JACC: Clinical Electrophysiology

Background: Accurate identification of macro-reentrant atrial tachycardia (AT) circuits is critical for successful ablation but remains challenging with conventional mapping techniques. The aim of this study was to automatically detect macro-reentrant AT loops from high-density local activation time (LAT) maps. Methods: We developed an algorithm for automated detection of macro-reentrant AT circuits using LAT-derived directed graphs. Compared to previous graph-based approaches, the algorithm is designed to identify the fastest-conducting reentrant pathways and cluster them by rotational orientation (clockwise vs. counterclockwise) to distinguish single- from dual-loop circuits. The algorithm was applied retrospectively to 60 macro-reentrant scar-related AT cases mapped with CARTO or Ensite from two institutions. The results were compared with blinded expert electrophysiologist annotations of loop location and single- vs. dual-loop classification. Results: The 60 cases included 16 right atrial and 44 left atrial ATs from 51 patients. Expert review identified 57% single-loop and 43% dual-loop circuits. Compared with expert annotation, the algorithm correctly identified anatomical loop locations with 88% accuracy and correctly distinguished single- vs. dual-loop ATs in 93% of cases. Conclusion: Our LAT graph-based algorithm automatically identified single- and dual-loop macro-reentrant AT circuits. Localizing these pathways may provide insight into circuit mechanisms and help guide ablation.

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.

The recently published EHRA/EACVI consensus statement on a standardized bi-atrial regionalization provides new opportunities for consistent regional analyses across patients, imaging modalities and clinical centers. To make this standardized regionalization widely accessible, we developed the open-source software DIVAID, which automatically divides bi-atrial geometries according to the proposed regions, ensuring consistency, reproducibility and operator independence. We evaluated the accuracy of the algorithm by comparing its results to manual expert annotations across 140 geometries from multiple modalities and centers. Veins were automatically clipped correctly in 81% and orifices annotated correctly in 100 % of cases. The median (interquartile range; IQR) Dice similarity coefficient (DSC) for left atrial regions was 0.98 (0.96 - 1.00) for DIVAID-expert and 0.98 (0.94 - 1.00) for inter-expert comparisons. For right atrial geometries, DSC was higher for DIVAID-expert than for inter-expert comparisons at 0.90 (0.80 - 0.95) and 0.88 (0.74 - 0.94), respectively. To assess the accuracy of regional boundaries, we computed the mean average surface distance (MASD) for boundaries derived from automatic or manual annotations. The median (IQR) MASD between DIVAID and experts was 0.17 mm (0.03 - 0.78) and 1.93 mm (0.65 - 3.96) in the left and right atrium, respectively. To conclude, DIVAID robustly divides anatomically diverse bi-atrial geometries according to the 15-segment model, while outperforming cardiac experts in both speed and consistency, and demonstrating an accuracy of regional boundaries comparable to the spatial resolution of cardiac imaging modalities. By providing automated, consistent atrial regionalization, DIVAID enables large-scale, standardized regional analyses and data-driven investigation of harmonized, multi-dimensional datasets, which may advance atrial arrhythmia research and personalized treatment strategies.

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.

BackgroundSympathetic modulation via the stellate ganglia is increasingly recognized as a contributor to ventricular arrhythmogenesis after myocardial infarction. However, the mechanisms by which autonomic remodeling interacts with chronic infarct substrates to shape arrhythmic vulnerability remain incompletely understood. ObjectivesTo test the hypothesis that left- and right-sided stellate ganglion-mediated SNS modulation differentially reshapes ventricular arrhythmic vulnerability in chronic post-infarcted substrates, and that the RVI detects changes in vulnerability beyond conventional stimulation-based inducibility. MethodsFourteen patient-specific ventricular models with chronic post-infarcted remodeling were reconstructed from imaging data. A total of 336 simulations were performed under different combinations of stellate ganglion modulation, border zone remodeling, and fibroblast density. Arrhythmic vulnerability was quantified using 3D RVI mapping during paced rhythms and compared with conventional stimulation-based inducibility outcomes. ResultsStellate ganglion modulation induced marked, regionally heterogeneous changes in repolarization timing, resulting in lower and more negative RVI values in vulnerable regions. More negative RVI values reflect increased propensity for wavefront-waveback interaction and reentry initiation. Across the cohort, stellate modulation consistently decreased RVImin, even when inducibility outcomes remained unchanged. These findings indicate that SNS modulation can create a substrate more permissive to reentry independently of whether ventricular arrhythmia is triggered during programmed stimulation. ConclusionsStellate ganglion-mediated sympathetic modulation dynamically reshapes ventricular arrhythmic vulnerability in chronic post-infarcted substrates. RVI provides a spatially resolved, vulnerability-based metric that complements inducibility testing by revealing autonomic-substrate interactions underlying arrhythmogenesis Condensed AbstractSympathetic modulation via the stellate ganglia can alter ventricular repolarization and promote arrhythmogenesis after myocardial infarction, yet clinical responses remain heterogeneous. Using 14 patient-specific post-infarction ventricular models, we simulated left- and right-sided stellate modulation across combinations of border zone remodeling and fibrosis (336 simulations). Stellate modulation induced regionally heterogeneous repolarization shortening and reduced RVI values, even when programmed stimulation inducibility remained unchanged. These findings suggest that RVI captures substrate-level vulnerability beyond binary induction testing and may improve mechanistic assessment of autonomic-substrate interactions in chronic infarct substrates.

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.

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 [≥]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

ObjectivePulsed field ablation (PFA) relies on irreversible electroporation to create nonthermal cardiac lesions, yet real-time indicators of electroporation progression and validated lethal electric field thresholds remain limited. This study aimed to develop a bioimpedance-based metric for real-time monitoring of cardiac electroporation, evaluate the impact of myocardial anisotropy under electroporation conditions, and derive waveform-specific lethal electric field thresholds. IntroductionCurrent PFA procedures lack direct intraoperative feedback on lesion formation, and uncertainty remains regarding the role of myocardial fiber orientation in shaping electric field distributions. Because electroporation dynamically alters tissue electrical properties, monitoring these changes during treatment may improve prediction of ablation outcomes. MethodsPFA was delivered to fresh ex vivo porcine ventricular tissue using clinically relevant and energy-matched waveforms with pulse widths from 1 to 100 {micro}s. Inter-burst broadband electrical impedance spectroscopy was performed using a low-voltage diagnostic waveform to quantify burst-resolved impedance changes. Lesions were visualized using metabolic staining, then finite element models incorporating nonlinear electroporation-dependent conductivity were used to compare anisotropic and homogenized electric field distributions. Lethal electric field thresholds were estimated by fitting simulated contours to measured lesion areas and validated using uniform electric fields generated by a parallel electrode array. ResultsAcross all waveforms, impedance measurements showed a rapid initial decrease followed by stabilization, indicating early electroporation saturation. Burst-to-burst percent change in impedance slope provided a consistent, waveform-agnostic metric of electroporation progression. Lesion morphology was not systematically influenced by fiber orientation, and modeling demonstrated that electroporation-induced conductivity increases homogenized tissue anisotropy. Lethal electric field thresholds increased with decreasing pulse width, ranging from 517 {+/-} 46 V/cm (100 {micro}s) to 1405 {+/-} 55 V/cm (1 {micro}s), and were validated under uniform field conditions. ConclusionBioimpedance-assisted monitoring enables real-time assessment of cardiac electroporation, while electroporation-induced homogenization supports simplified modeling and standardized PFA treatment design.

AimsGenome-wide association studies have identified numerous cardiac transcription factors in association with atrial fibrillation. Amongst these transcription factors, the paired-like homeodomain transcription factor 2 (PITX2) is the strongest genetic risk variant associated with atrial fibrillation. However, the downstream mechanisms of PITX2 are not completely understood. Here, we explore the role of PITX2 in oxidative metabolism and stress as a unifying mechanism of arrhythmogenesis. Methods and resultsTo identify PITX2 mechanisms, we performed transcriptomic analysis in Pitx2c-deficient neonatal rat atrial myocytes. We identify oxidative phosphorylation as the top dysregulated pathway and direct transcriptional targets lie in mitochondrial electron transport chain complexes I and IV. Using the Seahorse Extracellular Flux Analyzer, we identified a functional decrease in oxidative metabolism in Pitx2c-deficient cardiomyocytes. As electron transport chain complexes I and IV may generate reactive oxygen species (ROS) under mitochondrial dysfunction, we quantified mitochondrial specific ROS using MitoSOX and observed an increase in mitochondrial specific ROS in Pitx2c-deficient cardiomyocytes. We additionally assessed spontaneous cardiomyocyte calcium cycling using Fluo-8AM and observed an increased frequency of pro-arrhythmogenic mechanisms including early and delayed afterdepolarizations as inferred through calcium traces. Further, we identified sarcomere disassembly including a potential role of PITX2 in regulating Titin, where Pitx2c-deficient cardiomyocytes display Titin mis-localization within the sarcomeres. To assess whether ROS drives these phenotypes, we treated neonatal rat atrial myocytes with N-acetylcysteine, a potent ROS scavenger, and observed decreased early and delayed afterdepolarizations, as well as restoration of Titin localization. ConclusionPITX2C maintains atrial metabolism and redox balance; the loss of PITX2C results in reduced oxidative metabolism and an elevation in oxidative stress that ramifies cardiomyocyte dysfunction. Treatment with antioxidant restores AF-associated phenotypes including abnormal calcium cycling and sarcomere disassembly in Pitx2c-deficient atrial cardiomyocytes. TRANSLATIONAL PERSPECTIVEGenetic variants close to the PITX2 gene associate most strongly with atrial fibrillation. This study reveals a mechanistic link between multiple AF-associated phenotypes and mitochondrial dysfunction with subsequent accumulation of reactive oxygen species downstream of PITX2. Importantly, metabolic therapies and reducing oxidative stress may present a potential clinical strategy to reverse and prevent functional and structural remodelling related to AF.

BackgroundThe Aveir leadless pacemaker employs an active fixation method, enabling real-time monitoring of electrical parameters during implantation. However, comprehensive studies regarding the electrical parameters during this procedure are rare. ObjectiveThis study aims to analyze the electrical characteristics to further guide the implantation strategy and improve device stability and safety. MethodsThis multi-center retrospective study enrolled 119 patients (mean age 70.18 years; 59.58% female) who received the Aveir VR leadless pacemaker from November 2024 to May 2025 across ten centers in China. Intraprocedural variations in commanded electrogram (CEGM), current of injury (COI), impedance, pacing threshold, and sensing parameters were meticulously documented. ResultsCEGM mapping demonstrated various morphologies (R, RS, QR, QRS, and QS) aiding localization. During fixation, 58.82% of patients exhibited an increased COI from mapping to 0.5 turns, which was associated with reduced short-term pacing thresholds. From 0.5 to 1 turn, 52.94% showed further COI increases. ROC analysis revealed that an impedance increase has predictive value for short-term pacing thresholds, with an AUC of 0.634 and a cut-off value of 230 {Omega} (sensitivity 0.622, specificity 0.41). Lead stability showed a moderate correlation with impedance increase ({rho}=0.44, P<0.001), while the correlation with COI was weak. ConclusionDuring Aveir implantation, CEGM variations guide site localization. Initial COI increases (0-0.5 turns) are linked to optimal short-term thresholds. Monitoring impedance increase is vital, as a threshold of 230 {Omega} serves as a key indicator of device stability and fixation quality.

Background: AI-enabled electrocardiographic age (AI-ECG age) is a digital biomarker of electrophysiological cardiac health. Although cardiovascular physiology exhibits circadian organization, the circadian behavior of AI-ECG age and its structural correlates have not been defined in AF-naive individuals. Objectives: To determine whether AI-ECG age exhibits reproducible circadian patterns and whether disruption of these patterns is associated with left atrial (LA) remodeling, a marker of atrial myopathy. Methods: Continuous single-lead wearable ECGs were analyzed from two independent prospective cohorts (S-Patch [ClinicalTrials.gov: NCT05119725, registered November 2021]; Memo Patch [ClinicalTrials.gov: NCT05355948, registered May 2022]). In AF-naive participants with 48 hours of data, AI-ECG age was estimated every 10 minutes. Unsupervised clustering was used to identify intrinsic circadian trajectories. For clinical interpretability, participants were classified using a day-night difference cutoff (Age 0.6 years) as Restorative (Age >0.6) or Disrupted (Age 0.6). We assessed phenotype reproducibility and examined associations with left atrial volume index (LAVI) using multivariable regression and meta-analysis. Results: Unsupervised learning consistently identified three circadian trajectory patterns across cohorts. Under the simplified binary classification, the Restorative phenotype was observed in approximately half of the participants (47.6-50.2%). Phenotype reproducibility was moderate (Cohen's 0.518; ICC=0.51-0.54) and was not fully explained by conventional heart rate variability measures. Among participants with echocardiography (n=122), the Disrupted phenotype was associated with higher LAVI (adjusted mean difference 6.09 mL/m2; 95% CI 1.46-10.72; p=0.010) and higher odds of severe LA enlargement (adjusted OR 4.17; 95% CI 1.58?10.99; p=0.004), with negligible heterogeneity (I2=0%). Conclusions: Wearable-derived AI-ECG age exhibits circadian patterns in AF-naive individuals, with unsupervised learning identifying distinct trajectories. Attenuation of a nocturnal decline the Disrupted phenotype is associated with left atrial enlargement, independent of conventional comorbidities and static AI-ECG age metrics. These findings suggest that circadian electrophysiological aging phenotyping may capture a dimension of atrial structural vulnerability not reflected by point-in-time assessments, and support prospective studies to evaluate its clinical utility.

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.

Cardiac arrhythmias are abnormal heart rhythms characterized by disordered electrical dynamics that impair cardiac function and pose a major global burden of morbidity and mortality. Early and accurate prediction of arrhythmic anomalies from physiological time series is crucial for effective intervention, yet remains challenging due to the nonlinear, nonstationary, and individualized nature of cardiac dynamics. Despite significant advances in machine learning-based arrhythmia detection, most existing methods operate as static classifiers on electrocardiographic signals and lack online prediction, patient-specific adaptation, and mechanistic interpretability. From a dynamical-systems perspective, arrhythmias represent qualitative regime transitions, often preceded by subtle, temporally extended deviations that are difficult to detect in real time. Here we introduce CASCADE (Chaotic Attractor Sensitivity for Cardiac Anomaly Detection), an online and personalized anomaly forecasting framework built on a special type of reservoir computing called Dynamical Systems Machine Learning (DynML). DynML employs ensembles of continuous-time nonlinear dynamical systems as chaotic reservoirs to reconstruct and forecast short-term cardiac dynamics on a beat-to-beat basis, training only a linear readout. This design enables efficient online adaptation without retraining the underlying dynamical model. Rather than relying on static beat-level classification, CASCADE identifies arrhythmic events as failures of short-term predictability, manifested as statistically significant deviations between predicted and observed dynamics relative to subject-specific baselines. Detection performance is governed by the intrinsic dynamical complexity of the reservoir, quantified by topological entropy. Reservoirs operating near critical entropy regimes optimally amplify subtle, temporally extended irregularities in heartbeat dynamics, rendering incipient arrhythmic signatures linearly separable at the readout level. Topological entropy thus serves both as a predictor of model performance and a principled control parameter for reservoir design. When evaluated on the MIT-BIH Arrhythmia dataset, CASCADE achieved consistently high F1 scores, precision, recall, and overall accuracy across diverse patient populations, demonstrating strong generalizability across clinical and real-world settings. By integrating chaotic reservoir computing, entropy-guided tuning, and online personalized forecasting, CASCADE reframes arrhythmia detection as a problem of dynamical regime transition rather than static classification. This perspective provides a scalable, interpretable, and computationally efficient framework for real-time cardiac monitoring and early-warning clinical decision support.

Background and AimsHeart failure with preserved ejection fraction (HFpEF) exhibits profound phenotypic heterogeneity, which likely contributes to variable therapeutic response. We developed a physiology-informed digital twin-AI framework to predict individual hemodynamic and myocardial energetic responses to accelerated atrial pacing and tested whether simulated physiologic response corresponds to responders in the myPACE randomized clinical trial. MethodsPatient-specific digital twins were constructed for 146 HFpEF patients and used to train a variational autoencoder that generated a virtual HFpEF population (n = 25,000). The model simulated pacing-induced changes in left atrial pressure (LAP), systolic blood pressure (SBP), cardiac output (CO), and cardiac efficiency (CE; derived from myocardial oxygen-demand estimates). These simulations served as labels to train classifiers based on clinical variables available in myPACE, allowing us to examine associations with clinical end points and test a hypothesized relationship between CE and treatment response. ResultsSimulations revealed heterogeneous physiological responses, with 95.6% of virtual patients showing reduced LAP, 47.0% an SBP reduction greater than 8.5 mmHg, 93.8% increased CO, and 36.1% improved CE. Classifiers reproduced these patterns with high fidelity. In the myPACE trial, patients classified as having CE improvement or a larger SBP reduction experienced significantly greater 1-month improvements in quality-of-life scores and larger NT-proBNP reductions. ConclusionsA physiology-informed digital twin-AI framework can predict hemodynamic and energetic responses corresponding to clinical benefit in HFpEF patients receiving accelerated atrial pacing. CE improvement functioned as a mechanistic indicator, while SBP reduction served as an accessible clinical correlate, offering mechanistically grounded guidance for patient-specific pacing and motivating prospective validation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/26347199v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@4a550eorg.highwire.dtl.DTLVardef@163b85org.highwire.dtl.DTLVardef@19db16dorg.highwire.dtl.DTLVardef@1eb6cf5_HPS_FORMAT_FIGEXP M_FIG C_FIG

Background. Peripheral artery disease (PAD) may amplify procedural risk during atrial fibrillation (AF) catheter ablation, but dedicated evidence is lacking. We aimed to evaluate the association between PAD and in-hospital outcomes among adults undergoing AF ablation in the National Inpatient Sample (NIS). Methods. We identified inpatient AF ablation hospitalizations in the 2016 through 2020 National Inpatient Sample using ICD-10-PCS procedure codes and a concurrent AF diagnosis. PAD was identified from ICD-10-CM diagnosis codes used in prior claims-based PAD studies. Stabilized inverse probability of treatment weighting based on the propensity score was used to balance baseline differences. The primary outcome was in-hospital mortality. Fourteen secondary outcomes and 2 composite end points were prespecified. Results. Among 22,166 AF ablation hospitalizations, 899 (4.06%) involved patients with PAD. Compared with patients without PAD, those with PAD were older and had a substantially greater cardiovascular, renal, and smoking/tobacco comorbidity burden. In-hospital mortality did not differ significantly (1.39% vs 1.06%; aOR, 1.32; 95% CI, 0.66 - 2.64; P= 0.44). PAD was associated with higher odds of major bleeding (aOR, 1.62; 95% CI, 1.17 - 2.24; P = 0.004), vascular or access-site complications (aOR, 1.80; 95% CI, 1.04 - 3.12; P = 0.04), acute kidney injury (aOR, 1.31; 95% CI, 1.05 - 1.64; P = 0.02), and composite major adverse hospital events (aOR, 1.29; 95% CI, 1.05 - 1.59; P = 0.02). Total hospital charges were 13% higher (charge ratio, 1.13; 95% CI, 1.04 - 1.22; P = 0.003). Major bleeding, vascular/access-site complications, cardiac arrest, and composite major adverse in-hospital events remained elevated in sensitivity analysis. Conclusion. PAD was independently associated with higher bleeding risk, vascular or access-site complications, acute kidney injury, and composite major adverse hospital event during AF ablation, identifying a clinically relevant subgroup with elevated periprocedural risk.

Drug-induced inhibition of the delayed rectifier potassium (IKr) current predisposes to early afterdepolarisations (EADs) and cardiac arrhythmias. Here, we sought to determine the contribution of action potential duration (APD), APD variability and spontaneous calcium release from the sarcoplasmic reticulum (SR) in the formation of EADs. In isolated sheep ventricular myocytes, EADs were induced by combined inhibition of IKr with dofetilide and {beta}-adrenergic stimulation. The onset of EADs was preceded by increased beat-to-beat variability of APD. To isolate the role of APD in EAD initiation, the sarcoplasmic reticulum (SR) was depleted of calcium with caffeine. The first beat post-caffeine was associated with prolonged APD but not an EAD. During {beta}-AR stimulation, increasing ryanodine receptor open probability had no effect on APD but increased APD variability and induced both EADs and delayed afterdepolarisations (DADs). Targeting RyR open probability with K201 reversibly abolished afterdepolarisations. APD variability was a better predictor of EADs than APD alone. During an EAD, changes in [Ca2+]i preceded those of membrane depolarisation and the changes in [Ca2+]i were in the form of calcium sparks. In silico modelling demonstrated that membrane time constant effects account for the delay between changes in [Ca2+]i and membrane potential. In summary, using a drug-induced model of action potential prolongation with {beta}-AR stimulation, EADs are preceded by increased APD variability and an increase in Ca2+ sparks. Targeting SR function abolishes EADs. These results suggest a key role for SR Ca2+ overload in the formation of EADs and indicate that EADs and DADs share common mechanisms. Key PointsO_LIDrugs that prolong the cardiac action potential and ECG QT interval are a major cause of early afterdepolarisations and dangerous ventricular arrhythmias initiated by early afterdepolarisations. C_LIO_LIProlongation of the action potential is widely assumed to be the primary driver of these events. C_LIO_LIWe show that early afterdepolarisations are instead preceded by increased beat-to-beat variability of action potential duration and that this variability has better sensitivity and specificity for early afterdepolarisations than action potential duration. C_LIO_LISmall, spontaneous calcium release events known as calcium sparks occur before membrane depolarisation driving early afterdepolarisations. C_LIO_LISuppressing calcium release from the sarcoplasmic reticulum abolishes early afterdepolarisations, identifying calcium handling instability as potentially a key mechanism of drug-induced arrhythmia. C_LI

Background and Aims: Clinical interpretation of the precordial leads V1-V6 assumes that Wilson's central terminal (WCT) has a fixed anatomical location. Consequently, a positive signal corresponds to electrical activation spreading from WCT towards the respective electrode, and vice versa. However, the location of WCT has never been systematically investigated. Yet, a better understanding of WCT location could improve the interpretation of the precordial leads. This work aims to characterize the spatial expansion and location of the physical WCT i.e., the electrical potential defined by the WCT, during the P-wave on the body surface. Methods: An intensive analysis of body surface potential maps (BSPMs) during atrial depolarization in an in silico patient cohort and clinical data was conducted. Results: During the P-wave, the location of WCT was not stationary but the spatial extent and location varied across time as well as across individuals. Four distinct spatial patterns of WCT distribution on the body surface were identified in silico, and three of these were found in the clinical cohort. WCT signals agreed with BSPM signals at commonly assumed positions of WCT only for a small fraction of the P-wave. Conclusion: The spatial extension and location of WCT changes during the P-wave and thus should be considered when interpreting the precordial leads.

BACKGROUNDIn addition to lethal ventricular arrhythmias, arrhythmogenic cardiomyopathy (ACM) is associated with conduction abnormalities, bradycardias, and reduced expression of the scaffolding junctional protein zonula occludens-1 (ZO-1). Reduced ZO-1 expression is also seen in dilated cardiomyopathy, which is far more common than ACM. Conduction abnormalities are likewise a feature of ZO-1 cardiac-specific knockout (ZO-1cKO) mice. However, the role of ZO-1 in sinoatrial node (SAN) automaticity has not been studied. OBJECTIVETo investigate the role of ZO-1 in SAN automaticity and elucidate the mechanisms by which ZO-1 deficiency leads to SAN dysfunction. METHODSZO-1 cardiac-specific knockout (ZO-1cKO) mice were generated by crossing ZO-1 floxed mice with MHC-nuclear Cre mice. SAN/atrial tissue and isolated SAN cells were examined using optical mapping, single-cell patch clamp, and quantitative PCR techniques to assess functional alterations caused by ZO-1 loss. RESULTSZO-1cKO mice exhibited enlarged atria and SAN area compared to control mice, with normal left ventricular function. Electrocardiograms showed sinus bradycardia, sinus pauses and atrioventricular block. Optical mapping revealed a caudal shift in the SAN leading region and reduced intra-atrial conduction velocity in ZO-1cKO mice. Patch-clamp recordings from isolated SAN cells showed reduced spontaneous action potential frequency and diastolic depolarization rate, while voltage-clamp revealed a marked reduction in pacemaker current (If). CONCLUSIONZO-1 expression is essential for SAN automaticity. Its loss impairs SAN impulse generation by reducing pacemaker current and hampering atrial conduction, leading to bradyarrhythmia, conduction delay and block. These findings help explain impulse generation and conduction abnormalities in ACM and other cardiomyopathies.

Background: Response to cardiac resynchronization therapy (CRT) is heterogeneous in patients with non-left bundle branch block (non-LBBB) heart failure. Whether pre-implant substrate or procedural characteristics provide the more stable framework for predicting 1-year echocardiographic response remains uncertain. Methods: We retrospectively analyzed 120 non-LBBB patients undergoing CRT. The primary logistic model included left ventricular end-diastolic diameter (LVEDD), left ventricular ejection fraction (LVEF), left atrial diameter, log-transformed NT-proBNP, baseline QRS duration, fragmented QRS burden across V1?V6 leads, and pulmonary artery pressure. Missing predictor data were handled using multiple imputation with 20 datasets. Model performance was assessed using bootstrap internal validation and recalibration. A prespecified procedural extension added pacing strategy, posterolateral biventricular left ventricular lead location, left ventricular pacing threshold, and right ventricular lead position. Exploratory phenotyping and sensitivity analyses were performed. Results: Echocardiographic response occurred in 51 patients (42.5%). LVEDD (OR, 0.899 [95% CI, 0.826?0.978]; P=0.013) and LVEF (OR, 1.068 [95% CI, 1.000?1.140]; P=0.050) were the most informative predictors. The primary model showed apparent AUC 0.811 and Brier score 0.173, with optimism-corrected AUC 0.766 and calibration slope 0.765. Procedural extension showed no retained incremental value after validation. Exploratory phenotyping identified three response patterns with moderate stability. Conclusions: In non-LBBB CRT, baseline structural, biomarker, and electrocardiographic substrate provided the most stable framework for predicting 1-year echocardiographic response. Procedural variables added limited retained value, suggesting that pacing strategy should be interpreted alongside baseline substrate.

Background: Patients with Fontan circulation experience significant morbidity from supraventricular tachyarrhythmias (SVTs). However, the electrophysiological features of SVT and the efficacy and safety of catheter ablation in patients with Fontan circulation are poorly understood. This study aimed to elucidate the electrophysiological features of SVT and evaluate the efficacy and safety of catheter ablation in patients with Fontan circulation. Methods: Forty-nine patients (age, 29.2{+/-}10.0 years; 27 males) with functional single ventricle and Fontan circulation who had undergone electrophysiological study for SVT were retrospectively enrolled. Parameters analyzed included underlying congenital heart disease, Fontan type, conduit puncture technique, tachycardia mechanisms, tachycardia origin site, acute success rate, procedure-related complications, and recurrence. Results: Fifty-nine SVTs were induced, and 69 catheter ablations were performed. The Fontan types included atriopulmonary connection (APC, 18.4%), lateral tunnel (LT, 38.8%), and extracardiac conduit (ECC, 42.9%). Inducible tachycardias included intra-atrial reentrant tachycardia (IART, 39.0%), focal atrial tachycardia (AT, 28.8%), atrioventricular reentrant tachycardia (11.9%), atrioventricular nodal reentrant tachycardia (10.2%), and atrioventricular reciprocating tachycardia involving the twin atrioventricular nodes (10.2%). The right atrial (RA) lateral wall was the most common location of IART and focal AT. The acute success and complication rates were 73.5% and 4.1%, respectively. Recurrence rate was 34.7% during follow-up of 78.0{+/-}71.9 months. The cumulative recurrence rate was significantly lower in patients who underwent LT or ECC Fontan procedures than in those who underwent the APC Fontan procedure (P<0.001). Conclusions: Catheter ablation for SVT is effective and safe in patients who have undergone LT and ECC Fontan procedures.