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Adverse structural and electrical remodeling underlie persistent atrial fibrillation (PersAF). Restoration of sinus rhythm (SR) prior to ablation in PersAF may improve the underlying substrate, thus improving arrhythmia outcomes. The aim of this study was to evaluate if the presence of SR at time of ablation is associated with improved long-term arrhythmia outcomes of a limited catheter ablation (CA) strategy in PersAF.Patients with PersAF undergoing pulmonary vein isolation at our institution from 2014-2018 were included. We compared patients who presented for ablation in SR (by cardioversion and/or antiarrhythmic drugs [AADs]) to those who presented in AF. Primary outcome of interest was freedom from atrial arrhythmias (AAs) on or off AADs at 1 year after single ablation. Secondary outcomes included freedom from AAs on or off AADs overall, freedom from AAs off AADs at 1 year, and time to recurrent AF.Five hundred seventeen patients were included (322 presented in AF, 195 SR). The primary outcome was higher in those who presented for CA in SR as compared to AF (85.6% vs. 77.0%, p = 0.017). Freedom from AAs off AAD at 12 months was also higher in those presenting in SR (59.0% vs. 44.4%; p = 0.001) and time to recurrent AF was longer (p = 0.008). Presence of SR at CA was independently associated with the primary outcome at 12 months (OR 1.77; 95% CI 1.08-2.90) and overall (OR 1.89; 95% CI 1.26-2.82).Presence of SR at time of ablation is associated with improved long-term arrhythmia outcomes of limited CA in PersAF.

IMPORTANCE: Autonomic neuromodulation provides therapeutic benefit in ventricular tachycardia (VT) storm. Transcutaneous magnetic stimulation (TcMS) can noninvasively and nondestructively modulate a patient’s nervous system activity and may reduce VT burden in patients with VT storm. OBJECTIVE: To evaluate the safety and efficacy of TcMS of the left stellate ganglion for patients with VT storm. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, sham-controlled randomized clinical trial took place at a single tertiary referral center between August 2019 and July 2021. The study included 26 adult patients with 3 or more episodes of VT in 24 hours. INTERVENTIONS: Patients were randomly assigned to receive a single session of either TcMS that targeted the left stellate ganglion (n = 14) or sham stimulation (n = 12). MAIN OUTCOMES AND MEASURES: The primary outcome was freedom from VT in the 24-hour period following randomization. Key secondary outcomes included safety of TcMS on cardiac implantable electronic devices, as well as burden of VT in the 72-hour period following randomization. RESULTS: Among 26 patients (mean [SD] age, 64 [13] years; 20 [77%] male), a mean (SD) of 12.7 (10.3) episodes of VT occurred within the 24 hours preceding randomization. Patients had recurrent VT despite taking a mean (SD) of 2.0 (0.6) antiarrhythmic drugs (AADs), and 11 patients (42%) required mechanical hemodynamic support at the time of randomization. In the 24-hour period after randomization, VT recurred in 4 of 14 patients (29% [SD 47%]) in the TcMS group vs 7 of 12 patients (58% [SD 51%]) in the sham group (P = .20). In the 72-hour period after randomization, patients in the TcMS group had a mean (SD) of 4.5 (7.2) episodes of VT vs 10.7 (13.8) in the sham group (incidence rate ratio, 0.42; P

Background Across complex traits, common variants explain only a modest amount of variance, with SNP-heritability consistently below heritability estimates from close relatives. Here, we examined the contribution of rare variant to tobacco use risk in up to 26,000 individuals of European ancestry in the Trans-Omics for Precision Medicine (TOPMed) program with whole genome sequence (WGS;~30X coverage).Method We grouped about 35 million genetic variants by their minor allele frequencies (MAF) and linkage disequilibrium (LD) and estimated SNP-heritability for age of smoking initiation (N = 14,747), cigarettes smoked per day (N = 15,425), smoking cessation (N = 17,871) and initiation (N = 26,340) using linear mixed model. Rare variant population structure is detected and adjusted for by permutation procedure. We estimated an upper bound for narrow-sense heritability for tobacco use using available pedigrees consisting of close relatives in TOPMed.Results Rare variants with MAF 0.1–0.01%, mostly from non-protein altering region, accounted for 26% of variation in age of initiation and 15% for cessation. Follow-up analysis indicated that about one-third of these rare variants contribtion is potentially confounded with rare variants structure even after adjusting for principal components. After further conservative adjustment of population structure, we estimated SNP-based heritability to be 0.21 (SE = 0.08) for age of initiation, 0.15 (0.06) for cigarettes per day, 0.21 (0.09) for cessation, and 0.24 (0.07) for initiation, 1.8–4.5 times higher than previous SNP-based estimates. Our pedigree-based upper-bound for SNP-based heritability ranged from 0.18–0.35.Conclusion The substantial contribution of rare variants for several smoking phenotypes sheds light on the missing heritability and genetic etiology of tobacco use. It also informs fine-mapping strategies since the majority of the rare variant contribution was located in non-coding regulatory regions.

The goal of this study was to characterize the relationship between DF, the electroanatomic mapping (EAM) substrate, and outcomes of catheter ablation of VT in NICM.A substantial proportion of patients with nonischemic dilated cardiomyopathy (NICM) and ventricular tachycardia (VT) do not have scar detectable by cardiac magnetic resonance late gadolinium enhancement (LGE) imaging. In these patients, the significance of diffuse fibrosis (DF) detected with TThis study included 51 patients with NICM and VT undergoing catheter ablation (median age 55 years; 77% male subjects) who had no evidence of LGE on pre-procedural cardiac magnetic resonance. Post-contrast TBipolar LVAs were present in 22 (43%) patients (median extent 15 cmIn patients with NICM and no evidence of LGE undergoing catheter ablation of VT, DF estimated by using post-contrast T

Atherosclerotic plaque rupture and thrombosis remains the leading cause of death in the United States. We investigated the role of CD39, a potent ecto-enzymatic regulator of platelet activation and leukocyte trafficking, in atherosclerosis. We generated mice deficient in CD39 on a hyperlipidemic, apoE -/- background and noted a two-fold higher plaque burden in when compared to apoE -/- controls ( P =0.003). We noted higher levels of circulating markers of platelet activation, soluble P-selectin (39%) and RANTES (60%), in the CD39-deficient mice ( P =0.003 and P =0.015, respectively, n=7-11). CD39-haploinsufficient mice had 1.8-fold greater enhanced platelet reactivity in response to ADP compared to controls ( P =0.03, n=3-8). Macrophages from CD39-deficient mice had significantly higher lipoprotein uptake in vitro . Correspondingly, CD39 overexpression in RAW cells inhibited scavenger receptor expression and lipoprotein uptake. Altered fluid mechanics contribute to atherosclerosis, with non-laminar shear stress enhancing regional plaque formation as seen in arterial bifurcations. We examined coronal sections of aortas from apoE −/− mice and observed that CD39 is poorly expressed in the endothelium in regions of turbulent blood flow, where plaque develops, supporting our hypothesis that endothelial CD39 can be induced by fluid phase shear forces. HUVEC treated with physiologic laminar shear stress (LS) (15 dynes/cm 2 ) had a 5.9-fold increase in CD39 protein ( P =0.004, N=3-7) and a concordant increase in nucleotidase activity ( P =0.03 N=3) compared to static controls (SS). We identified Krüppel like factor 2 (KLF2) as an upstream candidate for transcriptional regulation of CD39 induction by fluid shear forces. Silencing KLF2 in vitro led to a 55% decrease in CD39 mRNA induction with LS vs SS controls ( P =0.002, N=3-4). Chromatin immunoprecipitation revealed that KLF2 binds to the CD39 ( P =0.01, N=3) and this binding was further enhanced under laminar shear stress ( P =0.0007, N=3). These data show that CD39, an anti-thrombotic, anti-inflammatory enzyme is a critical regulator of atherosclerosis by modulating platelet, macrophage and endothelial function and mechanistically identify KLF2 as a direct, upstream regulator of CD39 expression.