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.

AimsEarly discharge after electrophysiological procedures has gained increasing attention. However, definition of patient- and procedure-related prerequisites for successful and safe discharge strategies after atrial tachycardia (AT) ablation remains unknown. We therefore evaluated patient characteristics, procedural features, and outcomes according to index length of stay (LOS) following AT ablation. Methods and resultsThe multicenter observational SATELLITE registry enrolled consecutive patients undergoing AT rhythm control. Patients were stratified by LOS ([&le;]1, 2 and >2 nights) after catheter ablation. Among 670 patients (67 [IQR 56-75] years, 54.9% male), LOS was [&le;]1 night in 13.9%, 2 nights in 41.9% and >2 nights in 44.2%. LOS was only modestly predictable from clinical characteristics including age, sex, atrial fibrillation and prior atrial ablation (AUC 0.73). Discrimination improved after inclusion of procedural variables and early post-procedural events (AUC 0.77; P=0.0300), consistent with an increase in left atrial procedures (26.5% vs. 76.0% vs. 80.8%; P<0.0001), acute minor complications (3.2% vs. 2.5% vs. 14.5%; P<0.0001) and early recurrences of atrial arrhythmia (2.2% vs. 6.8% vs. 21.3%; P<0.0001). During 2.8{+/-}3.0 years of follow-up, LOS did not predict long-term outcomes including subsequent cardiovascular hospitalization (HR 1.19, 95% CI 0.78-1.81; P=0.4175). ConclusionDespite multiple comorbidities, most patients undergoing AT ablation need up to 2 nights of hospitalization. However, prolonged hospital stays before successful and safe discharge are common and associated with acute minor complications and early recurrences of atrial arrhythmia rather than comorbidities. Accordingly, discharge timing largely reflects the immediate peri-procedural clinical course, therefore challenging purely logistics-driven planning. Key Learning PointsO_ST_ABSWhat is already knownC_ST_ABSO_LIEarly discharge after electrophysiological procedures has gained increasing attention. C_LIO_LIDefinition of patient- and procedure-related prerequisites for successful and safe discharge strategies after atrial tachycardia (AT) ablation remains unknown. C_LI What this study addsO_LIDespite multiple comorbidities, most patients undergoing AT ablation need up to 2 nights of hospitalization. C_LIO_LIProlonged hospital stays before successful and safe discharge are common and associated with acute minor complications and early recurrences of atrial arrhythmia rather than comorbidities. C_LIO_LIDischarge timing largely reflects the immediate peri-procedural clinical course, therefore challenging purely logistics-driven planning C_LI Structured Graphical AbstractO_LIDespite multiple comorbidities, most patients undergoing AT ablation need up to 2 nights of hospitalization. However, prolonged hospital stays before successful and safe discharge are common and associated with acute minor complications and early recurrences of atrial arrhythmia rather than comorbidities. Accordingly, discharge timing largely reflects the immediate peri-procedural clinical course, therefore challenging purely logistics-driven planning. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/26345799v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@200309org.highwire.dtl.DTLVardef@1a745fcorg.highwire.dtl.DTLVardef@e3cd45org.highwire.dtl.DTLVardef@1b98c3e_HPS_FORMAT_FIGEXP M_FIG C_FIG

AimsCatheter ablation using radiofrequency (RF) or pulsed field (PF) energy is an effective treatment method for ventricular arrhythmia (VA). PF offers advantages in lesion formation in anatomically challenging regions. However, its acute effects on ventricular contractility during substrate modification require further elucidation. This study aimed to compare real-time hemodynamic changes associated with PF versus radiofrequency ablation in the left ventricle using stroke volume (SV) as a surrogate for myocardial response in regard to the safety of multiple lesion delivery within scarred myocardium. Methods and resultsWe conducted a prospective case series study of eight consecutive patients undergoing VA ablation using a dual-energy lattice-tip catheter (Sphere-9, Medtronic). Lesions were delivered to scarred regions identified via intracardiac echocardiography (ICE) and high-resolution 3D mapping. Hemodynamic monitoring was performed using a minimally invasive arterial waveform system (HemoSphere, Edwards Lifesciences). A total of 317 PFA and 41 RF lesions were delivered. PFA applications were associated with a transient SV reduction of 33.1{+/-}8.3 ml, with normalization post-delivery. RF lesions resulted in a minimal SV change ([&le;]10% from baseline value). SV reduction following PFA was consistent across lesion locations. All patients achieved post-procedural non-inducibility of clinical VT. ConclusionPF causes transient but reversible reductions in LV stroke volume during lesion delivery, likely reflecting acute electroporation-induced myocyte stunning rather than irreversible dysfunction. RF lesions did not produce similar changes. These findings suggest a favorable safety profile for PF in ventricular substrate ablation, including in cases of multiple lesion sets, and support its use in regions of scarring. Further studies are warranted to validate these observations and assess long-term outcomes.

Resident cardiac macrophages are understood to facilitate atrioventricular (AV) node conduction because they purportedly couple to AV node myocytes via connexin43 (Cx43) containing gap junctions. We tested this mechanism using biophysical modelling, high-resolution imaging of mouse and human AV conduction tissue, and pharmacological macrophage depletion. In silico, coupling macrophage membrane phenotypes to HCN4+ AV node myocytes imposed an electrotonic load that suppressed pacemaking and promoted conduction slowing, including stable 2:1 block in strand simulations. Anatomically, HCN4-defined components of the mouse AV conduction axis were essentially devoid of Cx43 and overlap of CD68+ macrophages and Cx43 was negligible in both mouse AV node and human penetrating bundle. Finally, near-complete macrophage depletion with CSF1R inhibition (PLX5622) did not alter AV electrical activity in vivo or ex vivo. Together, these data argue against a physiologically relevant role for Cx43-mediated macrophage-myocyte electrical coupling in normal AV node function. HIGHLIGHTSO_LIModelling predicts that AV node automaticity and conduction would be suppressed if macrophages coupled to AV node myocytes C_LIO_LIThe mouse AV conduction axis is essentially devoid of Cx43, currently considered responsible for macrophage-AV node myocyte coupling C_LIO_LIOverlap of macrophages and Cx43 expression is not discernible in the Cx43-expressing human distal AV node C_LIO_LIMacrophage depletion by CSF1R inhibition does not impact AV electrical activity in vivo or ex vivo C_LI

BackgroundCatheter ablation is an established rhythm control therapy for atrial fibrillation. However, as the extent of ablation increases, the risk of complications may also rise. This has motivated strategies that achieve pulmonary vein isolation with less lesion creation while preserving safety and effectiveness. MethodsIn this prospective, multicenter, randomized non-inferiority trial, 130 patients undergoing first-time ablation for paroxysmal or non-paroxysmal atrial fibrillation were assigned 1:1 to a voltage-guided stepwise pulmonary vein isolation approach or conventional circumferential antral pulmonary vein isolation with voltage blinded to operators. The primary end point was recurrence of atrial tachyarrhythmia within 12 months after ablation. ResultsAt 12 months, recurrence occurred in 23/65 (35.4%) in the stepwise group versus 13/65 (20.0%) in the control group (risk difference 15.4 percentage points; 90% confidence interval, 2.7-28.1), and non-inferiority was not demonstrated (one-sided P=0.520). The treatment group had a higher risk of recurrent atrial tachyarrhythmia than the control group (hazard ratio, 2.05; 95% confidence interval, 1.04-4.06), with longer procedure times and more frequent acute pulmonary vein reconnection after the initial lesion set. The treatment group had fewer acute complications than the control group (1.5% versus 9.2%; P=0.115), and esophageal thermal injury was observed only in the control group (3 cases). ConclusionsVoltage-guided stepwise pulmonary vein isolation failed to demonstrate non-inferiority to conventional circumferential antral pulmonary vein isolation for 12-month atrial tachyarrhythmia recurrence. ClinicalTrials.gov ID: NCT07354737

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.

BackgroundSex differences in the epidemiology of atrial fibrillation are well-documented; however, the underlying mechanisms remain poorly understood. This gap in knowledge is compounded by limited data on sex-specific atrial electrophysiology in the absence of disease. ObjectivesThe aim of this study was to investigate sex differences in atrial electrophysiology and arrhythmia susceptibility in a translationally-relevant rabbit model. MethodsDual optical mapping of transmembrane voltage and Ca2+ was performed on intact atria of young (3.5-5 months) male and female rabbit hearts. Baseline atrial electrophysiology and arrhythmia susceptibility were investigated using rapid pacing and premature stimulation and further tested with the parasympathomimetic carbachol. Sex and regional differences in gene expression were assessed using qPCR. ResultsFemales exhibited similar action potential duration (APD), but greater APD heterogeneity across the atria at slower rates, along with longer Ca2+ transient durations compared to males. Greater APD heterogeneity in females was rate-dependent and comparable to males at faster pacing frequencies; however, it was associated with greater susceptibility to transient reentrant arrhythmias with premature stimuli. After carbachol application, males had heightened vulnerability to arrhythmia. This was associated with cholinergic-mediated APD shortening in both atria in males, but only in the right atrium in females. Sex differences in carbachol responses were linked to variations in muscarinic receptor and acetylcholine-activated potassium channel gene expression. ConclusionsThese findings demonstrate sex and regional differences in atrial electrophysiology at baseline and in response to cholinergic stimulation in the healthy heart that may contribute to sex-specific mechanisms of arrhythmia.

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.

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.

BackgroundAcute myocarditis is typically self-limiting and resolves spontaneously in most cases. However, ventricular arrhythmias (VA) complications, which may be life-threatening are associated with higher rates of in-hospital complications and mortality. Catheter ablation is occasionally required for acute myocarditis associated ventricular tachycardia (VT), but data on its procedural use and outcomes, in this setting, remain limited. We aimed to determine the prevalence of VA among patients hospitalized for acute myocarditis and to evaluate the subset who underwent in-hospital VT ablation, including their acute outcomes. MethodsRetrospective analyzed data from the National Inpatient Sample (NIS) database for U.S. hospitalizations with a diagnosis of myocarditis between 2016 and 2019. In-hospital outcomes were compared between patients with and without VA. Subgroup analysis examined patients with acute myocarditis associated VT stratified by whether VT ablation was performed. Patient demographics, comorbidities, procedures, and outcomes were identified using ICD-10-CM codes. ResultsAmong an estimated 17,845 hospitalizations for acute myocarditis, 8.4% (n=1,505) had VA (including 7.7% with VT). Patients with VA were more likely to have structural heart disease, renal disease, infectious etiologies, anemia, and atrial arrhythmias, despite lower prevalence of some traditional cardiac risk factors. VA was associated with markedly worse outcomes, including 5.5-fold higher in-hospital mortality (10% vs 1.6%; p<0.001). Multivariate analysis revealed that VA during admission for acute myocarditis was an independent significant risk factor for cardiac complications (aOR=4.8), total complications (aOR=4.2) and in hospital mortality (aOR=5.1) (p<0.001 for each analysis). Among patients with VT, catheter ablation was performed in 13.7% (n=190), more commonly with infectious etiologies. Ablated patients, compared to those without ablation, experienced significantly higher rates of in-hospital complications (73.7% vs 42.3%; p<0.001) and mortality (15.8% vs 6.7%; p<0.001). ConclusionsVA complicating acute myocarditis, portends significantly worse in-hospital outcomes. Although ablation was performed in approximately 1 in 7 patients with VT, those undergoing the procedure had less favorable acute results. Further prospective research is warranted to define optimal criteria for ablation and expected outcomes in this high-risk population.

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

BackgroundLeft atrial (LA) remodeling, a hallmark of chronically elevated LA pressure, is characterized by enlargement and functional impairment. While global and reservoir LA functions are well described, the role of LA booster function and its failure remains poorly defined. ObjectivesTo characterize LA booster function using cardiac computed tomography angiography (CCTA) and to evaluate the relationship between LA preload, booster performance, remodeling, and clinical outcomes. MethodsWe retrospectively analyzed 975 patients who underwent spiral CCTA between 2010 and 2018. Phasic LA and LV volumes were obtained, from which LA reservoir and booster functions were derived. LA performance curve was constructed by plotting LA pre-A volume (preload) against LA booster stroke volume. Clinical outcomes (heart failure, stroke, or cardiovascular death) were analyzed based on the LA performance curve. ResultsLA pre-A volume strongly correlated with LA end-systolic volume (r=0.92, p<0.001). The LA booster stroke volume displayed an inverted U-shaped relation to LA pre-A volume (linear coefficient 0.64, P<0.0001; squared coefficient-0.0029, P<0.0001). The atrial booster function curve reached its vertex at 107 mL (95% CI 90 to 113 mL), indicating that the booster pump response for the increased preload is exhausted at this point. Booster dysfunction was associated with impaired reservoir function (r=0.77, p<0.001) and reduced LA systolic flow rates (-0.79, P<0.001). Patients with increased LA pre-A volume but reduced booster volume ("LA failure") exhibited the highest event rate of the combined endpoint of heart failure, stroke or cardiovascular mortality (43.2%, 95% CI 33.6-54.2%). ConclusionsLA enlargement predominantly serves to increase LA pre-A volume to sustain booster function. LA contractile dysfunction affects global LA function via a concomitant reduction in LA reservoir volume. LA failure can be defined as reduced booster contraction despite elevated preload, portending poor clinical outcomes.

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.

We present a deep learning model that predicts left atrial (LA) volume from standard 12-lead ECG recordings and basic patient data. This approach offers a low-cost, scalable alternative to MRI-based LA volume measurement, which remains the clinical gold standard but is often inaccessible. Our model performs regression directly on LA volume targets and leverages Shapley values to provide interpretable feature importance. Results highlight the predictive value of ECG signals and demonstrate that patient features such as weight and height contribute meaningfully to the estimation.

BackgroundPressure-volume (PV) loop analysis remains the gold standard for assessing the intrinsic global diastolic properties of the left ventricle (LV). Traditional fitting techniques rely on local, phase-constrained fittings and are limited due to their sensitivity to noise, landmark selection, violation of assumptions, and non-convergence. ObjectiveTo develop and validate DIA-PINN, a physics-informed neural network (PINN) framework capable of calculating intrinsic diastolic properties of the LV from measured instantaneous PV data, combining mechanistic interpretability with machine learning flexibility. MethodsInstantaneous LV diastolic pressure was modeled as the sum of 1) time-dependent relaxation-related pressure and 2) volume-dependent recoil and stiffness-related pressures. DIA-PINN was trained using time, LV pressure and volume as inputs, enforcing data fidelity, model consistency, and physiological plausibility within the loss function. Performance was evaluated in 4,000 Monte Carlo simulations of LV PV-loops, and in clinical data from 59 patients who underwent catheterization (39 with heart failure and normal ejection fraction and 20 controls). DIA-PINN derived indices were compared to those obtained from a previously validated global optimization method (GOM). ResultsOn the simulation data, DIA-PINN accurately recovered all constitutive indices (intraclass correlation coefficients near unity) and improved GOM performance. On the clinical data, diastolic indices derived using DIA-PINN strongly correlated with GOM estimates (R>0.90, p<0.001) but were insensitive to initialization. DIA-PINN performed best under vena cava occlusion, as varying preload improved parameter identifiability. ConclusionsWhen applied to instantaneous pressure-volume data, a generalizable PINN framework, DIA-PINN, provides an improved method for assessing global intrinsic diastolic properties of cardiac chambers. New & NoteworthyOur work introduces DIA-PINN, a physics-informed neural network framework to process instantaneous ventricular pressure-volume data, solving a mechanistic model of diastole with machine learning techniques. Compared to current conventional or optimization-based approaches, the PINN provides the most reliable estimates of diastolic stiffness, relaxation, and elastic recoil, unsensitive to initialization. By embedding physiological constraints into network training, this approach achieves robust, interpretable, and clinically applicable quantification of gold-standard metrics of intrinsic global diastolic chamber properties.

BackgroundPathogenic desmin (DES) variants have been implicated in early-onset atrial disease, yet the mechanisms by which desmin dysfunction alters atrial structure and function remain unclear. Desmin anchors the cytoskeleton to the nuclear envelope (NE) through the linker of nucleoskeleton and cytoskeleton (LINC) complex, suggesting that defects in this network may drive atrial cardiomyopathy. MethodsHuman desmin wild-type (WT) and the pathogenic variants p.S13F, p.N342D, and p.R454W were stably expressed in HL-1 atrial cardiomyocytes. Desmin organization, nuclear morphology, LINC-complex integrity (nesprin-3, lamin A/C), and DNA leakage, assessed by cyclic GMP-AMP synthase (cGAS), were analyzed by confocal microscopy. Action potential duration (APD) and calcium transients (CaT) were measured optically. Human myocardium samples from DES variant carriers were analyzed for validation. Data-independent acquisition (DIA) mass spectrometry profiled atrial proteomes from desmin-network (DN) and titin variant carriers and controls. The heat-shock proteins (HSPs) inducer geranylgeranylacetone (GGA) was evaluated for rescue effects. Resultsp.N342D caused severe filament-assembly defects with prominent perinuclear aggregates, whereas p.S13F showed mixed phenotypes with frequent perinuclear aggregates, and p.R454W largely preserved filamentous networks. p.N342D and p.S13F induced nuclear deformation with disrupted nesprin-3 and lamin A/C distribution. In p.N342D and p.S13F, desmin aggregates drove focal lamin A/C accumulation, nuclear envelope (NE) rupture, DNA leakage, and increased cGAS activation. DES variants significantly shortened APD20/90 and reduced CaT amplitude, indicating pro-arrhythmic electrical remodeling. Atrial proteomics revealed a DN-specific signature enriched for cytoskeletal, NE, intermediate filament, and chaperone pathways, consistent with the structural injury observed in vitro. GGA prevented desmin aggregation and nuclear morphology changes, and mitigated APD shortening in p.N342D-expressing cardiomyocytes. Human myocardium from DES variant carriers showed concordant desmin aggregation and polarized lamin A/C distribution. ConclusionsDES variants induce a desmin-dependent atrial cardiomyopathy characterized by cytoskeletal disorganization, disruption of LINC-complex, NE rupture with DNA leakage, and pro-arrhythmic electrophysiological remodeling. These findings provide mechanistic insight into how DN variants promote atrial disease. HSPs induction by GGA partially restores structural and functional integrity, identifying a potential therapeutic approach for desmin-related atrial cardiomyopathy. Clinical perspectiveWhat is new? O_LIPathogenic DES variants induce a previously unrecognized atrial cardiomyopathy characterized by desmin aggregation, and desmin-network (DN) collapse, disruption of the linker of nucleoskeleton and cytoskeleton (LINC) complex, and nuclear envelope rupture with DNA leakage. C_LIO_LIVariants that lead to desmin aggregation (e.g., p.N342D) cause focal lamin A/C polarization, cyclic GMP-AMP synthase (cGAS) activation, and structural injury at the nuclear envelope. C_LIO_LIDES variants produce pro-arrhythmic electrical remodeling, including action potential duration shortening and impaired Ca{superscript 2} handling in HL-1 atrial cardiomyocytes. C_LIO_LIAtrial proteomics from DN variant carriers reveals enrichment of pathways related to cytoskeletal, nuclear envelope, intermediate filament, and chaperone, supporting a desmin-dependent remodeling program. C_LIO_LIThe heat-shock protein inducer geranylgeranylacetone (GGA) prevents desmin aggregation, restores nuclear morphology, and mitigates electrical and Ca{superscript 2} handling remodeling. C_LI What are the clinical implications? O_LIThese findings establish DN dysfunction as a distinct cause of atrial cardiomyopathy, providing a mechanistic basis for the association between pathogenic DES variants and atrial arrhythmias, including atrial fibrillation. C_LIO_LINuclear envelope rupture and cytosolic DNA leakage represent new mechanistic evidence which links cytoskeletal injury and atrial arrhythmogenesis. C_LIO_LIIdentifying structural vulnerability in DES variant carriers fosters awareness of genetic counseling for atrial disease, enabling early detection and risk stratification. C_LIO_LIThe protective effects of GGA suggest that restoring proteostasis may be a therapeutic strategy for desmin-related atrial cardiomyopathy and potentially other genetic atrial diseases. C_LI Novelty and significance statementO_ST_ABSNoveltyC_ST_ABSThis study identifies a desmin-dependent atrial cardiomyopathy driven by cytoskeletal aggregation, LINC-complex disruption, and nuclear envelope rupture with DNA leakage. We show that pathogenic DES variants are associated with pro-arrhythmic molecular remodeling and that human atrial proteomics confirm nuclear envelope and cytoskeletal injury as core features. Importantly, the heat-shock protein-inducer GGA rescues structural, molecular, and electrophysiological defects, revealing a modifiable pathway in desmin-mediated atrial disease. SignificanceThese findings provide the first integrated mechanistic explanation linking DN variants to atrial cardiomyopathy. By uncovering nuclear envelope rupture and cGAS activation as key drivers of atrial cardiomyopathy, this work expands the molecular framework for inherited atrial disease and highlights proteostasis enhancement as a potential therapeutic strategy for patients carrying DES and related cytoskeletal variants. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/26348559v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1fb0bfborg.highwire.dtl.DTLVardef@cfc00borg.highwire.dtl.DTLVardef@1493578org.highwire.dtl.DTLVardef@1556b61_HPS_FORMAT_FIGEXP M_FIG C_FIG

Class imbalance in clinical electrocardiogram (ECG) datasets limits the diagnostic sensitivity of automated arrhythmia classifiers, particularly for rare but clinically significant beat types. We propose a three-stage hybrid generative pipeline that combines a spectral-guided conditional Variational Autoencoder (cVAE), a class-conditional latent Denoising Diffusion Probabilistic Model (DDPM), and a Quantum Latent Refinement (QLR) module built on parameterized quantum circuits to augment minority arrhythmia classes in the MIT-BIH Arrhythmia Database. The QLR module applies a bounded residual correction guided by Maximum Mean Discrepancy minimization to align synthetic latent distributions with real class-specific latent banks. A lightweight 1D MobileNetV2 classifier evaluated over five independent random seeds and four augmentation ratios serves as the downstream benchmark. Our findings establish latent diffusion augmentation as an effective strategy for imbalanced ECG classification and motivate further investigation of quantum-classical hybrid methods in cardiac diagnostics.