John D. Hummel

Background: Electrographic flow (EGF) mapping is an FDA 510(k)‐cleared method for visualizing atrial activation wavefronts in atrial fibrillation (AF). Its clinical efficacy in detecting AF sources was demonstrated in the FLOW‐AF randomized controlled trial, and the underlying machine learning strategy used to develop and refine EGF source detection has been recently detailed. However, EGF mapping metrics can also characterize other properties of atrial wavefront propagation—most notably Electrographic Flow Consistency (EGFC) as a measure of the health of the atrial substrate. Patients with low EGFC have been found to have recurrent AF more frequently than those with high EGFC. EGFC may therefore be additive to source presence to phenotype AF patients based on mechanism of disease and recurrence likelihood. Objectives: Present the EGFC‐based Kaplan–Meier curves for each study arm of FLOW‐AF and explore the clinical relevance of EGFC using prospective studies. Methods: Unipolar electrograms were recorded using 64‐electrode basket catheters in AF patients across three clinical trials. The EGF algorithm then processed these recordings to reconstruct wavefront propagation patterns. EGFC was quantified from the vector length at each point in space and averaged across spatial coordinates and mapping positions to determine the mean EGFC for each patient. As applicable, EGFC and related EGF map characteristics were compared with 12‐month freedom from AF, patient demographic factors, and bipolar voltage mapping data. Results: Primarily, mean biatrial EGFC < 0.62 was found to be the best metric at predicting recurrent AF in No Source and Treatment patients in FLOW‐AF: it had 86% ± 11% accuracy after fivefold cross‐validation. Among these patients, those with EGFC ≥ 0.62 had 6% recurrence vs. 51% recurrence in those with EGFC < 0.62; p < 0.001. Control patients with sources post‐procedure had 77% vs. 100% recurrence in respective EGFC groups; p = 0.032. Follow‐up analyses showed that EGFC dropped from 0.58 ± 0.15 to 0.51 ± 0.14 (paired p = 0.041) in a subgroup of patients who underwent repeat mapping 103 ± 22 days later, but it was not affected by pulmonary vein isolation (PVI) or source ablation (paired p > 0.30). It was also higher among de novo and paroxysmal AF patients than redo ( p = 0.043) and non‐paroxysmal AF patients ( p = 0.022), respectively. Among the group of patients with low EGFC and no sources post‐procedure, recurrent patients had increased EGFC spatial variability ( p = 0.026) and more near‐threshold sources with source activity ≥ 25% but < 26.5% ( p = 0.038). Lastly, EGFC was globally and locally correlated to bipolar voltage across multiple rhythms, atria, mapping software and analysis techniques ( p = 0.009). Conclusions: EGFC may provide insights on the substrate health of the patient and is predictive of recurrence likelihood. An understanding of EGFC may therefore increase mechanistic understanding of the progression and therapeutic strategies for AF ablation that can be tailored to the individual patient. Clinical Trial Registration: FLOW‐AF: NCT04473963; FLOW EVAL‐AF: NCT06260670; AF‐FLOW Global Registry: NCT05481359.

Aims: There is still conflicting evidence if women with persistent atrial fibrillation (AF) profit from a pulmonary vein isolation (PVI) plus strategy. We evaluated the efficacy of a spatio-temporal dispersion-targeted ablation strategy in women from the TAILORED-AF trial. Methods and results: In TAILORED-AF, 370 patients were randomised to either a personalised, artificial intelligence (AI)-guided tailored ablation or to PVI-only. AF substrate mapping data and 12-month ablation outcomes were compared between women and men. Overall, 21% patients were female (70.4 ± 6.9 vs. 64.5 ± 8.5 years for men, P < 0.001). While spatio-temporal dispersion extent was similar between groups, left atrial low-voltage surface area (<0.2 mV) was significantly larger in women (P < 0.01). In women, the single-procedure freedom from AF (76% vs. 50%, log-rank P < 0.001) and any atrial arrhythmia (56% vs. 38%, log-rank P < 0.05) were significantly superior to PVI alone with a tailored procedure. In the PVI-only group, the single-procedure freedom from AF (50% vs. 70%, log-rank P < 0.001) and any atrial arrhythmia (38% vs. 61%, log-rank P < 0.001) were significantly lower in women. After a tailored ablation, no significant differences were observed between women and men regarding freedom from AF (76% vs. 91%, log-rank P = 0.07) or any atrial arrhythmia (56% vs. 62%, log-rank P = 0.69) free survival. Conclusion: Compared to men, PVI-only in women with persistent AF leads to a significantly lower freedom from atrial arrhythmia. A personalised spatio-temporal dispersion-targeted ablation strategy led to a higher rate of freedom from any atrial arrhythmia than standard PVI after a single procedure in women and comparable outcomes between women and men. Registration identification: clinicaltrials.gov NCT04702451

Background: Pulmonary vein isolation (PVI) is the cornerstone therapy for symptomatic drug‐refractory atrial fibrillation yet is not curative in a large segment of patients. Focal and rotational drivers are proposed to be involved in atrial fibrillation mechanisms but their ablation has produced variable outcomes. REAFFIRM (The Randomized Evaluation of Atrial Fibrillation Treatment with Focal Impulse and Rotor Modulation Guided Procedures) trial (NCT‐02274857) objective was to compare the safety and effectiveness of conventional ablation with and without Focal Impulse and Rotor Modulated (FIRM) ablation, guided by global basket mapping, for the treatment of persistent atrial fibrillation. Methods: Three hundred seventy‐five patients were enrolled and randomized at 18 centers. The Intent‐to‐Treat population consisted of 350 patients (171 FIRM, 179 Conventional). Primary effectiveness was defined as single procedure freedom from atrial fibrillation/atrial tachycardia recurrence at 3 to 12 months post index procedure. Results: Three hundred twenty‐four patients completed the 12‐month follow‐up. Patients in the FIRM arm had a larger left atrium ( P P =0.09). Conclusions: Intention‐to‐treat analysis failed to provide evidence for the superiority of adding ablation of focal or rotational sites to conventional ablation. Registration: URL: https://clinicaltrials.gov ; Unique Identifier: NCT‐02274857.

BACKGROUND: Despite over a century of clinical electrocardiographic studies showing that women exhibit a faster resting heart rate (HR), the mechanisms underlying sex differences in HR remain unresolved. Moreover, inappropriate sinus tachycardia primarily affects women, whereas men are at a higher risk for conduction block and atrial fibrillation. We hypothesized that the sexual dimorphism of genes responsible for sinoatrial node (SAN) pacemaking and signaling pathways may contribute to the sex differences in HR and susceptibility to arrhythmias. METHODS: Human SAN central pacemaker and right atrial tissue were isolated from nondiseased ex vivo donor hearts. Gene expressions were quantified and validated using the transcriptomic panel and quantitative polymerase chain reaction. Gene set enrichment analysis, Ingenuity Pathway Analysis, and human-specific SAN models were utilized to define regulatory mechanisms and functional impacts of sex-biased gene transcription. RESULTS: We identified differentially expressed region- and sex-specific genes, with gene sets enriched in HR regulation (eg, TBX3 , HCN1 ) and metabolism (eg, ADIPOQ , LEP ) pathways in female SAN. In contrast, differential genes and gene sets involved in collagen biosynthetic processes, fibrogenesis (eg, EGR1 ), and immune response (eg, IL6 , CXCL8 ) pathways were enriched in males SAN and right atrial. Ingenuity Pathway Analysis predicted significant roles for TBX3 and estradiol in the sex-specific expression of genes involved in SAN function. Computational simulations showed that the sex-specific SAN differences in I _f (pacemaker current; HCN1 ) and I _Ca,L (L-type calcium current; CACNA1D ) can explain the faster HR in female SAN, with female SAN having a lower threshold for inappropriate sinus tachycardia, whereas male SAN are more vulnerable to sinus arrest. CONCLUSIONS: The human SAN exhibits region-specific sexual dimorphism in pacemaking gene sets. Higher expression of TBX3 and HCN1 in female SAN may underlie faster HR and increased susceptibility to inappropriate sinus tachycardia in women, whereas enriched gene sets related to inflammation and collagen biosynthesis in men may predispose them to conduction impairments and atrial fibrillation risk.

Background: There is a paucity of data regarding the optimal timing of left atrial appendage closure (LAAC) and whether scheduling delays increase the risk for adverse outcomes. Objectives: This study sought to assess the incidence and predictors of adverse events among patients awaiting LAAC. Methods: This single‐center retrospective study assessed all patients who underwent LAAC from January 2017 to March 2020. The primary study endpoints were the rate and characteristics of adverse events occurring from the time of initial shared decision to pursue LAAC until the time of LAAC. Adverse events were defined as clinically significant bleeding or anemia, thromboembolic complications, or death. Patients were censored after successful closure or the first adverse event. Results: Two hundred and sixty‐five patients underwent LAAC with demographics notable for age 73.5 ± 8.1 years, 98 (37%) females, left ventricular ejection fraction 52.3% ± 10.4%, CHA ₂ DS ₂ ‐VASc 4.8 ± 1.4, and HAS‐BLED 3.2 ± 1.2. Median time from shared decision to insurance approval and insurance approval to LAAC were 18 (IQR 28) and 44 (IQR 40) days, respectively. Seventeen (6%) patients suffered an adverse event, including 15 (88%) cases of bleeding or anemia and 2 (12%) cases of thromboembolism. Multivariate analysis demonstrated that increased time to LAAC (odds ratio [OR] 1.31, 95% confidence interval [CI] [1.15, 1.50], p < 0.001) and higher HAS‐BLED score (OR 1.67, CI [1.11, 2.59], p = 0.017) were associated with significantly increased risk for adverse events. Conclusion: Prolonged time to LAAC and higher HAS‐BLED score portend an increased risk for adverse events while awaiting LAAC. Expedited closure is warranted in high‐risk patients.

Introduction: Among patients with non‐valvular atrial fibrillation (AF) and percutaneous left atrial appendage closure (LAAC) undergoing direct current cardioversion (DCCV), the need for and use of LAA imaging and oral anticoagulation (OAC) is unclear.Objective: The purpose of this study is to evaluate the real‐world use of transesophageal echocardiography (TEE) or cardiac computed tomography angiography (CCTA) before DCCV and use of OAC pre‐ and post‐DCCV in patients with AF status post percutaneous LAAC.Methods: This retrospective single center study included all patients who underwent DCCV after percutaneous LAAC from 2016 to 2022. Key measures were completion of TEE or CCTA pre‐DCCV, OAC use pre‐ and post‐DCCV, incidence of left atrial thrombus (LAT) or device‐related thrombus (DRT), incidence of peri‐device leak (PDL), and DCCV‐related complications (stroke, systemic embolism, device embolization, major bleeding, or death) within 30 days.Results: A total of 76 patients with AF and LAAC underwent 122 cases of DCCV. LAAC consisted of 47 (62%), 28 (37%), and 1 (1%) case of Watchman 2.5, Watchman FLX, and Lariat, respectively. Among the 122 DCCV cases, 31 (25%) cases were identified as “non‐guideline based” due to: (1) no OAC for 3 weeks and no LAA imaging within 48 h before DCCV in 12 (10%) cases, (2) no OAC for 4 weeks following DCCV in 16 (13%) cases, or (3) both in 3 (2%) cases. Among the 70 (57%) cases that underwent TEE or CCTA before DCCV, 16 (23%) cases had a PDL with a mean size of 3.0 ± 1.1 mm, and 4 (6%) cases had a LAT/DRT on TEE resulting in cancellation. There were no DCCV‐related complications within 30 days.Discussion: There is a widely varied practice pattern of TEE, CCTA, and OAC use with DCCV after LAAC, with a 6% rate of LAT/DRT. LAA imaging before DCCV appears prudent in all cases, especially within 1 year of LAAC, to assess for device position, PDL, and LAT/DRT.