Heart Rhythm

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: 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.

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.

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.

BackgroundRemote monitoring (RM) enables convenient follow-up of patients with cardiac implantable electronic devices. In remote-only monitoring (RM-only) in-person visits are only scheduled if needed based on RM findings. This study evaluated the feasibility and safety of long-term RM-only of pacemaker (PM) patients. MethodsAll patients with Biotronik PM were included in the analysis. Data on the number and causes of additional in-office device interrogations, actions due to the transmissions, hospitalizations and performance of RM were collected from a large cohort of pacemaker patients followed by RM-only. ResultsIn total 606 patients (302 female) with mean age of 78{+/-}12 years were included in the analysis. During the mean follow-up of 2.8 years 445 additional in-office device interrogations were made in 287 patients (0.3 interrogations / year), and in 110 (25%) of these cases changes to device programming were made. In a subgroup analysis of 100 patients with at least one year of prior appointment-based device monitoring, the need for in-office visits was 6.9 times higher per follow-up year than in RM (IRR=6.9, 95% CI 4.9-9.9; p<0.001). The hospitalization rate in the entire cohort during RM was 0.3 / year with no difference in the rate of hospitalizations between the two monitoring methods (IRR 1, 95% CI 0.8-1.4, p=0.8). The success of daily transmissions was 91.7 %. ConclusionOur real-word data indicate that RM-only offers an efficient and safe method for long-term follow-up of pacemaker patients.

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.

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

BACKGROUNDSotalol loading intravenously enables achieving blood levels of sotalol that are observed at maximal steady-state concentration (Cmax ss) in one-day permitting the measurement of maximum QTc effects. Rapid evaluation of the QTc effects permits determination of arrhythmic risk and thus permits discharge in 24-hours instead of the usual three-day oral load hospitalization. Given the expense of IV Sotalol an oral loading test strategy is presented that also achieves Cmax ss blood levels rapidly, permitting a one-day hospitalization for QTc evaluation. METHODPharmacokinetic parameters referred to in the literature derived from normals as well as patients was utilized for population pharmacokinetic modeling and simulation.to obtain the Cmax ss concentrations for patients with normal renal function, creatinine clearance (CrCl) > 90 ml/min), as well as for patients with a CrCl of 60-89, 30-59, and 10-29 ml/min). Using pharmacokinetic simulations, an oral loading dose, as well as a second oral dose were determined that would reach the estimated Cmax ss in each of the groups based on renal function. RESULTSFor target dosing of 120 mg oral sotalol BID in patients with a CrCl >90 ml/min an oral loading dose of 200 mg provides a peak sotalol level of 1,420 ng/ml in 3-4 hours post dosing. The Cmax ss target is 1,299 ng/ml resulting in a 9% overshoot. The Cmax ss concentration provides a means of evaluating QTc effects within 24-hours. Oral loading regimens are described for varying additional renal function levels (CrCl 60-90, 30-59 and 10-29 ml/min) along with the time to first oral dose and follow-up dosing. The initial test dose can be based on an 80 or 120 mg oral sotalol maintenance dosing strategy. CONCLUSIONSEmploying an oral loading strategy may permit QTc evaluation and one-day discharge, preserving the pharmacoeconomic advantage of a Cmax ss test strategy. Clinical PerspectiveO_ST_ABSWhat is Known?C_ST_ABSO_LIIntravenously loading of sotalol enables achieving blood levels that are observed at maximal steady-state concentration (Cmax ss) in one-day permitting the measurement of maximum QTc effects. C_LIO_LIRapid evaluation of the QTc effects permits determination of arrhythmic risk and thus permits discharge in 24-hours instead of the usual three-day oral load hospitalization C_LI What the Study AddsO_LIWith oral sotalol loading, the Cmax ss can also be achieved in one-day permitting the measurement of maximum QTc effects and discharge from the hospital in 24-hours instead of the usual three-day inpatient initiation of oral sotalol. C_LI

PurposeObstructive sleep apnea (OSA) is a common comorbidity in heart failure (HF) patients with prevalence increasing as HF severity worsens. While CPAP/BiPAP has been shown to reduce disease burden and mortality in the general HF population, it is unclear whether these benefits extend to patients with left ventricular assist devices (LVADs). We sought to determine whether OSA affects long-term survival in newly implanted LVAD patients and whether CPAP/BiPAP treatment confers mortality benefits. MethodsThis single-center retrospective study included patients who underwent LVAD implantation between January 2007 and February 2022. Recipients were stratified by OSA status (OSA vs No-OSA), and those with OSA were further categorized based on CPAP/BiPAP compliance. Comparative statistics and Kaplan-Meier survival analyses were performed, with log-rank tests used to compare groups and assess survival differences. A Cox proportional hazards model was conducted to evaluate the association between risk factors and survival among patients with OSA and No-OSA. ResultsBefore LVAD implantation, patients with OSA had higher body mass index, hypertension, and a higher rate of implantable cardioverter-defibrillator placement than those without OSA. OSA was not associated with increased postoperative complications. Although survival did not differ significantly between OSA and No-OSA patients (p=0.33), CPAP/BiPAP-compliant OSA patients had significantly better survival than noncompliant patients (p=0.0099). ConclusionsLVAD patients with OSA who consistently use CPAP/BiPAP have better survival than those who do not. CPAP/BiPAP is a simple, low-risk treatment that can reduce mortality in this population. Therefore, increased perioperative screening for OSA should be considered for patients receiving LVADs. Multicenter studies are needed to confirm our findings further.

BackgroundGuideline-directed medical therapy (GDMT) has been shown to improve mortality and/or symptoms in heart failure with reduced ejection fraction (HFrEF). Medical devices also play an important role in improved quality of life and overall symptom relief for HFrEF patients. Baroreflex Activation Therapy (BAT) increases parasympathetic nervous system activity by stimulating the carotid baroreceptors, thereby reducing symptoms. Herein, we analyzed the effects of BAT on hospitalization, atrial arrhythmia (AA), and ventricular arrhythmia (VA) rates. MethodsA retrospective cohort study was conducted consisting of HFrEF patients treated with BAT at Keck Hospital of USC between 11/2014 and 11/2022. We compared median pre-BAT hospitalization, AA, and VA rates to post-BAT rates at both 6- and 12-months using Wilcoxon Signed Rank tests. ResultsAmong 31 patients on BAT, 38.7% met criteria for receiving all four GDMT classes for at least 12 months prior to BAT. Among these, 91.7% had an implantable cardioverter defibrillator (ICD) implanted for [&ge;]12 months pre- and post-BAT. Average pre- vs. post-BAT all-cause hospitalization rates were significantly different only at 12 months [1.3 {+/-} 1.4 vs 0.3 {+/-} 0.9, respectively (p=0.05)]. Borderline significant pre-post comparisons were noted including decreased VA rate at both 6 and 12 months and increased AA rate at 12-months (p=0.06 for all). ConclusionIn HFrEF patients on full GDMT, BAT was associated with a significant reduction in hospitalization rates at 12 months. There were no significant changes in AA or VA rates.

Structured AbstractO_ST_ABSBackgroundC_ST_ABSGuideline recommendations for infective endocarditis (IE) prophylaxis have narrowed significantly over the past decade. However, these recommendations are derived from adult data and may not adequately account for the unique risk factors for IE in pediatric and congenital heart disease (CHD) patients with cardiac implantable electronic devices (CIEDs). ObjectiveTo characterize contemporary IE cases and prophylaxis practices among members of the Pediatric and Congenital Electrophysiology Society (PACES) and assess how these practices align with or diverge from current international guidelines or practice recommendations. MethodsA cross-sectional, web-based survey was distributed to PACES members worldwide. Questions addressed prophylaxis practices for CIED implantation, reinterventions, and bacteremia-inducing procedures, as well as clinician experience with IE in patients with CIED. Responses were analyzed descriptively. ResultsSubstantial practice heterogeneity was identified across multiple clinical scenarios. Although most clinicians aligned with guideline recommendations for patients with structurally normal hearts, nearly all respondents (92.3%) reported recommending lifelong prophylaxis for patients with complex or repaired CHD. Among 35 reported IE cases, 97% occurred in transvenous systems, 77% occurred >6 months post-implantation, and 90% lacked a clear procedural or infectious trigger. Despite successful device extraction in 77% of cases, significant morbidity and mortality were observed. ConclusionCurrent practice patterns among pediatric and congenital electrophysiologists reflect uncertainty regarding the applicability of adult-derived IE prophylaxis guidelines to younger patients with CIEDs. High observed morbidity, long-term device exposure, and distinct anatomic considerations highlight the need for pediatric-specific risk stratification and updated guidance.

General anesthetics enable invasive experimentation but can affect cardiovascular and respiratory physiology, biasing preclinical outcomes. We compared five anesthetic regimens in adult male Wistar rats, tribromoethanol (TBE, 250 mg/kg i.p.), chloral hydrate (CH, 400 mg/kg i.p.), ketamine-xylazine (KX, 80/10 mg/kg i.p.), thiopental (TP, 80 mg/kg i.p.), and isoflurane (ISO, 4% induction, 2% maintenance), to investigate integrated cardiorespiratory and biochemical markers. Femoral arterial catheterization allowed continuous blood pressure (BP) and derived heart rate (HR) recordings, while ventilation was assessed through pletysmography at baseline (awake), during induction, and recovery phases of anesthesia. Variability was evaluated in the time and frequency domains, including HR, systolic blood pressure (SBP), and spontaneous baroreflex sensitivity. In an independent cohort of rats, butyrylcholinesterase (BChE), CK-MB, cTnI, and LDH were measured. Baseline BP was unchanged by TBE and TP, whereas all anesthetics affected HR. Minute ventilation and breathing frequency were reduced with all agents, while tidal volume decreased with KX and TBE only. LDH and cTnI were unaffected, BChE was reduced by KX, TBE, and ISO, and CK-MB increased with CH and KX. Variability analysis showed that all anesthetics depressed pulse-interval and SBP variability and shifted spectral power toward higher frequencies, while baroreflex sensitivity and effectiveness were consistently reduced. During recovery, KX and TP restored most variability indices, whereas CH, TBE, and ISO showed persistent suppression. These findings highlight distinct profiles of cardiovascular depression and biomarker responses across anesthetics and underscore the importance of accounting for autonomic variability when selecting different anesthetics in experimental protocols. HighlightsO_LIFive anesthetic regimens were tested in rats. C_LIO_LIAll anesthetics reduced ventilation, and KX and TBE also reduced tidal volume. C_LIO_LICH and KX increased CKMB, while KX, TBE and ISO reduced BChE. C_LIO_LIAll anesthetics reduced blood pressure variability and baroreflex sensitivity. C_LIO_LIVariability recovered with TP and KX, whereas CH, TBE and ISO showed persistent suppression. C_LI

BackgroundGenetic testing is now recommended for select patients with early-onset atrial fibrillation (AF). Hemochromatosis is an autosomal recessive syndrome that occurs in patients who carry two pathogenic or likely-pathogenic (P/LP) variants in HFE. HFE is included on some genetic testing panels used for patients with AF. Hemochromatosis causes cardiomyopathy due to iron overload in the ventricle; however, it is unknown whether AF can be an early manifestation that is identified by genetic testing. MethodsA total of 347 patients were referred to a dedicated AF precision medicine clinic. The clinical diagnostic evaluation included an H&P, 12-lead ECG, ambulatory ECG monitoring, and cardiac imaging (cardiac MRI and/or TTE). Genetic testing was performed using CLIA-approved laboratories: Labcorp/Invitae, GeneDx, or Vanderbilt University Medical Center. HFE was included on the cardiomyopathy panel used by 2 of the 3 laboratories. ResultsHFE was tested in 165 participants (median age 46 years [IQR 35-55], 115 [70%] male, 149 [90%] White). Six participants (4%) had two pathogenic variants in HFE. All of them were C282Y/H63D compound heterozygotes. Forty-one participants (25%) were heterozygous carriers of one pathogenic HFE variant. Among the 6 participants with 2 pathogenic HFE variants, the median ferritin level was 346 mcg/L [IQR 262, 496] (normal <300 mcg/L males, <200 mcg/L females). Three participants (50%) met laboratory criteria for iron overload. One individual had isolated ferritin elevation with normal transferrin saturation. All 6 underwent cardiac MRI as part of the genetic evaluation for early onset AF, and there was no evidence of cardiac siderosis based on cardiac T1 mapping median 990 ms [IQR 968-1024] (normal 960-1030 ms). Dedicated sequences to evaluate for iron overload demonstrated short hepatic T2* in one individual, indicating presence of hepatic iron overload (9 ms, normal >11.4 ms; liver iron concentration 3.4 mg/g, normal <2 mg/g). Three out of 6 participants were referred for a hematology evaluation and 2 out of 6 were started on therapeutic phlebotomy. ConclusionGenetic testing can identify patients with early-onset AF who are genetically susceptible to hemochromatosis, have evidence of iron overload, and receive early intervention with therapeutic phlebotomy. These results suggest HFE should be sequenced as part of genetic testing for early-onset AF, but larger sample sizes are needed to confirm these results.

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.

Background Heterotaxy (HTX) describes abnormal left-right arrangement of the organs, often associated with complex congenital heart disease (CHD). HTX is enriched in the respiratory condition primary ciliary dyskinesia (PCD) due to defective nodal cilia. A subset of patients presents with HTX and mild respiratory phenotypes but normal respiratory cilia function. The mechanisms underlying situs defects in these non-PCD patients remain unclear. Methods Retrospective diagnostic data were analysed from 73 HTX patients who had been referred to the Royal Brompton Hospital PCD Diagnostic Service (1997 to 2023). Data included clinical history, high-speed video microscopy, transmission electron microscopy of ciliary ultrastructure, PCD genotype and clinical imaging for cardiac and abdominal situs. Results 30 patients were diagnosed with PCD, and 43 patients did not have PCD. CHD was observed in both PCD and non-PCD groups. Atrioventricular discordance was more frequent in non-PCD HTX (20.9% vs 0%; p=0.0102). Midline Liver position was also enriched in the non-PCD HTX group compared to PCD patients with HTX (54.3% vs 25.9% p=0.0377). TEM revealed 24.4% of the non-PCD patients had extra ciliary microtubules and 24.4% demonstrated microtubular disorganization. Review of diagnostic results from 2,823 referred patients showed a higher incidence of ultrastructural ciliary anomalies, such as extra microtubules or microtubular disorganisation, in individuals with CHD who did not have PCD (p=0.04 when compared to patients without CHD, regardless of HTX). Quantitative ciliary function assessment demonstrated preserved or higher ciliary beat amplitude in non-PCD HTX compared to PCD patients. Conclusions In conclusion, HTX can be linked to respiratory ciliary dysfunction, even in patients without classical PCD. Subtle ciliary defects in non-PCD HTX patients associate with higher rates of CHD and abnormal organ situs. Genetic and phenotypic diversity in HTX highlights the need for expanded genetic testing and future multicentre studies to assess outcome.

IntroductionAdverse drug reactions (ADRs) remain a major public health issue, and genetic factors contribute importantly to interindividual variability in drug response. Pharmacogenetic testing helps reduce ADR risk by optimizing drug selection and dosage, particularly in monogenic disorders. Material and MethodsWhole-exome sequencing of 6,739 samples from the Russian population was performed using the MGIEasy Universal DNA Library Prep Set on the DNBSEQ-G400 platform (MGI). Variants in 48 genes were examined, focusing on inherited arrhythmias (Long QT syndrome, Short QT syndrome, Timothy syndrome, Andersen-Tawil syndrome, Brugada syndrome, Atrial fibrillation, Catecholaminergic polymorphic ventricular tachycardia), enzyme deficiencies (Glucose-6-Phosphate Dehydrogenase Deficiency [G6PDD], Porphyrias), Dravet Syndrome (DS) and Malignant Hyperthermia (MH). All identified variants had been reported at least once as pathogenic (P) or likely pathogenic (LP) in ClinVar, along with those occasionally classified as variants of uncertain significance (VUS). Each variant was manually re-evaluated according to ACMG criteria. ResultsA total of 75 unique variants in 18 genes were observed in 119 individuals (1.77%), including 21 carriers and 13 women with a G6PD mutation. Of these, 46 variants were classified as P, 21 as LP, and 8 as VUS. Missense variants accounted for the largest proportion (73.33%). The most affected genes were KCNQ1 (24/119), which exhibited the highest number of unique variants (18), G6PD (20/119), SCN1A (15/119), and RYR1 (14/119). Regarding associated conditions, mutations linked to arrhythmias were found in 51 individuals, MH in 27, G6PDD in 20, DS in 15, and Porphyrias in 6. ConclusionsIncorporating genetic information on both common and rare clinically actionable variants into therapeutic decision-making has the potential to improve medication safety, reduce preventable ADRs, and enhance the effectiveness of personalized pharmacotherapy.

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

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.

BACKGROUND: Observational studies have suggested an association between obstructive sleep apnea (OSA) and myocardial infarction (MI), but whether this relationship is causal or largely reflects shared risk factors remains unclear. METHODS AND RESULTS: We performed a 2-sample Mendelian randomization (MR) analysis to evaluate the causal effect of OSA on MI. Summary statistics for OSA were obtained from FinnGen, and MI data were obtained from the UK Biobank, with external validation using CARDIoGRAMplusC4D. Mediation MR was used to assess 13 potential mediators, and a 6-step multivariable MR framework was applied to estimate the direct effect of OSA after sequential adjustment for potential confounders. Reverse MR was conducted to test possible reverse causality. Genetically predicted OSA liability was associated with increased MI risk (odds ratio [OR] per log-OR increase, 1.0024 [95% CI, 1.0010-1.0039]; P=0.001). Body mass index (BMI) was the strongest mediator, explaining 35.94% of the association (P=0.030), whereas systolic blood pressure (SBP) showed minimal mediation (0.28%; P=0.678). In stepwise multivariable MR, the OSA-MI association was attenuated after adjustment for BMI and SBP (P=0.156), suggesting partial confounding by shared cardiometabolic risk. In a model including SBP and atrial fibrillation (AF), AF remained independently associated with MI (P=0.004), whereas OSA showed only a marginal direct effect (P=0.050). Reverse MR found no evidence that MI influenced OSA risk. CONCLUSIONS: These findings support a causal association between OSA and MI and suggest that this relationship may be mediated in part through obesity-related and arrhythmia-related pathways. AF may represent an important intermediate component of OSA-related cardiovascular risk beyond traditional hemodynamic factors. Keywords: obstructive sleep apnea; myocardial infarction; Mendelian randomization; mediation analysis; obesity.