JACC: Clinical Electrophysiology

Background: Pulsed-field ablation (PFA) systems increasingly provide impedance-based contact indicators, such as tissue proximity indication (TPI), derived from local impedance changes relative to a blood-pool baseline. These indicators are largely binary and do not quantify post-application catheter?tissue energy coupling. We evaluated Bipolar Local Impedance Delta (BiLID), the peri-application bipolar local impedance drop, as a complementary impedance-based index of delivered energy coupling. Methods: We retrospectively analyzed 1,556 VARIPULSE applications in 23 patients undergoing pulmonary vein isolation. BiLID was derived from 29,822 paired pre-/post-ablation impedance measurements obtained from numeric local impedance readouts displayed by the mapping system, without proprietary data export or waveform estimation. Reproducibility was assessed by intraclass correlation. Associations with TPI status, vein anatomy, application order, and peak creatine kinase-MB (CK-MB) were examined using linear mixed-effects models with within-patient clustering and exploratory patient-level analyses. Results: BiLID showed excellent interobserver reproducibility and increased stepwise with the number of TPI-positive electrodes per pair (0?2; P < 0.0001), while varying widely among TPI-positive signals. BiLID differed by electrode position and was lower during right than left pulmonary vein ablation (both P < 0.0001). Total BiLID correlated with peak CK-MB (r = 0.71; 95% CI, 0.42?0.87; P = 0.0001), whereas application count (r = 0.16, P = 0.4711) and TPI-positive signals (r = 0.26, P = 0.2334) did not. Lower CK-MB elevation was associated with larger left atrial volume index, female sex, and heart failure, suggesting substrate-modulated biomarker release. Conclusions: BiLID is a reproducible, continuous index of catheter?tissue energy coupling that complements pre-delivery binary contact indicators by quantifying the response after PFA delivery. It captures graded contact quality and anatomical heterogeneity and may inform individualized, coupling-guided PFA titration.

Background: Three pulsed-field ablation (PFA) systems are FDA-approved for atrial fibrillation (AF), yet whether their safety profiles differ from each other and from radiofrequency (RF) ablation has not been systematically characterized using real-world adverse event data. We compared platform-specific complication profiles across three FDA-approved PFA systems and contemporary RF catheters in MAUDE. Methods: We analyzed 2,262 manually adjudicated MAUDE adverse event reports (760 PFA, 1,502 RF) through July 2025. Neurologic events underwent independent adjudication into five tiers by three auditors. Disproportionality was assessed using Reporting Odds Ratios (ROR) with Benjamini-Hochberg (BH) correction. Results: Pooled PFA had significantly lower BH-adjusted ROR for tamponade (0.52, 95% CI 0.41-0.67) and esophageal injury (0.09, 0.01-0.66), consistent with a tissue-selective reporting profile across platforms. Platform-level analysis, however, revealed substantial heterogeneity: the stroke signal was driven by Varipulse (ROR 16.41, 8.61-31.28) and was not observed with Farapulse (ROR 1.26, NS). Pooled PFA had higher ROR for imaging-confirmed stroke (3.84, 2.27-6.49) and arrhythmia (2.57, 1.91-3.45). Coronary vasospasm (24 vs. 0 events) and hemolysis (15 vs. 1 events) were PFA-specific. Composite serious adverse events were similar. In a pre-specified extension period analysis (August-December 2025), the pooled PFA stroke signal attenuated to non-significance (ROR 1.60, 0.89-2.85), consistent with notoriety bias following the FDA Safety Communication. Conclusions: PFA adverse-event reporting shows substantial platform heterogeneity across approved systems. Varipulse was associated with a disproportionate neurologic reporting signal, while all PFA platforms show tissue-selective reporting patterns relative to RF. These findings support platform-aware clinical decision-making and post-market surveillance.

Background: Characterizing cardiac activation by its site of origin, propagation, and conduction velocity underlies arrhythmia diagnosis and management, but invasive electrophysiology (EP) mapping requires vascular access, fluoroscopy, and sedation. Magnetocardiography (MCG) enables contactless mapping, and recent solid-state sensors remove the cost, cryogenic, and shielding barriers of legacy systems. We assessed the feasibility of a novel solid-state MCG system for noninvasive arrhythmia site-of-origin (SOO) localization and activation reconstruction, benchmarked against electrocardiographic imaging (ECGi). Methods: In nine swine implanted with right atrial and right ventricular pacing leads, we recorded MCG and ECGi simultaneously during atrial and ventricular pacing. Invasive epicardial contact EP mapping provided the activation-time reference and MRI-derived lead-tip location the SOO reference. Local activation time (LAT), conduction velocity (CV), and SOO were compared on a co-registered chamber mesh. SOO error was the Euclidean distance to the MRI lead tip; LAT and CV agreement with EP were quantified by Pearson r and compared using Wilcoxon signed-rank tests. Results: Across 17 datasets (8 atrial, 9 ventricular), median SOO error was lower for MCG than ECGi in the atrium (19.6 vs 31.2 mm; p=0.023) and ventricle (12.0 vs 26.1 mm; p=0.074). LAT agreement with EP was comparable between modalities and higher in the ventricle (MCG r=0.63; ECGi r=0.68) compared with the atrium (MCG r=0.40; ECGi r=0.53), each correlating with invasive EP mapping above chance. CV agreement was modest and numerically higher for MCG in the ventricle. Conclusions: Solid-state MCG was feasible for noninvasive site-of-origin localization and activation mapping, with accuracy comparable to ECGi, motivating larger prospective studies to define its clinical role in noninvasive mapping.

Background: Catheter ablation is the most effective rhythm control strategy for atrial fibrillation (AF); however, recurrence remains common. Current post-ablation management follows largely population-level protocols, constrained by the absence of tools that can anticipate not merely whether, but when, an individual patient will experience recurrence. The emergence of multimodal artificial intelligence (AI) presents a new opportunity to address this unmet clinical need. Objective: To develop a predictive model for time-to-AF-recurrence post-ablation using pre-procedural bi-atrial imaging, clinical covariates, and procedural characteristics, within a novel multimodal AI and survival analysis framework. Methods: We analyzed a retrospective cohort of 437 AF patients who underwent catheter ablation with follow-up censored at 36 months. MARTA-AF (Multimodal AI Recurrence and Time-to-event Analysis post-Ablation in AF) was trained on pre-procedural bi-atrial images, and covariates/procedural characteristics, and integrated into a survival model to generate time-varying recurrence probability estimates. Model interpretability was achieved by quantifying contribution of covariates/procedural characteristics to predicted survival probabilities. Results: MARTA-AF successfully predicted time-varying recurrence risk up to three years post-ablation. Patients were effectively stratified into low- and high-risk groups, with statistically significant discrimination sustained over the follow-up period. The model demonstrated consistent performance across clinically relevant subgroups, including sex, age, and AF type. Incorporation of right atrial shape features improved time-to-AF-recurrence prediction. Interpretability analyses identified key recurrence predictors. Conclusions: MARTA-AF delivers individualized, time-varying AF recurrence risk forecasts and enables stratification into clinically meaningful risk groups. This framework has the potential to transform post- ablation management into a proactive paradigm and to support informed clinical decision-making prior to ablation.

Catheter ablation is an established rhythm-control strategy for atrial fibrillation, but outcomes in persistent atrial fibrillation (PsAF) remain heterogeneous across evolving strategies and energy modalities. An updated synthesis is needed to define current effectiveness and adverse-event profiles in the modern ablation era. We conducted a systematic review and meta-analysis of prospective clinical trials of catheter ablation for PsAF published from 2010 through December 2025. We included randomized and nonrandomized prospective interventional studies reporting effectiveness and adverse events, and pooled outcomes using random-effects models. Prespecified subgroup analyses evaluated ablation strategy (pulmonary vein isolation [PVI] vs PVI with adjunctive lesion sets [PVI+]), ablation modality (radiofrequency [RF], cryoballoon [CRYO], and pulsed field [PF]), and endpoint definition (recurrence-only vs composite measures). Thirty-two studies (9,194 patients) met inclusion criteria; 28 (7,948 patients) contributed to effectiveness analyses. The pooled 12-month arrhythmia-free proportion was 0.65 (95% CI, 0.61-0.68), with substantial heterogeneity. Effectiveness was numerically higher with PVI+ than PVI-only (0.66 [0.60-0.72] vs 0.63 [0.59-0.67]), similar for PF (0.65 [0.57-0.72]) and RF (0.65 [0.61-0.69]), and slightly lower for CRYO (0.64 [0.54-0.74]). Recurrence-only endpoints yielded higher effectiveness than composite endpoints (0.67 [0.63-0.71] vs 0.60 [0.55-0.64]). Safety analyses included 32 studies (9,002 patients). Adverse events were low but heterogeneous (0%-14.56%); pooled vascular access and pericardial complication incidences were each 1%, while thromboembolic events, accessory organ injury, and mortality were rare (pooled 0%). PF ablation showed numerically lower overall complication incidences than RF and CRYO. In contemporary trials, catheter ablation for PsAF shows moderate effectiveness and low overall adverse-event risk. Adjunctive strategies and PF ablation are promising, but no approach is consistently superior. These findings support tailored, patient-specific ablation selection in PsAF.

Background: Abnormal ventricular repolarisation in hypertrophic cardiomyopathy (HCM) may predispose patients to lethal arrhythmias, but repolarisation in HCM remains poorly spatially characterised. Integrating spatial cardiac magnetic resonance with ECG data has the potential to map electrical function throughout the ventricles. This study applied novel digital twin inverse ECG methods to map repolarisation patterns underlying abnormal T-waves in HCM. Methods: Patient-specific full ventricular electrophysiological models were iteratively refined to match the patient 12-lead ECG. Data from 32 healthy volunteers and 69 HCM patients were analysed, with inferred substrates incorporating activation times, repolarisation times, and rate-corrected action potential durations (APDcs). Patients were stratified by T-wave phenotype to identify distinct spatial repolarisation signatures associated with different ECG presentations. Results: Clinical 12-lead ECGs were accurately reproduced by the inferred ventricular models in 95 of 101 cases. Healthy volunteers (N=30) and HCM patients with normal T-waves (N=33) were characterised by apex-to-base APDc gradients of 60 ms (40?80) and 60 ms (30?80), respectively. HCM patients with V1-V3 T-wave abnormalities (N=6) had attenuated apex-to-base APDc gradients of 30 ms (-20?40) driven by apical-to-mid anterior APDc prolongation, greatest at the apical segment (?APDc vs. healthy: 54 ms; 95% CI: 23?84 ms). HCM patients with V4-V6 T wave abnormalities (N=21) had reversed apex-to-base APDc gradients of -20 ms (-40?0) driven by apical-to-mid APDc prolongation, most severe at the apical segment (?APDc vs. healthy: 94 ms; 95% CI: 74?120 ms). Despite significant APDc prolongation, only 4 of 69 HCM patients had QTc > 480 ms, due to masking by the intrinsically healthy longer APDcs at the ventricular base. Conclusions: Distinct spatial distributions of APDc prolongation, not necessarily mirroring the distribution of hypertrophy, underlie different ECG repolarisation phenotypes in HCM and may be missed by the QTc interval.

Background: Iatrogenic atrial septal defect (iASD) is a known consequence of transseptal catheterization. Left atrial intracardiac echocardiography (LA ICE) requires additional septal instrumentation, yet data on persistent iASD after pulsed field ablation (PFA) with an LA ICE workflow remain limited. We evaluated the incidence, predictors, and one-year clinical significance of persistent iASD in this setting. Methods: Consecutive patients undergoing PFA for atrial fibrillation with LA ICE were prospectively evaluated with transthoracic echocardiography before ablation and at one year, including systematic agitated saline contrast. Persistent iASD was defined as residual interatrial shunting on color Doppler at follow-up, classified as small (<3 mm), moderate (3-5 mm), or large (>5 mm). Groups were compared by t-test and chi-square test. Results: Among 850 patients, persistent iASD was identified in 153 (18.0%) at one year; 97 (63.4%) were small and 56 (36.6%) moderate, with no large defects. All shunts were left-to-right. No stroke or transient ischemic attack, paradoxical embolism, hypoxemia, right-heart enlargement, or septal closure occurred. Persistent iASD was associated with female sex (64.7% vs 48.1%), longer septal dwell time (52{+/-}12 vs 31{+/-}11 min), higher left atrial pressure (28{+/-}4 vs 12{+/-}3 mmHg), lower LVEF (32{+/-}11% vs 54{+/-}14%), and larger-caliber sheaths ([&ge;]17 Fr; 80.4% vs 48.2%; all p<0.001). Conclusions: Persistent iASD following PFA with LA ICE occurs in approximately one in five patients but is predominantly small, exclusively left-to-right, and clinically benign at one year. Persistence is associated with mechanical and hemodynamic factors, particularly sheath caliber, rather than the ablation energy source.

Background Atrial fibrillation (AF) is a leading cause of stroke, cardiovascular morbidity, and mortality. Atrial myopathy, characterized by progressive metabolic, electrical, and structural changes, creates the arrhythmogenic substrate that drives AF. Defining the key drivers of atrial myopathic processes is essential for targeted therapies that can mitigate AF progression. Here we explore how reduced ERBB4 expression contributes to the development of left atrial myopathy. Methods We analyzed the Cleveland Clinic Biobank to compare left atrial ERBB4 levels in patients grouped by AF diagnosis. To investigate the impact of reduced ERBB4 levels on atrial tissue substrate, we created mouse models of cardiac-specific Erbb4 deficiency using Mlc2a (myosin light chain 2a)-Cre. Comprehensive physiological assessments were performed. Transcriptomic analyses of the left atrium were performed in an Erbb4 haploinsufficient mouse model and compared with human atrial datasets. Molecular validation of key dysregulated pathways was performed. Results We found that left atrial ERBB4 levels are reduced in patients with AF. Adult cardiomyocyte-specific Erbb4 heterozygous (Erbb4fl/+;Mlc2a-Cre) mice exhibited prolonged P-wave duration in the absence of ventricular dysfunction. Left atrial transcriptomic analysis in Erbb4 haploinsufficient mice showed upregulation of pathways related to fibrosis, apoptosis, and coagulation, and downregulation of pathways related to fatty acid metabolism and mitochondrial function, mirroring changes observed in pressure overload mouse models. A cross-species transcriptomic comparison revealed significant overlap between ERBB4-correlated gene expression and functional pathways in adult human atria and mice with Erbb4 haploinsufficiency. Validating the transcriptomic data, protein and functional assays demonstrated increased fibrosis, apoptosis, and oxidative stress in the mutant left atrial tissue. Conclusion Left atrial ERBB4 levels are reduced in AF patients. A mouse model of Erbb4 deficiency and human atrial transcriptomic analyses highlight a role for ERBB4 in supporting normal atrial metabolism while protecting against inflammation, apoptosis, and fibrosis.

Background and Aims: Machine learning has shown potential in predicting ablation targets for ventricular tachycardia (VT) in an animal model. This study progresses to externally validating deep learning approaches for human data. Methods: The development and external validation dataset included 21 and 13 patients, respectively, with structural VT undergoing catheter ablation. In the development datasets, electrophysiological studies were conducted using the AdvisorTM HD grid (EnsiteTM X), while both CARTO and Ensite Precision were used in the validation dataset. In each patient, VT ablation targets were defined as mapping points within 8 mm of VT isthmuses. Three advanced machine learning models were trained using cardiac mapping data acquired in both omnipolar and unipolar configurations during sinus rhythm and ventricular pacing. Discrimination was evaluated using nested leave-one-out cross-validation at patient level. Results: Overall, graph convolutional networks (GCNs), which integrate intracardiac signal waveforms with three-dimensional electroanatomical geometries, achieved the highest performance, with optimal results obtained from unipolar electrograms acquired in sinus rhythm (median AUC 0.793, sensitivity 83.6%, specificity 69.0%). This may be partly explained by the inclusion of repolarization dynamics in unipolar electrograms and the higher point density of sinus rhythm maps. Comparable performance was observed in the external dataset. Conclusion: This study demonstrates that graph convolutional networks applied to sinus rhythm EGM waveforms collected during substrate mapping can localise critical components of VT re-entry circuits. This approach has potential to provide fast and accurate ablation guidance without the need to induce and map VT, improving safety and efficacy of VT catheter ablation.

The heart maintains systemic perfusion through the coordinated function of its four chambers: the left and right atria and ventricles. Each chamber has distinct structural, functional, and molecular properties tailored to its role in circulation, which may result in chamber-specific differences in myofilament structure and regulation between atria and ventricles. To test this hypothesis, we employed muscle mechanics and X-ray diffraction to investigate functional and structural differences in porcine left atrial (LA) and left ventricular (LV) tissue. Here, we report the first X-ray diffraction study of atrial tissue, demonstrating that under resting conditions, myosin filaments in LA adopted a more ON-like, structurally distinct configuration compared with those in LV. Under contracting conditions, LV generated greater force and exhibited higher sinusoidal stiffness than LA across multiple calcium concentrations. LA showed faster kTR than in LV, with no calcium-dependence, in contrast to the calcium-dependence of kTR seen in LV. Structurally, the distinct myosin head configuration seen in the relaxed LA persisted during contraction. Furthermore, using the troponin inhibitor MYK-7660 to inhibit active contraction, we showed that, unlike LV, LA showed no direct calcium-dependent thick filament activation, reconciling discrepancies between fast rat and slow porcine ventricular myocardium regarding calciums role in thick filament regulation. Altogether, our study reveals that LA myosin filaments adopt a molecular architecture and regulatory mechanism distinct from their LV counterparts, suggesting that myosin filament structure and regulation have evolved differently to meet the unique functional demands of each cardiac chamber. Moreover, atrial disease is often associated with cardiomyopathy-related genetic variants, highlighting the atrial myocardium as an important therapeutic target and understanding atrial-specific regulatory mechanisms provides new insights into therapeutic strategies for atrial diseases.

Background Pulse-field ablation (PFA) is regarded as a non-thermal ablation modality, but there is an increasing range of complications that could be due to thermal effects. Methods The hydrogel undergoes permanent colour change when a target temperature is reached allowing direct visualisation of the surface thermal footprint and depth. Comparative lesion sets using a variable loop circular catheter (VP), circular over-the-wire catheter (PS) and pentaspline catheter (FP) were performed. Protocols included single and stacked applications with variation of force, irrigation, and voltage. The hydrogel lesions were analysed en-face and by section using digital image analysis. Results All 3 PFA catheters tested had significant thermal footprints. The VP catheter had the largest mean surface footprint (156.1mm2) and thermal depth (1.31mm) compared to the other two catheters (PS 55.4mm2 & 1.1mm, FP 29.8mm2 & 1.05mm, p<0.005). Increasing irrigation showed a trend to reduce thermal footprint but did not achieve statistical significance. Increasing voltage increased thermal footprint, but increasing force had negligible effect. Stacked lesions incrementally increased thermal lesion footprint and depth in all catheters. Thermal depths of up to 2.4mm were observed. Areas of darkening and degradation of the hydrogel were observed with the VP and FP catheters, consisting of up to 47% of lesion area. No darkening was observed with the PS catheter. Conclusions There are significant thermal footprints in all the systems tested. Temperatures exceeding 60oC have been demonstrated, comparable to radiofrequency ablation, and this may explain the mechanism of injury in some reports of collateral damage during PFA.

Optogenetic defibrillation uses light-gated ion channels to terminate cardiac arrhythmias through targeted illumination. Previous studies assessed the feasibility of using either cation (e.g. ChR2) or anion (e.g. GtACR1) non-selective channels, both of which depolarise resting cardiomyocytes upon photoactivation. In contrast, recently identified light-gated K+-channels (e.g. WiChR) suppress cardiomyocyte activity while maintaining the membrane potential near its resting state. Here, we use biophysically detailed simulations to compare the defibrillation potential of ChR2, GtACR1, and WiChR. Single-cell simulations show that activation of ChR2 and GtACR1 markedly increase diastolic intracellular Ca2+ concentration (by 42.6% and 52.6%, respectively), whereas WiChR induces only minimal changes (4.0% increase), suggesting a lower pro-arrhythmogenic risk. WiChR activation, however, slightly increases intracellular Na+ levels (by 15.1% compared to 0.1% and 3.4% for ChR2 and GtACR), consistent with the residual Na+ permeability of all currently available K+-selective channelrhodopsins. Simulations of human ventricles and atria demonstrate that GtACR1 most effectively terminates re-entrant arrhythmias at low light intensities, while WiChR achieves comparable efficacy at light levels [&ge;]5 mW/mm2. Complementary tissue-scale simulations reveal that defibrillation is either based on depolarisation within the excitable gap, followed by fast Na+ channel inactivation (depolarising variants ChR2 and GtACR1), or based on a reduction in membrane resistance supporting arrhythmia termination at sufficiently high light levels (large-conductance ion channels GtACR1 and WiChR). Overall, our findings identify channelrhodopsin ion selectivity as a key determinant of both arrhythmia termination success and mechanisms underlying defibrillation. Key points summaryO_LIWe use computational simulations to compare non-selective cation (ChR2), anion (GtACR1), and K+-selective channelrhodopsins (WiChR) for optogenetic termination of re-entrant arrhythmia. C_LIO_LISingle-cardiomyocyte simulations suggest that ChR2 and GtACR1 activation can cause progressive accumulation of intracellular Ca2+, which is minimised when using WiChR. C_LIO_LISimulations of human left ventricles and atria indicate that GtACR1 is most effective in terminating re-entrant arrhythmia at low light intensities, while WiChR becomes similarly effective at higher intensities. C_LIO_LITissue-scale simulations indicate distinct defibrillation mechanisms: Excitable gap extinction by de-novo action potential initiation followed by inactivation of fast Na+ channels for depolarising channelrhodopsins (ChR2, GtACR1), and reduction in membrane resistance for the large-conductance channels (GtACR1, WiChR), effectively clamping the membrane potential at each channels reversal potential at high light levels. C_LI

Aims: Fatty liver disease has been associated with atrial fibrillation (AF), yet the liver-heart axis, the interplay between hepatic fibro-inflammation, systemic metabolism, and genetic susceptibility, remains poorly defined. We aimed to characterize this axis and its association with incident AF. Methods and Results: In this prospective cohort study, liver fibrosis was assessed via four biochemical indices and magnetic resonance imaging (corrected T1 [cT1]). We integrated metabolome-wide causal mediation (249 nuclear magnetic resonance [NMR] features) with Elastic Net modelling, cardiac phenomapping (cardiac magnetic resonance and electrocardiogram), and unsupervised clustering. A metabolomic risk score (MRS) was derived and evaluated for gene-environment interactions with an AF polygenic risk score (PRS) and for incremental prediction beyond CHARGE-AF, ARIC, and C2HEST. Among 403,974 UK Biobank participants (median follow-up 13.18 years), 26,677 developed incident AF. High-risk NAFLD fibrosis score (NFS; HR 1.54, 95% CI 1.43-1.66), Fibrosis-4 index (FIB-4; HR 1.53, 95% CI 1.44-1.62), and liver MRI cT1 (HR 1.41, 95% CI 1.11-1.79) were independently associated with AF. Phenomapping identified a dual-track axis: (1) systemic inflammation and lipotoxicity linked to electrophysiological alterations without chamber dilation, and (2) fatty-acid imbalance associated with structural enlargement. Three metabolomic clusters emerged; a "Fibro-Inflammatory" phenotype exhibited distinct metabolomic derangements, ketogenic stress, and a high residual AF risk independent of traditional comorbidities. The MRS compounded AF risk across all PRS strata and improved prediction beyond CHARGE-AF ({Delta}AUC +0.005; cNRI 10.2%), ARIC ({Delta}AUC +0.006; cNRI 11.7%), and C2HEST ({Delta}AUC +0.042; cNRI 32.2%). Conclusions: Liver fibrosis is a robust predictor of AF. A fibro-inflammatory hepatic-metabolomic signature defines a modifiable axis that potentiates genetic susceptibility and enhances AF risk stratification. Targeting liver-derived metabolic dysfunction may offer a new therapeutic avenue for AF prevention.

Radiofrequency ablation is a mainstay of cardiac rhythm management despite high recurrence rates. Current radiofrequency ablation catheters are limited by poor contact with trabeculated cardiac tissue that promotes uneven heating with hot spots that cause collateral damage and regions of incomplete ablation that promote recurrence. Herein, we report on a conductive hydrogel coating of radiofrequency ablation catheters to improve tissue contact while promoting efficient energy transfer. A method was developed to graft a polyether urethane diacrylamide hydrogel to the distal tip of the catheter that maintained stable adhesion following drying, sterilization, and rehydration. The coating also remained intact after passage through an introducer sheath and 50 cycles of radiofrequency ablation at clinical power. The hydrogel-coated catheter demonstrated enhanced tissue contact that was dependent on hydrogel modulus. Hydrogel-mediated ablation prevented steam pop incidence and generated homogeneous lesions in an ex vivo ablation model; however, increased hydrogel conductivity is needed to achieve comparable lesion dimensions as the bare metal catheter and prevent coating damage at higher power. Collectively, these results establish a tunable hydrogel coating method that addresses limitations of conventional radiofrequency ablation and offers a promising approach to enhance the safety and efficacy of cardiac ablation therapies.

Background: Andersen-Tawil syndrome type 1 (ATS1) is caused by loss-of-function mutations in KCNJ2, which encodes the inward rectifier K+ channel Kir2.1, a key determinant of IK1. Impaired Kir2.1 destabilizes membrane excitability and predisposes to ventricular arrhythmias. Most ATS1 variants disrupt channel regulation by phosphatidylinositol 4,5-bisphosphate (PIP2), but whether specific mutations confer differential arrhythmic risk remains unclear. Objective: To determine whether ATS1 variants disrupting Kir2.1-PIP2 interactions define distinct arrhythmic risk profiles and establish a mechanistically informed framework for risk stratification. Methods: We performed a pooled patient-level analysis of 225 ATS1 patients carrying KCNJ2 variants impairing Kir2.1-PIP2 interaction. Inclusion of 22 clinical and electrocardiographic variables were used to identify mutation-specific risk profiles and predictors for arrhythmia risk. The approach was validated in a multicenter cohort of 20 ATS1 patients. Functional validation was performed using patient-derived iPSC-CMs, cardiac-targeted mouse models, and structural in silico analyses. Results: ATS1 variants segregated into three discrete clusters corresponding to high-, intermediate-, and low-risk arrhythmic phenotypes, establishing a mutation-dependent hierarchy of arrhythmic risk. Regression analyses identified six variables independently associated with severe arrhythmic outcomes. Patient-derived iPSC-CM demonstrated graded impairment of electrical propagation and arrhythmia susceptibility, with a hierarchy in conduction velocity, CV:Control > R82W > R218W > G215D). Cardiac-targeted ATS1 mouse models reproduced the clinical risk stratification. Structural modeling showed that high-risk variants localize near the channel pore and disrupt Kir2.1-PIP2 interactions through mutation-specific mechanisms. Conclusions: ATS1 caused by Kir2.1-PIP2-disrupting variants is not a uniform disorder but comprises biologically distinct subgroups with predictable differences in arrhythmic severity. Integrating genetics, functional phenotyping, and structural modeling provides a mechanistically grounded framework for ATS1 risk stratification and precision therapy development.

The cardiac sodium channel NaV1.5 initiates each heartbeat by generating the rapid depolarizing upstroke of the action potential. Dysregulation of NaV1.5 gating can produce cardiac arrhythmias by slowing inactivation, increasing late sodium current (INa,L), and impairing electrical stability. Here, we show that phosphatidylinositol-4,5-bisphosphate (PIP2) is a critical membrane cofactor that stabilizes NaV1.5 gating. Acute PIP2 depletion in human iPSC-derived cardiomyocytes, produced by activation of endogenous AT1 receptors, activation of an engineered M3q-DREADD, or optogenetic recruitment of CRY2-pseudojanin, shifted voltage dependence, slowed fast inactivation, and increased INa,L. These effects were prevented by augmenting intracellular PIP2, required PLC activity when driven by Gq-coupled receptors, and were independent of downstream Ca2+ or PKC signaling. Unlike the skeletal-muscle isoform NaV1.4, NaV1.5 displayed PIP2-dependent shifts in both activation and steady-state inactivation, indicating isoform-specific lipid coupling. Induced-fit docking and molecular dynamics simulations identified a PIP2-interaction interface between the domain IV voltage sensor and pore that contains disease-linked residues. The disease-reported variant R1644C weakened and redistributed the predicted PIP2-contact network, produced elevated basal INa,L, showed enhanced sensitivity to PIP2 depletion, and caused an approximately 30-fold reduction in apparent functional PIP2 sensitivity in excised patches. These findings define a lipid-dependent mechanism that stabilizes NaV1.5 gating and reveal how physiological Gq signaling and inherited channel variants can converge on the channel-PIP2 axis to promote proarrhythmic late sodium current.

Cardiomyocytes die and do not regenerate after an injury such as a myocardial infarction (MI), a leading cause of mortality worldwide. Following MI, cardiac fibroblasts (CFs) proliferate and differentiate into myofibroblasts, which then produce increased collagen and extracellular matrix (ECM) leading to fibrosis. Fibrosis can weaken cardiac output via excessive stiffening and interference with electric signal transmission, but can also prevent wall rupture under load (reviewed in (1)). Thus, dampening fibrosis has been investigated as a potential therapeutic intervention. Most mammalian cells possess a single primary cilium involved in intercellular communication. We investigated the role of CF primary cilia in sensing injury signals and initiating fibrotic remodeling. We found that deleting CF cilia reduced fibrosis and improved cardiac output after MI, demonstrating that cilia act as a signaling hub that amplifies the fibrotic response in the injured heart.

RationaleSCN1B encodes the {beta}-subunits of the main cardiac voltage-gated sodium channel, NaV1.5. Variants are linked to cardiac conduction disease, often with concealed phenotypes. Whether {beta}1-subunits regulate conduction through nanoscale intercalated disc (ID) structures, e.g. perinexi, and ephaptic coupling remains unresolved. ObjectiveTest whether Scn1b haploinsufficiency induces latent conduction abnormalities that are unmasked by perturbations in extracellular nanodomains. Methods and ResultsAdult Scn1b+/- mice and wild-type (WT) littermates underwent multiscale phenotyping (qRT-PCR, Western blot, patch clamp, transmission electron microscopy (TEM), ex vivo optical mapping, in vivo ECG). Scn1b+/- hearts showed [~]50% reductions in Scn1b mRNA and {beta}1 protein without changes in canonical conduction proteins. Peak sodium current, baseline conduction velocity ex vivo, and baseline QRS duration in vivo were unchanged. However, TEM revealed increased baseline perinexal width in Scn1b+/- hearts. Osmotic expansion of the perinexus with mannitol slowed conduction to a greater extent in Scn1b+/- hearts and prolonged QRS duration in vivo. In contrast, perinexal narrowing with dextran 2MDa selectively increased conduction velocity in Scn1b+/- hearts. ConclusionsScn1b haploinsufficiency preserves baseline excitability and conduction but structurally remodels the ID at the nanoscale, increasing sensitivity to extracellular nanodomain perturbations. These data support a structural role for {beta}1-subunits in ephaptic coupling, and that conduction is maintained over a range of perinexal widths with pathological conduction slowing occurring beyond a critical width. Importantly, osmotic stress unmasks a concealed conduction phenotype, identifying extracellular nanodomain stability as a potential therapeutic target to mitigate arrhythmia risk in SCN1B-associated disease.

Three-dimensional genome organization stabilizes cell-type-specific gene expression, yet the tissue-restricted factors that maintain chromatin insulation remain poorly understood. Here, we identify the muscle-specific ribosomal protein Rpl3l as an unexpected nuclear regulator of genome architecture in atrial cardiomyocytes. Rpl3l is enriched in the nucleus and nucleolus, where it binds its own genomic locus and stabilizes a CTCF-anchored chromatin boundary that represses the T-type calcium channel gene Cacna1h. Loss of Rpl3l weakens local chromatin insulation, increases long-range contacts across the Rpl3l-Cacna1h locus, derepresses Cacna1h, and increases susceptibility to atrial fibrillation (AF), which is suppressed by pharmacological inhibition of T-type calcium channels. Furthermore, AF-associated RPL3L variants exhibit impaired nucleolar localization, reduced rRNA binding, and defective repression of CACNA1H in human iPSC-derived atrial cardiomyocytes. Together, these findings reveal a ribosomal protein-chromatin axis linking genome insulation to ion-channel dosage control and cardiac rhythm stability, expanding the repertoire of cell-type-specific genome architecture regulators.

The electrocardiogram (ECG) encodes the electrical activity of the heart across multiple timescales, yet standard clinical analysis collapses this rich signal into a handful of scalar measurements that discard most of the waveform's structure. Whether the frequency signals lost in this reduction carry heritable biological information relevant to cardiovascular disease risk remains unclear. Here we decompose resting 12-lead ECGs from 47,052 White British UK Biobank participants into 84 frequency-specific energy features using Daubechies-6 wavelet analysis across 12 leads and 7 decomposition levels, and perform independent genome-wide association analyses on each feature. We identify 67 independent loci and refine these to 101 high-confidence causal variants (posterior inclusion probability > 0.80) through Bayesian fine-mapping; associated loci converge on genes governing cardiac conduction and myocardial integrity, including SCN5A, TTN, KCNQ1, and DSP, alongside less-characterized cardiomyopathy candidates. SNP-based heritability estimates range from 0.03 to 0.26, with the strongest signals in mid-frequency bands (D6-D4, ~4-32 Hz) of Lead I and aVR, and strong inter-lead genetic correlations indicate a coordinated genetic architecture underlying the waveform. Integrating these features with FinnGen R12 cardiovascular phenotypes reveals genetic correlations reaching 0.56 with heart failure, driven predominantly by energy in the highest-frequency band (D1, 125-250 Hz), a spectral range routinely filtered from clinical ECGs and previously regarded as acquisition noise. These results reframe the electrocardiogram as a multi-frequency genetic phenotype, expand the set of cardiac loci discoverable from ECG data, and implicate high-frequency cardiac electrical activity as an underexplored dimension of cardiovascular disease risk.