BACKGROUND: The variable loop circular catheter has been shown to be a safe, effective pulsed field ablation catheter for atrial fibrillation treatment. After the commercial launch of the initial waveform (Seq1), a new waveform (Seq2 30 mL/min ) was developed that reduces electrode surface temperature and ablation delivery time (20–3.8 seconds). This study compares the safety and efficacy of Seq1 versus Seq2 across 2 irrigation rates and 2 dosing conditions. METHODS: Twenty-four Yorkshire pigs were treated with pulsed field ablation using the variable loop circular catheter. Subjects were randomized into 3 pulse recipe/irrigation arms (Seq1 4 mL/min , Seq1 30 mL/min , and Seq 2 30 mL/min ). Each group was split into a 1× nominal and a 2×-dose group, resulting in 6 total study groups. Animals were monitored for 28±2 days postablation for follow-up remapping procedures before euthanization. Gross necropsy and histopathology were performed on day 28±2. RESULTS: In all groups, 100% acute and chronic pulmonary vein isolation effectiveness was observed, as indicated by transmural, circumferential, pulmonary vein lesions with no evidence of collateral injury. Transmurality in the left atrial appendage, LA roof, and posterior wall was 75% to 100% across all groups and absent at the mitral isthmus. No catheter thrombus/char was observed at Seq2 30 mL/min or Seq1 30 mL/min . With Seq1 4 mL/min , thrombus/char occurred in 25% (1×) and 100% (2×). Hemolysis and myocardial injury marker changes were similar between all groups, with a notable increase in the 2× groups. On echocardiography, Seq2 30 mL/min microbubbles were rated as few or none, while Seq1 4 mL/min and Seq1 30 mL/min were mostly rated moderate or shower. CONCLUSIONS: Consistently durable pulmonary vein isolation was observed across all groups, including Seq1 4 mL/min , Seq2 30 mL/min , and Seq1 30 mL/min across both dosing conditions. Seq2 30 mL/min was associated with a reduced ablation delivery time (3.8 seconds), zero catheter thrombus formation, and few microbubbles. Higher irrigation flow in Seq1 30 mL/min also mitigated catheter thrombus formation but did not reduce microbubble generation.
BACKGROUND: Type 2 long-QT syndrome results from KCNH2 -encoded Kv11.1 loss-of-function, but whether secondary inward-current dysfunction amplifies dysfunction remains unclear. METHODS: We characterized sodium ( SCN5A , I Na ) and L-type calcium channel ( CACNA1C , I Ca ) function in KCNH2-G604S and variant-corrected isogenic control induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). Whole-cell patch-clamp measured action potential duration at 90% repolarization (APD90), and potassium (I Kr ), sodium (I Na ), and calcium (I Ca, L ) currents. Fluo-4 imaging quantified calcium transients. A modified Kernik-Clancy iPSC-CM model incorporated experimentally measured persistent I Na,L and I Ca,L fractions and simulated isolated and combined current defects. RESULTS: KCNH2-G604S caused severe I Kr loss-of-function (72.5% reduction). APD90 was prolonged in G604S-iPSC-CMs (765±58 ms) compared with isogenic controls (368±37 ms; P <0.005), with early afterdepolarizations in 50% of G604S cells. Nifedipine, verapamil, and mexiletine successfully shortened APD90 and abolished early afterdepolarizations. Compared with isogenic control, I Na,L (0.60±0.1% versus 0.26±0.06%; P <0.01), persistent I Ca,L (2.88±0.55% versus 1.26±0.35%; P <0.05), and calcium transient decay times ( P <0.0001) were greater in G604S iPSC-CMs. Increased persistent I Ca,L was phenocopied by E-4031 in isogenic controls and reduced by nifedipine in G604S iPSC-CMs. In silico modeling revealed that the I Kr defect alone prolonged APD90 to only 620 ms. The addition of the observed I Na,L defect had a small additive effect (+20 ms); however, incorporating persistent I Ca,L synergistically extended APD90 to 758 ms, replicating the experimental phenotype. Flux dynamics analysis indicated that this persistent Ca 2+ entry suppresses the forward-mode sodium-calcium exchanger, forcing a compensatory reliance on sarcoplasmic-endoplasmic reticulum Ca-ATPase that primes for calcium instability. CONCLUSIONS: The KCNH2-G604S variant drives a severe multihit phenotype via primary I Kr loss-of-function and secondary state-dependent gain-of-function in persistent I Ca,L . These comprehensive validations demonstrate that the remodeled persistent I Ca,L acts as the essential amplifier driving extreme action potential duration prolongation and Ca 2+ mishandling.
BACKGROUND: Patients with nonischemic cardiomyopathy (NICM) and ventricular tachycardia are at increased risk for adverse HF outcomes, and abnormal left ventricular (LV) substrate identified by endocardial unipolar and bipolar low-voltage areas (LVAs) may aid in risk stratification. This study assessed the association of LV unipolar and bipolar LVAs with end-stage HF outcomes in patients with NICM undergoing ventricular tachycardia ablation. METHODS: Patients with NICM and LV ejection fraction (EF) <50% undergoing ventricular tachycardia ablation from 2019 to 2023 were included. Endocardial voltage mapping defined confluent (>2 cm 2 ) unipolar LVAs as <8.27 mV and bipolar LVAs as <1.5 mV during sinus or paced rhythm. End-stage HF outcomes included HF death, LV assist device implantation, or heart transplant. Multivariable Cox proportional hazards regression analysis assessed associations between unipolar/bipolar LVAs and end-stage HF outcomes. RESULTS: One hundred eleven patients with NICM (mean age, 64.6±9.8 years; 81.1% male; mean LVEF, 33.8±11.7%) were included. During a median follow-up of 28.1 months (interquartile range, 18–46), 28 (25.2%) patients experienced end-stage HF outcomes. Unipolar LVA (hazard ratio, 1.03 per 1% increase [95% CI, 1.01–1.05]; P =0.002) and LVEF (hazard ratio, 1.04 per 1% decrease [95% CI, 1.00–1.09]; P =0.03) were independently associated with higher end-stage HF risk, while bipolar LVA was not (hazard ratio, 0.98, 1% increase [95% CI, 0.96–1.01]; P =0.25). A 3-point risk score based on the Youden index, unipolar LVA ≥70% (2 points), 35% to 70% (1 point), and LVEF ≤25% (1 point), had 82.1% sensitivity and 77.1% specificity for predicting end-stage HF in scores ≥2. CONCLUSIONS: In patients with NICM undergoing ventricular tachycardia ablation, unipolar LVA and LVEF are independent predictors of end-stage HF outcomes. Integrating these predictors yields a prognostic score to identify patients at the highest risk of end-stage HF outcomes.
BACKGROUND: Pulsed field ablation is now widely used for atrial fibrillation (AF) ablation, but atrial tachyarrhythmia recurrence remains common and postablation risk tools are limited. We assessed whether a validated sinus‑rhythm artificial intelligence— enabled ECG AF probability score, and its early postablation change, predicts recurrence after pulsed field ablation. METHODS: We studied consecutive patients undergoing index pulsed field ablation across 3 Mayo Clinic sites (February 2024–March 2025) with ≥1 sinus‑rhythm ECG within 180 days preprocedure. Baseline artificial intelligence—enabled ECG AF score (range 0–1) was the mean across baseline ECGs. Recovery indices (RI30/60/90), defined as mean postprocedure artificial intelligence—enabled ECG score within days 1–30/60/90 minus baseline, predicted post‑blanking recurrence using corresponding 30‑, 60‑, and 90‑day blanking windows. The primary outcome was time to first documented AF/atrial flutter/atrial tachycardia episode >30 seconds, ascertained via clinic ECGs, ambulatory monitoring, and device interrogations. Cox regression adjusted for prespecified clinical and echocardiographic covariates assessed associations; Harrell C‑statistic quantified discrimination. RESULTS: Among 1052 patients (67±10 years; 33% women), median baseline score was 0.35; 320 (30%) recurred over 188 days. Higher baseline score independently predicted recurrence (hazard ratio per 0.1 increase, 1.08 [95% CI, 1.03–1.14]). Scores rose on day 0 after ablation, then declined over subsequent weeks, with persistently higher, less‑improving trajectories among patients who recurred (time×recurrence interaction P <0.001). Day 0 score was not independently associated with recurrence after adjustment. Attenuated early recovery (higher recovery index) was independently associated with recurrence, most robustly for RI-90 (hazard ratio per 0.1 increase, 1.15 [95% CI, 1.07–1.24]), and improved discrimination beyond baseline and covariates (C‑statistic, 0.63–0.67; ΔC=0.04). Findings were consistent in a historical thermal ablation cohort. CONCLUSIONS: Baseline and early postablation dynamics of a sinus‑rhythm artificial intelligence—enabled ECG AF probability score are associated with pulsed field ablation recurrence and may aid multivariable risk stratification; prospective validation is warranted.
