Introduction: We aimed to clarify the effect of vein of Marshall (VOM) ethanol infusion for treating VOM triggers and/or mitral flutter after first-attempt endocardial ablation in patients with nonparoxysmal atrial fibrillation (AF). Methods and Results:Of the 254 consecutive patients (age, 56 ± 10 years; 221 male) undergoing catheter ablation for drug-refractory nonparoxysmal AF, 32 (12.6%) received VOM ethanol infusion. The patients were stratified into group 1 (pulmonary vein isolation [PVI], substrate modification, VOM ethanol infusion), group 2 (PVI, substrate modification), and group 3 (PVI alone). Propensity-matched analysis (N = 128) of long-term outcomes (3.9 ± 0.5 years) revealed a higher AF recurrence risk in group 2 (hazard ratio [HR], 4.17; 95% confidence interval [95% CI], 1.63-10.69; P = .003) and group 3 (HR, 1.82; 95% CI, 1.09-3.04; P = .021) than in group 1, as well as a higher atrial arrhythmia recurrence risk in group 2 than in group 1 (HR, 2.42; 95% CI, 1.16-5.03; P = .018). A higher procedural termination rate was observed in group 1 than groups 2 and 3 (41.7% vs 17.2% vs 18.8%; P = .042). On multivariate analysis, VOM ethanol injection was an independent predictor of freedom from recurrence of AF (HR, 0.20; 95% CI, 0.08-0.52; P = .001) and atrial arrhythmia (HR, 0.35; 95% CI, 0.17-0.74; P = .005), whereas a left atrial diameter >45 mm and hypertension were independent risk factors for recurrence. Periprocedural complications rates were comparable among the groups.Conclusion: Adjunctive VOM ethanol infusion is effective and safe for treating nonparoxysmal AF in patients with VOM triggers and/or refractory mitral flutter, providing good long-term freedom from AF and atrial arrhythmia. K E Y W O R D S ablation, atrial arrhythmia, atrial fibrillation, ethanol infusion, recurrence, vein of Marshall

Background Acute failure of radiofrequency ablation (RFA) of ventricular arrhythmias (VAs) occur in 10%‐20% of patients and is partly attributed to inadequate lesion depth acquired with standard ablation protocols. Half‐normal saline (HNS)‐irrigation is a promising strategy to improve the success rate of VA ablation. Objective This study investigated the efficacy of HNS‐irrigated ablation after a failed standard plain normal saline solution (PNSS)‐irrigated ablation on idiopathic outflow tract ventricular arrhythmia (OT‐VA). Method This is a prospective observational study of consecutive patients undergoing RFA of idiopathic OT‐VA comparing the efficacy of additional HNS‐irrigated ablation for failed standard PNSS‐irrigated ablation. Acute failure was defined as persistence of spontaneous VA or persistent inducibility of the clinical VA. Results Out of 160 OT‐VA cases (51 ± 15‐year‐old, 62 males), 31 underwent HNS irrigation after a failed standard PNSS‐irrigated ablation. The HNS group had a significantly longer procedure time (60.06 ± 43.83 vs 37.51 ± 33.40 minutes; P = .013) and higher radiation exposure (31.45 ± 20.24 vs 17.22 ± 15.25 minutes; P = .001) than the PNSS group but provided an additional acute success in 21 of 31 (67.7%) patients. Over a follow‐up duration of 7.8 ± 4.6 months, 24 recurrences were identified, including 8 (25.8%) in the HNS and 16 (12.4%) in the PNSS group, with lower freedom from recurrence in the HNS group (log rank P = .009). No major complication was observed. Conclusion HNS‐irrigated ablation after failed standard PNSS‐irrigated ablation is safe and additionally improves acute ablation success by 67.7% for idiopathic OT‐VA but with a higher rate of recurrence on follow‐up. Whether the application of HNS as initial irrigant could result in better outcome requires further investigation.

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Background: The sinoatrial node (SAN) is characterized by the microenvironment of pacemaker cardiomyocytes (PCs) encased with fibroblasts. An altered microenvironment leads to rhythm failure. Operable cell or tissue models are either generally lacking or difficult to handle. The biological process behind the milieu of SANs to evoke pacemaker rhythm is unknown. We explored how fibroblasts interact with PCs and regulate metabolic reprogramming and rhythmic activity in the SAN. Methods: Tbx18 (T-box transcription factor 18)-induced PCs and fibroblasts were used for cocultures and engineered tissues, which were used as the in vitro models to explore how fibroblasts regulate the functional integrity of SANs. RNA-sequencing, metabolomics, and cellular and molecular techniques were applied to characterize the molecular signals underlying metabolic reprogramming and identify its critical regulators. These pathways were further validated in vivo in rodents and induced human pluripotent stem cell-derived cardiomyocytes. Results: We observed that rhythmicity in Tbx18-induced PCs was regulated by aerobic glycolysis. Fibroblasts critically activated metabolic reprogramming and aerobic glycolysis within PCs, and, therefore, regulated pacemaker activity in PCs. The metabolic reprogramming was attributed to the exclusive induction of Aldoc (aldolase c) within PCs after fibroblast-PC integration. Fibroblasts activated the integrin-dependent mitogen-activated protein kinase-E2F1 signal through cell-cell contact and turned on Aldoc expression in PCs. Interruption of fibroblast-PC interaction or Aldoc knockdown nullified electrical activity. Engineered Tbx18-PC tissue sheets were generated to recapitulate the microenvironment within SANs. Aldoc-driven rhythmic machinery could be replicated within tissue sheets. Similar machinery was faithfully validated in de novo PCs of adult mice and rats, and in human PCs derived from induced pluripotent stem cells. Conclusions: Fibroblasts drive Aldoc-mediated metabolic reprogramming and rhythmic regulation in SANs. This work details the cellular machinery behind the complex milieu of vertebrate SANs and opens a new direction for future therapy.