Methods We performed screening for rare variants (minor allele frequency ≤0.001) in SCN10A in CCSD patients with an onset at a young age under 65 or those who had a family history of pacemaker implantation (PMI) (n=40; 18 female; mean age, 41±18 years). We transiently expressed engineered variants in ND 7/23 cells, and conducted whole-cell voltage clamp experiments to clarify the functional properties of the Nav1.8 current. Results We identified nine rare variants in SCN10A in 7 patients. Two patients were carriers of two rare variants in SCN10A and 5 were carriers of one rare variant in SCN10A. Four patients were affected with sinus node dysfunction, 1 were atrioventricular block, and 2 were both dysfunctions. We performed electrophysiological study for 8 of 9 rare variants. It demonstrated that 2 rare variants showed gain-of-function, and 3 rare variants showed loss-of-function. We finally determined 5 likely pathogenic variants in SCN10A in 5 patients (12.5%) according to the ACMG standards and guidelines. All 5 patients underwent a pacemaker implantation at an average age of 43±16. Conclusions These results demonstrate that SCN10A variants play a pivotal role in enhanced susceptibility of CCSD. We suggest the importance for screening SCN10A variants in clinical settings. Funding Acknowledgement Type of funding source: None

Recent observational studies have suggested that catheter ablation for atrial fibrillation (AF) is significantly associated with reduced risk for stroke, cardiovascular events and all-cause death. However, little is known whether late recurrence of AF after catheter ablation is associated with worse clinical outcomes. We aimed to clarify whether late recurrence of AF after catheter ablation is associated with major adverse cardiac and cerebrovascular events (MACCE). We retrospectively investigated 2,737 participants (74.4% men, mean age 63.4±10.3 years, 62.7% paroxysmal AF) who received first catheter ablation for AF and completed follow-up more than 3 months after the procedure from AF Frontier Ablation Registry, a multicenter cohort study in Japan. We evaluated an association between late recurrence of AF after catheter ablation and first MACCE in cox-regression hazard models adjusted for known risk factors. MACCE were defined as stroke/transient ischemic attack (TIA), cardiovascular events or all-cause death. Late recurrence was defined as AF relapse more than 3 months after the procedure. During a mean follow-up period of 25.2 months, 2,070 patients (75.6%) were free from AF after catheter ablation and 122 patients (4.5%) had MACCE (ischemic stroke 18 [14.8%], hemorrhagic stroke 16 [13.1%], TIA 7 [5.7%], hospitalization for heart failure 19 [15.6%], acute coronary syndrome 19 [15.6%], hospitalization for other cardiovascular events 24 [20%] and all-cause death 19 [15.6%]). The MACCE occurred significantly more frequently in the recurrence group than in non-recurrence group (7.5% vs. 3.5%; hazard ratio [HR] 1.85; 95% confidence interval [CI] 1.28–2.65; P=0.001) (Figure). Multivariate analysis revealed that baseline age (HR 1.05; 95% CI 1.03–1.08; P<0.001), heart failure (HR 1.76; 95% CI 1.17–2.66; P=0.007), old myocardial infarction (HR 4.49; 95% CI 2.59–7.81; P<0.001), non-ischemic cardiomyopathy (HR 2.56; 95% CI 1.47–4.46; P=0.001), left atrial diameter (HR 1.22 per 5-mm increase; 95% CI, 1.06–1.41; P=0.006) and recurrence of AF (HR 1.69; 95% CI 1.17–2.44; P=0.005) were independently associated with the incidence of MACCE after catheter ablation. In the Japanese multicenter cohort of AF ablation, late recurrence of AF was independently associated with increased MACCE, suggesting the significance of sinus rhythm maintenance by catheter ablation. Kaplan-Meier curves for MACCE Type of funding source: None

Abstract Background High plasma B-Type natriuretic peptide (BNP) level is associated with cardiac events or stroke in patients with atrial fibrillation (AF). However, it is still unknown whether BNP predicts worse clinical outcomes after catheter ablation ofAF. Purpose We aimed to see if plasma BNP level is associated with major adverse cardiac and cerebrovascular events (MACCE) after catheter ablation of AF. Methods We retrospectively analyzed 1,853 participants (73.1% men, mean age 63.3±10.3 years, 60.7% paroxysmal AF) who received first catheter ablation of AF with pre-ablation plasma BNP level measurement and completed follow-up more than 3 months after the procedure from AF Frontier Ablation Registry, a multicenter cohort study in Japan. We evaluated an association between plasma BNP level before catheter ablation and first MACCE in cox-regression hazard models adjusted for known risk factors. MACCE were defined as stroke/transient ischemic attack (TIA), cardiovascular events or all-cause death. Results The mean plasma BNP level was 120.2±3.7 pg/mL. During a mean follow-up period of 21.9 months, 57 patients (3.1%) suffered MACCE (ischemic stroke 8 [14.0%], hemorrhagic stroke 5 [8.8%], TIA 5 [8.8%], hospitalization for heart failure 11 [19.2%], acute coronary syndrome 9 [15.8%], hospitalization for other cardiovascular events 8 [14.0%] and all-cause death 11 [19.2%]). Plasma BNP level of patients with MACCE were significantly higher than those without MACCE (291.7±47.0 vs 114.7±3.42 pg/mL, P<0.001). Multivariate analysis revealed that plasma BNP level (hazard ratio [HR] per 10 pg/mL increase 1.014; 95% confidence interval [CI] 1.005–1.023; P=0.001), baseline age (HR 1.052; 95% CI 1.022–1.084; P=0.001), heart failure (HR 2.698; 95% CI 1.512–4.815; P=0.001), old myocardial infarction (HR 3.593; 95% CI 1.675–7.708; P=0.001) and non-ischemic cardiomyopathy (HR 2.676; 95% CI 1.337 - 5.355; P=0.005) were independently associated with MACCE. At receiver-operating characteristic curve analysis, plasma BNP level before catheter ablation ≥162.7 pg/mL was the best threshold to predict MACCE (area under the curve: 0.71). Kaplan-Meier curve analysis (Figure) showed that the cumulative incidence of MACCE was significantly higher in patients with a BNP ≥162.7 pg/mL than in those with a BNP below 162.7 pg/mL (HR 4.85; 95% CI 2.86–8.21; P<0.001). Conclusions Elevation of plasma BNP level was independently related to the increased risk of MACCE after catheter ablation ofAF. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Bristol-Meiers Squibb