Heart Rhythm

Background: Congenital junctional ectopic tachycardia (cJET) is a rare, potentially life-threatening arrhythmia suspicious for a genetic basis, yet its molecular underpinnings remain incompletely defined. The POPDC2 gene, involved in cardiac pacemaking and membrane trafficking of interacting ion channels, has not previously been conclusively linked to human tachyarrhythmias. This study investigates a novel POPDC2 variant (p.Leu245Pro) identified in a family with autosomal dominant cJET. Methods: Exome sequencing was performed to identify co-segregating variants in the affected family. Functional analysis of the POPDC2 p.Leu245Pro variant was conducted by molecular dynamics (MD) simulations, a membrane targeting assay, and a bimolecular fluorescence complementation assay. Additionally, the impact of the variant on Nav1.5 and TREK-1 currents was characterized in Xenopus oocytes. Results: The p.Leu245Pro POPDC2 variant showed a destabilization of the POPDC1-POPDC2 dimer interface, resulting in impaired heterodimer formation and membrane localization. Electrophysiological studies in Xenopus oocytes demonstrated that the mutant protein significantly affected Nav1.5 and TREK-1 currents. These findings support a functional impact of the POPDC2 p.Leu245Pro variant relevant to cardiac conduction. Conclusions: Our results provide the first functional evidence implicating POPDC2 in cJET and support its role as a novel candidate gene in tachyarrhythmic disease. This study enhances the understanding of genetic contributions to cJET and suggests further investigation of POPDC2 in other forms of supraventricular tachyarrhythmias.

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 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.

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

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: Concomitant arrhythmogenic right ventricular cardiomyopathy (ARVC) and mitral valve prolapse (MVP) has only been described in case reports. Little is known about genetic and phenotypic characteristics of these patients. Objective: To describe the prevalence, genetics, and imaging characteristics of MVP in ARVC patients. Methods: We identified 111 definite ARVC cases through medical record review, arrhythmia/cardiomyopathy targeted gene panels, and contrast cardiac magnetic resonance data. MVP was diagnosed on echocardiography as mitral leaflet displacement greater than 2 mm above the annular plane in systole, with borderline MVP defined as less than or equal to 2 mm. Results: We found MVP/borderline MVP in 14% of ARVC patients. Cardiac arrest occurred in 20% of those with MVP/borderline MVP compared to 16% without valve abnormalities. Among 69 ARVC patients with identified genetic variants, PKP2 mutations were highly prevalent (64%), particularly in those with MVP (83%). Most MVPs had posterior prolapse (73%) and trace/mild mitral regurgitation (87%). None had mitral annular disjunction. ARVCs with MVP had higher LV mass (93 vs. 75 g/m2, p = 0.02) and a higher prevalence of LV wall motion abnormalities (27% vs. 5%, p = 0.02) compared to ARVCs without valve abnormalities. Conclusions: MVP is prevalent in ARVC and characterized by PKP2 variants in most cases. Typical features of arrhythmic MVP like bileaflet involvement and annular disjunction are rare in ARVC with MVP; features of arrhythmogenic left-sided cardiomyopathy (increased LV mass index and wall motion abnormalities) are more common. Further studies are needed to understand the role of MVP in arrhythmic risk stratification of ARVC.

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.

BackgroundDoxorubicin (DOX) causes sex-specific cardiotoxicity. Metabolic impairment is a well-established cardiotoxic effect of DOX treatment that can contribute to other detrimental effects such as increased reactive oxygen species, reduced ATP, inflammation etc. We hypothesized that preserving cardiac metabolism by exercise can attenuate DOX cardiotoxicity. MethodsMale and female C57BL/6J mice at 15 weeks of age were randomly assigned to one of four groups, 1) Control (sedentary), 2) EX (exercised, treadmill running), 3) DOX (doxorubicin at 5 mg/kg/week for 6 weeks), and 4) EXDOX (exercise + doxorubicin). Echocardiography was performed every other week during the 6-week protocol to measure cardiac mechanical function. At the end of the protocol, optical mapping and seahorse analysis were performed to measure electrophysiology and metabolism, respectively. RNA sequencing, cytokine array assay and transmission electron microscopy were also performed to determine sex-specific mechanisms of DOX cardiotoxicity. ResultsDOX reduced stroke volume and left ventricular diameter in males only and exercise did not prevent these effects of DOX. In female mice, DOX prolonged action potential duration (APD) and slowed conduction velocity (CV), and importantly, exercise prevented DOX-induced CV slowing. Exercise-induced cardioprotection against DOX in female mice was associated with preservation of aerobic metabolism and attenuation of inflammation which modulated ion channel gene expression. Specifically, Cacna1c was increased in both DOX and EXDOX females, but not in males and correlated with APD prolongation. Interestingly, despite CV slowing, Gja1 and Scn5a were increased. However, increased Kcnj8 along with metabolic impairment could cause membrane hyperpolarization and underlie CV slowing. ConclusionsDOX cardiotoxicity is sex specific. Mechanical dysfunction is more prevalent in DOX-treated males while arrhythmogenic electrical remodeling is more prevalent in DOX-treated females. Exercise therapy during DOX did not prevent DOX induced mechanical dysfunction in male hearts but attenuated electrical remodeling in females by preserving metabolism and attenuating inflammation.

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

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

Background: Higher METS-IR has been shown to be associated with a higher risk of major adverse cardiovascular events, but data are lacking regarding cardiac arrhythmias. Objectives: The aim of this study was to assess the association between METS-IR and atrial fibrillation/flutter, ventricular arrhythmia and bradyarrhythmia. Methods: Data from the Atherosclerosis Risk in Communities study spanning 1987 to 2013 was utilized for this analysis. METS-IR scores were assessed at baseline (1987-1989) and arrhythmia episodes were identified using ICD-9 codes. Multivariate-adjusted Cox proportional hazard models were constructed to evaluate the relationship between METS-IR and arrhythmia risk, with dose-response analyses conducted. In addition, we analyzed the predictive value of METS-IR for arrhythmias. Results: Over a mean follow-up of 21.9 years, 2493 cases of AF, 688 cases of bradyarrhythmia, and 1315 cases of ventricular arrhythmia were recorded. Each interquartile range increase in METS-IR was associated with a 49% higher risk of atrial fibrillation(P<0.001), 29% higher risk of bradyarrhythmia(P<0.001), and 42% higher risk of ventricular arrhythmia(P<0.001). After correction for relevant confounders, the METS-IR index was significantly and positively associated with the risk of new-onset atrial fibrillation, bradyarrhythmia, and ventricular arrhythmia (P overall<0.05, P for non-linearity>0.05). Most of the results of the subgroup analyses were not significantly different. The inclusion of METS-IR in the base model improves the predictive value of the risk of arrhythmogenesis. Conclusions: There is a significant association between METS-IR and increased risk of arrhythmias.

Background: Atrial Fibrillation (AF) is the most prevalent cardiac arrhythmia worldwide, representing the primary cardiac etiology of stroke. In recent years, direct oral anticoagulants (DOACs) have shown favorable results in terms of efficacy and safety in the prevention of thromboembolism in patients with AF. TROMBIX-DZ study investigated the safety and efficacy of rivaroxaban in routine clinical settings in response to the need for real-world evidence on the use of DOACs. Methods: We carried a national, multicenter, prospective, observational cohort study to evaluate the safety and efficacy of rivaroxaban in Algerian patients with atrial fibrillation. Patients were followed-up at 3 months intervals for 1 year. The primary outcome of this study was to evaluate the safety of rivaroxaban, reported as the frequency of treatment-emergent serious adverse events (SAEs); Secondary outcomes assessed the frequency of thromboembolic events, adverse events (AEs), and treatment persistence. Results: TROMBIX-DZ enrolled 398 eligible patients with AF from 19 specialized public and private cardiology centers across different regions in Algeria. The mean age was 70.5 {+/-} 11.94. 71.9% of patients received once daily rivaroxaban 20mg, and 28.1% received the 15mg dose. The most common comorbidities included, hypertension (77.1%), diabetes (28.6%) and heart failure (25.4%), prior strokes and TIA (8.8%), and prior major bleeding (3.1%). The mean CHA2DS2-VASc score was 3.147 {+/-} 1.3, and the mean HAS-BLED score was 1.682 {+/-} 1.198; 14.06% of patients had Creatinine clearance < 50 ml/min. A total of 5.77% had treatment-emergent AE, and 1.76% had treatment-emergent SAE. The incidence rate (events per 100 patient-years) of treatment-emergent major bleeding events, treatment-emergent thromboembolic events and all-cause death during the study period were 2.1, 0.9, and 4.18, respectively. Treatment persistence was 75.88% at the end of the study. Conclusion: TROMBIX-DZ study, the first cohort in the Maghreb region, provides important insights into the safety and efficacy of rivaroxaban in Algerian population with atrial fibrillation receiving standard medical care. Rates of major bleeding and stroke were low and broadly consistent with previous international real-world registries. Trial registration number: Clinicaltrial.gov: (NCT06184204). Keywords: Direct oral anticoagulants, Rivaroxaban, Atrial fibrillation, Major bleeding, Stroke, Thromboembolism, The Maghreb region, Real-world.

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.

Background: Postoperative atrial fibrillation (POAF) affects up to 50% of cardiac surgery patients and is linked to higher morbidity, longer hospital stays and increased thromboembolic risk. Early identification of at-risk patients remains challenging. Calcitonin (CT), a hormone with anti-fibrotic effects, may serve as a novel biomarker. Methods: In 491 patients undergoing elective cardiac surgery, baseline serum CT was measured preoperatively using CT-specific enzyme-linked immunosorbent assay (ELISA). Patients with pre-existing AF were excluded. Associations between CT levels and POAF incidence and onset were evaluated using logistic regression, Cox proportional hazards models, and Kaplan-Meier analysis. Results: Among 248 patients with detectable CT levels, 88 patients developed POAF. Higher baseline CT was independently associated with lower risk of POAF (OR 0.68 per 5 pg/ml increase; 95% CI 0.51-0.89; P = 0.009) and delayed arrhythmia onset (adjusted HR 0.941; 95% CI 0.898-0.980, P = 0.0026) after adjusting for covariates. Kaplan-Meier analysis demonstrated a graded relationship between increasing CT levels and reduced cumulative incidence of POAF. In this cohort, baseline CT showed greater discriminative ability than CRP and BNP, although overall model performance remained moderate. Conclusion. Higher preoperative circulating CT levels are associated with reduced risk and delayed onset of POAF following cardiac surgery. These findings suggest that calcitonin may have the potential as a biomarker for perioperative risk stratification in POAF. Given the observational design and single-centre setting, further validation in independent cohorts and studies integrating mechanistic insights are warranted.

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

Background: Atrial high-rate episodes (AHRE) detected by cardiac implantable electronic devices (CIEDs) are associated with increased thromboembolic risk, yet their clinical significance and optimal anticoagulation strategy remain uncertain, particularly in the absence of electrocardiogram (ECG)-confirmed atrial fibrillation. Methods: We conducted a nationwide cross-sectional survey of UK clinicians involved in CIED follow-up. The survey assessed anticoagulation decision-making in AHRE, including episode-duration thresholds, cumulative burden, CHA2DS2-VA use, additional ECG monitoring, and anticoagulant choice. Only responses from UK-based consultant clinicians were included and analysed descriptively. Results: A total of 51 responses were received; 38 met the inclusion criteria and were analysed. Most respondents (86.8%) reported having reviewed AHRE alerts within the preceding six months, indicating that AHRE are commonly encountered in clinical practice. A [&ge;]24-hour episode was the most common threshold for anticoagulation (44.7%), although many clinicians reported lower thresholds or individualised approaches. Nearly half (44.7%) did not consider cumulative AHRE burden in decision-making. CHA2DS2-VA thresholds also varied, most commonly [&ge;]2 or [&ge;]1. Additional ECG monitoring was infrequently performed. Direct oral anticoagulants were universally preferred, with apixaban the most commonly selected agent (73.7%). Conclusion: There is substantial variation in UK clinical practice regarding anticoagulation for AHRE, reflecting ongoing uncertainty and lack of clear guidance. These findings highlight the need for evidence-based thresholds to support consistent and informed clinical decision-making.

Cardiogenic shock (CS) is associated with high short-term mortality and the use of temporary mechanical circulatory support (tMCS) devices, especially left-sided microaxial flow pumps (Impella, Abiomed), has increased in recent years. However, few studies have investigated tMCS's effect on right ventricular-pulmonary artery (RV-PA) hemodynamics and its impact on clinical outcomes. We retrospectively analyzed all adult patients implanted with Impella 5.5 at our institution with acute myocardial infarction or acute decompensated heart failure-induced CS between 2019 to 2023. We found that Impella 5.5 led to an early improvement in RV-PA hemodynamics, even in patients with poor baseline RV function. In addition, we found that RV function itself did not predict death, post-heart transplant right ventricular-primary graft dysfunction, or post-left ventricular assist device severe RV failure. However, an increase in right atrial:pulmonary capillary wedge pressure ratio (RA/PCWP) despite tMCS support was a powerful prognosticator. Our study sheds important insight into anticipated hemodynamic changes after Impella 5.5 placement, supports the use of early tMCS even in patients with marginal RV function in the setting of left heart disease, and highlights the importance of serial assessment of RA/PCWP as a key determinant of CS outcomes.

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.

Background: Heterotopic caval valve implantation using the TricValve(R) (OrbusNeich P&F) is a unique interventional approach for treatment of severe Tricuspid Regurgitation in patients who are deemed ineligible for surgery. Given the complexity and novelty of TricValve(R) implantation, there is a pressing need for robust clinical data to evaluate its safety, efficacy, and long-term outcomes. Our study assesses the clinical results of patients followed up for 1 year from our center. Methods: Retrospective, single center registry involving patients who have undergone TricValve(R) Transcatheter Bicaval Valves System (OrbusNeich P&F) implantation for the treatment of severe tricuspid regurgitation. Results: Fourteen patients were included. The mean age was 67.5 {+/-} 8.7 years, with high surgical risk (mean EuroSCORE II 6.1 {+/-} 3.7). Procedural success was achieved in thirteen patients, with no reported in-hospital mortality or stroke among all fourteen patients. At 1-year, significant improvements were observed in New York Heart Association (NYHA) functional class (86% Class III at baseline to 0% Class III at 1 year, P=0.002) and Kansas City Cardiomyopathy Questionnaire (KCCQ-12) scores (mean 32.0 {+/-} 7.4 to 42.4 {+/-} 12.0, P=0.015). TR Regurgitant Volume significantly decreased (65.5 {+/-} 16.9 ml to 38.2 {+/-} 13.6 ml, P=0.005). No deaths or strokes occurred during follow-up. Rehospitalization due to heart failure occurred in 14% (2 out of 14) of patients. Conclusion: In this single-center registry of high-risk patients, TricValve(R) implantation was associated with a favorable safety profile, significant reduction in tricuspid regurgitant volume, and meaningful improvements in functional status and quality of life at 1 year follow-up.

AimsHeart failure with preserved ejection fraction (HFpEF) afflicts millions annually and current treatments provide symptomatic relief. Here, we investigate the therapeutic potential of synthetic human Relaxin-2 (RLX) at reversing diastolic dysfunction (DD) and reducing arrhythmia vulnerability. Methods and ResultsMale ZSF1 rats were placed on a normal diet (ND, N=10 controls) or a high-fat diet (HFD, N=11), resulting in the development of DD in 11-weeks, based on serial echocardiograms (enlarged left atrium (LA), wall thickness, doppler flow: E/e). Once HFpEF was confirmed, control and HFpEF rats were randomly treated with Relaxin (400{micro}g/kg/day RLX, N=6) or the vehicle (N=5) for 2-weeks using implanted minipumps. Echocardiograms were repeated at weeks 1 and 2, then hearts were isolated, optically mapped, subjected to programmed electrical stimulation (PES) and tissues dissected for immuno-fluorescence (IF), and qPCR analysis. Circulating levels of glucose, RLX and NT-pro-ANP were measured, pre- and post-treatment. Echocardiograms indicated that RLX reversed DD by reducing LA dimensions and E/e. Optical mapping revealed that 1/3 of HFpEF hearts exhibited sustained atrial and ventricular arrhythmia which were blocked by RLX as it tended to increase conduction velocity (CV). Based on IF, RLX increased Nav1.5, Connexin-43, {beta}-catenin and Wnt1 expression. There were no significant changes in fibrosis in this HFpEF model. NT-pro-ANP was elevated in HFpEF and reduced towards control values by RLX. qPCR analysis showed that RLX decreased DKK1 and MMP1A and increased SCN5A expression compared to Vehicle treatment (N=6 and 5, respectively). ConclusionsThe ZSF1 model showed clear signs of HFpEF, including DD, enlargement of the LA, enhanced hemodynamic stress, increased vulnerability to sustained AF and VF, and elevated glucose and blood pressure. RLX treatment largely reversed DD, hemodynamic stress, and suppressed sustained arrhythmias. RLX elicited cardiac genomic changes, most likely through Wnt/canonical signaling, demonstrating RLXs potential as a therapy for HFpEF.