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: 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.

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.

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.

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.

Background: Cardiomyopathy and channelopathy (CC) gene variants have been linked to sudden cardiac arrest (SCA) or death (SCD) in small, selected pedigree or post-mortem studies of arrhythmic mitral valve prolapse (MVP). However, the utility of clinical whole exome sequencing (WES) panels as a risk stratification tool in unselected MVP samples is unknown. Objectives: The goal of the study was to test the utility of clinical WES panels with CC variant screening for arrhythmic risk stratification in MVP. Methods: We performed research based WES in 203 consecutive MVPs without other arrhythmic substrate. Variants were filtered for rare (<0.1%) and protein altering variants in 157 CC genes within an existing clinical panel and annotated with a clinical significance predictor. Overall frequency of CC variants was compared to a sample of general population exomes from gnomad v4.1.0. We assessed a composite severe arrhythmic outcome of SCD or frequent ectopy/ventricular tachycardia or ventricular fibrillation/SCA requiring catheter ablation or defibrillator implantation, respectively. Results: CC variants were more common in MVPs compared to the general population (RR: 4.3, p < 0.01). Pathogenic/Likely Pathogenic (P/LP) variants were identified in 18 MVPs (9%; 8 CC variants among 12 genes). P/LP variants were independently associated with the composite arrhythmic outcome after adjustment for traditional imaging parameters of risk including mitral annular disjunction and bileaflet involvement (OR: 1.23 [95% CI: 1.03 to 1.47], p = 0.01). P/LP variant carriers were at greater arrhythmic risk in time to event analyses starting at birth (HR: 2.87 [95% CI: 1.24 to 6.62], p = 0.01). Conclusions: A subset of MVPs with P/LP variants in CC genes are at higher arrhythmic risk. A clinical WES panel inclusive of CC variants may represent a valuable arrhythmic risk stratification tool in MVP beyond traditional imaging parameters.

Background: Cardiac resynchronization therapy (CRT) fails in 30% of patients, often due to suboptimal left ventricular pacing site (LVPS) selection. Current practice lacks tools for pre-procedural, patient-specific LVPS optimization within the accessible coronary sinus (CS) tributaries. This study aimed to develop a digital twin and an explainable ML-based clinical decision support framework to address this issue. Methods: Personalized 3D cardiac models incorporating ventricular anatomy, myocardial fibrosis, and CS anatomy were constructed from CT and LGE-MRI for 74 CRT candidates. Finite-element Eikonal simulations of biventricular pacing generated patient-specific electrophysiological features at candidate LVPS. A Machine Learning (ML) classifier was trained on a hybrid feature set of pre-procedural clinical variables and model-derived indices, validated by leave-one-out cross-validation. SHAP analysis provided a physiologically interpretable rationale for each prediction. The framework was applied to a pilot cohort of 19 patients with reconstructed 3D CS anatomy to generate a spatial likelihood map of CRT response across all clinically implantable pacing sites within each patient's CS. Results: The ML classifier outperformed the reference Feeny clinical calculator under LOO-CV (accuracy 0.78 vs 0.58; F1-score 0.75 vs 0.43), AUC=0.78, sensitivity=0.80, specificity=0.77. Bootstrap analysis yielded mean AUC=0.85 (95% CI 0.70-0.95). In the pilot CS cohort, the framework identified that 8 of 13 clinical non-responders had no accessible CS site predicted to yield a positive response, supporting redirection towards alternative pacing strategies. In the remaining 5, alternative implantable sites with high predicted response probability were identified. SHAP analysis confirmed that dominant predictors were patient-specific in their relative contributions, supporting individualized over heuristic-based LVPS selection. Conclusion: This pilot study demonstrates the feasibility of a digital twin and explainable ML framework as a pre-procedural clinical decision support tool for CRT planning, stratifying patients and identifying optimal implantable sites with transparent anatomical rationale. Prospective validation and regulatory evaluation are required before clinical deployment.

Ventricular tachycardia (VT) and ventricular fibrillation (VF) are the leading electrical causes of sudden cardiac death, but automated detection is limited by strong class imbalance, where lethal arrhythmias account for fewer than 22% of ECG segments. In this setting, standard classifiers can achieve high accuracy by predicting normal rhythm in most cases while missing many lethal events, a failure mode referred to as rare-class collapse. We evaluated six imbalance-handling approaches: naive logistic regression, inverse-frequency reweighting, label-distribution-aware margin loss (LDAM), cost-sensitive training, two-stage cascade classification, and anomaly detection on 15,614 ECG segments from three PhysioNet databases (VTaC, VFDB, CUDB), with an overall normal-to-lethal ratio of 3.6:1. All methods were assessed at a fixed operating point of 95% specificity using recall, area under the precision-recall curve (AUPRC), and missed-lethal-event rate (MLER). The naive model achieved 45.1% recall (MLER = 0.549), missing 564 of 1,027 lethal events despite 84.1% accuracy. The two-stage cascade performed best, with 65.2% recall, AUPRC of 0.821, and MLER of 0.348, reducing missed events by 37% and achieving the highest decision-curve net benefit. Per-source analysis showed near-complete VF detection (recall up to 0.975) but much lower VT detection (recall 0.183), suggesting a feature-space limitation due to spectral similarity between organized VT and rapid sinus rhythm. Overall, the results show that evaluation metrics strongly influence the visibility of rare-class failure, and that cascade-based methods outperform simpler reweighting approaches for detecting lethal arrhythmias.

Aims: Prognostic stratification and individual management are essential in the heterogeneous population of non-ischemic dilated cardiomyopathy (NIDCM). We applied unsupervised machine learning (ML) clustering in NIDCM cohorts, using semi-automated artificial intelligence (AI)-based cardiac magnetic resonance imaging (CMR) measurements with multimodal data to identify distinct phenotypes, characterize echocardiographic remodeling trajectories, and evaluate prognostic significance. Methods and results: We analyzed 347 patients with NIDCM from two tertiary centers who underwent CMR and echocardiography at baseline, with follow-up echocardiography at a median 12 months. The cohort was randomly divided into derivation (n=242) and validation (n=105) sets using stratification by the composite outcome. Remodeling trajectories were evaluated using follow-up echocardiographic changes, and associations with outcomes were assessed by multivariable Cox regression adjusted for age and sex. Using eleven comprehensive clinical, laboratory, echocardiographic, and CMR-derived variables, partitioning around medoids clustering identified three phenotypes: (i) a younger, male-predominant preserved phenotype; (ii) a metabolic, fibrotic-remodeling phenotype; and (iii) an atrial fibrillation-predominant biventricular dysfunction phenotype. Cluster 1 showed the most favorable prognosis, whereas Cluster 3 had the highest risk of the composite outcome. Although LV reverse remodeling occurred across all clusters, Cluster 3 was characterized by attenuated LA reverse remodeling, suggesting persistent LA dysfunction. Conclusion: Unsupervised ML-based clustering of NIDCM patients, integrating AI-derived CMR parameters with multimodal data, identified three clusters exhibiting distinct patterns in longitudinal echocardiographic trajectories and outcomes. This strategy may enable more individualized management in heterogeneous NIDCM.

Electrocardiographic (ECG) interval measurements underpin clinical decision-making and large-scale cardiovascular research, yet existing automated methods are often developed using small, heterogeneous datasets with limited expert annotation and uncertain generalisability to population cohorts. We developed a deep learning framework for automated PR, QRS, and QT interval estimation and established a large expert-curated reference dataset using UK Biobank (UKB) ECGs. The reference dataset comprises 11,330 lead-level annotations from 12-lead ECGs in 1,030 randomly selected UKB participants, generated using a standardised annotation protocol with independent expert review. A 1D convolutional neural network was trained to segment ECG waveforms and derive PR, QRS, and QT intervals. Performance was evaluated against expert annotations, UKB CardioSoft measurements, an open-source signal-processing toolbox, and a wavelet-based delineation method. Clinical validity was evaluated through associations with incident atrial fibrillation and major adverse cardiovascular events (MACE). Inter-observer agreement was high (ICC 0.81 - 0.97). In a held-out test set, the deep learning model achieved mean absolute errors of 7.7 ms (PR), 7.5 ms (QRS), and 4.9 ms (QT), outperforming all comparator methods, with minimal bias relative to expert annotations. Review of distributional outliers confirmed >80% validity for most interval measurements. Among 46,749 participants with follow-up (median 4 years), prolonged QTc derived by the deep learning model showed stronger associations with incident MACE (hazard ratio 2.9, 95% CI 2.1 - 4.0) than wavelet-based measurements (1.7, 1.4 - 2.0) or CardioSoft (1.1, 0.9 - 1.4). This expert-curated reference dataset and validated deep learning framework provide a scalable foundation for reproducible ECG phenotyping in UKB and beyond.

Purpose: RF-induced heating remains a major barrier to MRI access for patients with epicardial cardiac implantable electronic devices (CIEDs). Although ISO/TS 10974 Tier-3 transfer function (TF) methods are established for unbranched leads, no analogous framework exists for bifurcated leads, in which branch asymmetry and inter-branch coupling may substantially alter heating. We developed and validated a cumulative transfer function (cTF) framework to address this gap. Methods: Following ISO/TS 10974 Tier-3 formalism, we measured, calibrated, and validated cTFs for a commercial 35 cm bipolar epicardial lead at 1.5 T. The framework explicitly accounts for branch-specific response and cross-branch coupling. Validation was performed with 24 canonical lead configurations in a homogeneous phantom and, without recalibration, in a heterogeneous anthropomorphic pediatric phantom with clinically derived trajectories. A single-branch TF approximation served as a comparator. The validated cTF was applied to predict RF heating across adult and pediatric human models at multiple imaging landmarks. Results: Compared with the single-branch TF approximation, the cTF reduced prediction error by nearly 70% in the primary validation dataset. In secondary validation, the cTF maintained low error across clinically relevant trajectories and imaging landmarks. In human models, the framework revealed marked anatomy- and landmark-dependent variation in predicted heating for the tested 35 cm lead, with low predicted heating in pediatric models and substantially higher heating in selected adult chest and upper abdominal imaging scenarios. Conclusion: The cTF provides a validated framework for RF-heating assessment of bifurcated leads and substantially improves prediction accuracy over single-branch TF approximations that neglect branch coupling.

Background: Short and long sleep duration have been linked to atrial fibrillation (AF), but their influence on arrhythmia recurrence after catheter ablation is uncertain. We evaluated the association between nocturnal sleep duration and the risk of recurrent arrhythmias in patients undergoing catheter ablation for AF in the PREDIMAR trial. Methods: The PREDIMAR study is a multicentre, randomized, controlled, single-blind trial evaluating a Mediterranean diet enriched with extra-virgin olive oil for preventing arrhythmia recurrence after catheter ablation for AF. Nocturnal sleep duration was categorized as adequate (6?8 h/day) or inadequate (<6 h/day or >8 h/day). Multivariable Cox regression models estimated the association between sleep duration and the risk of recurrent atrial flutter (AFL) or AF. Results: Among 720 participants, we observed 226 incident cases of AF relapse and 107 cases of AFL. Inadequate nocturnal sleep duration was associated with a significantly higher risk of AFL recurrence compared with adequate sleep (adjusted HR = 1.87; 95% CI 1.18?2.96). No significant association was observed for AF recurrence (HR = 0.99; 95% CI 0.70?1.41). The association with AFL recurrence was particularly evident in patients with persistent AF at baseline before ablation (adjusted HR = 3.42; 95% CI 1.47?7.97), whereas no significant relationship was observed in those with baseline paroxysmal AF. Conclusions: Inadequate nocturnal sleep duration (<6 h/day or >8 h/day) may increase the risk of AFL recurrence following AF ablation. These findings highlight the relevance of sleep habits as a modifiable behavioural factor potentially influencing post-ablation outcomes.

Heart failure with preserved ejection fraction (HFpEF) commonly coexists with atrial fibrillation (AF), but shared mechanisms remain unclear. In this study, we hypothesized that Pitx2, a transcription factor located near the strongest genetic locus associated with AF in humans, increases susceptibility to HFpEF-like remodeling. We also sought to understand pathways that might be central to this increased risk. Male and female Pitx2+/- mice and wild-type littermates received 3-week subcutaneous osmotic pump infusion of saline or angiotensin II (Ang II; 500 ng/kg/min). Cardiac structure and function were assessed by echocardiography and catheterization, and functional capacity by exercise treadmill. RNA transcriptomic profiling was performed to identify candidate pathways. In a separate cohort, Ang II-treated mice were randomized to oral GKT136901 (30 mg/kg/day) or vehicle during infusion. After Ang II infusion, Pitx2+/- mice developed exaggerated HFpEF-like changes, including greater left ventricular hypertrophy, left atrial enlargement, diastolic dysfunction, elevated left ventricular end-diastolic pressure, and reduced treadmill performance. RNA-seq showed enrichment of metabolic and stress-response pathways with selective upregulation of Nox4, confirmed by RT-qPCR. GKT136901 attenuated structural remodeling, diastolic dysfunction indices, elevated filling pressures, and cardiomyocyte hypertrophy, but did not improve endurance. These findings implicate redox signaling, including Nox4, in AF genetic susceptibility-HFpEF interactions.

Ensheathing pericytes extend multiple projections that wrap around capillary vessels to regulate diameter and direct blood flow distribution across the microvascular network. At capillary bifurcations, individual projections wrap around branches of different diameters, positioning the pericyte to simultaneously regulate multiple vessel segments. Using optogenetic tools in acta2-opto-1AR and acta2-CatCh mice, we show that Gq-coupled receptor activation confines contractile responses to the projection receiving the stimulus, whereas direct membrane depolarization propagates to projections wrapping neighboring capillary branches via gap junction-independent mechanisms. Computational modeling revealed that TRPM4, a Ca2+-activated nonselective cation channel, uniquely couples local Ca2+ signals to voltage-gated Ca2+ channel activation in projections on neighboring branches at physiologically relevant channel abundances. Ca2+ imaging identified two kinetically distinct event populations: slow, low-amplitude IP3R-mediated events and fast, high-amplitude VGCC-mediated transients. Sustained low-amplitude signals selectively maintained TRPM4 activation and enabled cross-projection propagation, whereas brief high-amplitude transients drove rapid channel inactivation. Proximity ligation assays confirmed nanoscale colocalization of TRPM4 and IP3 receptors in pericytes. Focal IP3 photolysis produced constriction across projections wrapping multiple capillary branches that was abolished by TRPM4 blockade and enhanced by PKC-mediated augmentation of TRPM4 expression. These findings identify an IP3R-TRPM4 signaling axis as a molecular switch that gates whether capillary constriction remains branch-specific or coordinates across the pericyte, enabling precise stimulus-dependent control of blood flow distribution in the microvasculature.

After myocardial infarction (MI), pathological autonomic remodeling, including vagal dysfunction and sympathoexcitation, occurs and predisposes to ventricular arrhythmias (VT/VF). The underlying factors that drive this remodeling, including the observed neuroinflammation and glial activation, remain unknown. We hypothesized that sympathetic nociceptive afferents underlie this remodeling post-MI. Epidural resiniferatoxin (RTX, to ablate sympathetic cardiac afferent neurons) vs. saline was administered in pigs prior to MI and autonomic and electrophysiological effects assessed four to six weeks post-infarction. Acute effects of afferent ablation after chronic MI were also assessed in a separate group of animals. Baroreflex sensitivity and vagal tone, as measured by parasympathetic neuronal activity and cardiac nociceptive responses, were improved in infarcted animals which received epidural RTX prior to MI. These animals also demonstrated reduced spinal cord inflammation and glial activation, downregulation of circulating stress and inflammatory pathways, and stabilization of electrophysiological parameters, with reduced VT/VF-inducibility. Epidural RTX after chronic MI also acutely restored vagal function and decreased VT/VF. These data suggest that cardiac spinal nociceptive afferents directly contribute to VT/VF susceptibility and MI-induced autonomic remodeling, including oxidative stress, inflammation, glial activation, and reduced vagal function, providing novel insights into the causal role of these afferents in driving sympathovagal imbalance after MI.

Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal storage disease caused by pathogenic variants in NPC1 or NPC2. Sudden death can occur due to seizures, but cardiac involvement has not been well defined. We performed 12-lead electrocardiograms (ECG) in 14 adult NPC patients (8 male, 6 female). Cardiac structure and function were examined in Npc1-/- adult mouse hearts, alongside wild-type controls. Glycosphingolipid accumulation was quantified by high-performance liquid chromatography, fibrosis and collagen deposition were quantified using Massons Trichrome (M&T) and Picrosirius Red (PR) staining. Whole-heart morphology, including chamber size and wall thickness, was assessed. Ex vivo ECG recordings assessed conduction abnormalities and arrhythmias. RNA-seq transcriptomics characterised molecular pathways altered in Npc1-/- hearts. 8/14 patients showed ECG abnormalities including abnormal QRS transitions (N=8), increased QRS amplitude (N=4), fascicular block (N=2), and abnormal T wave inversion (N=1). 13 patients also had transthoracic echocardiograms identifying mildly impaired LV systolic function (N=2) and increased wall thickness/LV mass (N=4). In Npc1-/- mice, age-related glycosphingolipid accumulation was associated with pronounced ventricular fibrotic remodelling. There was a significant increase in stained connective tissue area and connective tissue to cardiac tissue ratio in both MT and PR staining. ECG from Langendorff-perfused Npc1-/- hearts showed QT prolongation and atrioventricular conduction abnormalities under isoprenaline stress. Transcriptomics revealed major changes in Npc1-/- hearts, consistent with histological fibrosis and linking NPC to inflammation-driven remodelling and arrhythmogenesis. These findings support routine cardiac screening in NPC patients and highlight the need for further studies to improve management and treatment.

We conducted a scaling evaluation of unlabeled pretraining for electrocardiogram foundation model performance. One-dimensional vision transformer masked autoencoders were pretrained across increasing ECG volumes and fine-tuned for rhythm, morphology, diagnostic, and structural heart disease tasks. Models pretrained below 400,000 ECGs failed to consistently exceed controls without self-supervised pre-training, whereas 600,000 to 800,000 ECGs improved AUROC across tasks, suggesting a minimum threshold for effective ECG representation learning.

Background: Postoperative atrial fibrillation (POAF) is a frequent complication following coronary artery bypass grafting (CABG) and is associated with increased acute morbidity and resource utilization. However, its independent role in driving post-discharge adverse events in contemporary practice remains debated. Objective: To evaluate the association between POAF and short-term outcomes after CABG, and to utilize empirical Bayesian risk updating to stratify 90-day post-discharge vulnerabilities. Methods: A retrospective cohort analysis of 4,684 adult patients who underwent isolated CABG in Florida between January 1, 2021, and June 30, 2024, was conducted, excluding those with documented preoperative AFib. We employed multivariable negative binomial and logistic regression models to assess length of stay (LOS), discharge disposition, 90-day readmission, and 90-day composite complications. Additionally, a Bayesian Beta-Binomial conjugate model with an objective Jeffreys Prior was utilized to estimate the posterior probabilities of adverse outcomes across key clinical phenotypes. Results: POAF occurred in 355 patients (7.58%). Multivariable analysis demonstrated a 30% relative increase in expected LOS (IRR 1.30, 95% CI [1.23 - 1.36], P < .001) and 33% higher odds of facility discharge (OR 1.33, 95% CI [1.03 - 1.72], P = .030) for patients with POAF. However, POAF was not independently associated with 90-day readmission (OR 1.25, P = .063) or composite complications (OR 1.20, P = .118). Chronic heart failure (CHF) emerged as the dominant predictor. Bayesian risk updating revealed that while the baseline posterior probability for a 90-day complication was 27.2%, the synergistic presence of both POAF and CHF radically shifted this posterior risk to 42.6% (Probability of Direction > 0.999 vs. baseline). Conclusions: POAF prolongs hospitalization and drives non-home discharges, but it does not independently dictate 90-day morbidity. Bayesian stratification demonstrates that post-discharge outcomes are predominantly driven by underlying chronic conditions. Effective reduction of readmissions requires robust transition-of-care frameworks, empowering primary care clinicians to aggressively optimize heart failure and metabolic disease rather than focusing solely on the acute surgical arrhythmic event.