Atrial fibrillation (AF) is associated with reduced quality of life and frequent hospitalizations. Integrated nurse-led care (NLC) has proven beneficial in unselected AF patients, but evidence specific to patients undergoing catheter ablation is limited. We aimed to assess the impact of a structured nurse-led intervention in patients undergoing first-time AF ablation. NURSECAT-AF was a single-center prospective randomized clinical trial comparing usual care with NLC, which incorporated an AF educational program, peri-procedural support, and risk factor management. Consecutive patients without heart failure referred for first-time AF ablation were randomized to NLC or usual care. NLC visits were scheduled at 15 days preablation, 15 days, and 6 months postablation. The primary end point was quality of life at 12 months postablation using the arrhythmia-specific scale in tachycardia and arrhythmia. Secondary outcomes included arrhythmia recurrence, readmissions and emergency visits, and symptom burden at 1 year and AF knowledge and satisfaction at 3 months. Of 116 patients screened, 66 were randomized (33 per group; mean age 63±10 years; 67% male). At 12 months, the NLC group showed statistically significant better quality of life (baseline-adjusted arrhythmia-specific scale in tachycardia and arrhythmia difference +4 points [95% CI, 1.8-6.3]; P=0.0007) than usual care, and presented with less arrhythmia recurrences (odds ratio, 0.2 [95% CI, 0.05-0.78]) and emergency visits (odds ratio, 0.2 [95% CI, 0.06-0.66]). Patients assigned to NLC also presented with a lower symptom burden, higher satisfaction, and greater disease knowledge. Risk factor profile was improved in the NLC group, with higher rates of smoking cessation, engagement in regular physical activity, and weight optimization. Nurse-led management enabled more frequently diagnosing obstructive sleep apnea. Nurse-led, integrated care for patients undergoing AF ablation improves the quality of life, clinical outcomes, and risk factor management at 1 year postprocedure. These findings support the incorporation of structured nurse-led interventions in the peri-ablation care pathway. URL: https://www.clinicaltrials.gov; Unique identifier: NCT05333445.
Despite the growing popularity of electronic cigarettes, evidence is mounting that vaping induces autonomic nervous system imbalance, cardiac arrhythmia, and potentially even cardiac arrest. The ingredients menthol, WS-3, and WS-23 are cooling agents that enhance the appeal of electronic cigarettes (e-cigs) but bear unknown risks when inhaled. We systematically evaluated how these coolants influence the impacts of e-cigs on cardiac and cellular electrophysiology in mice and human induced pluripotent stem cell-derived cardiomyocytes, respectively. Mice were exposed by inhalation to e-cig aerosols generated from standard e-liquid solvents and 2.5% nicotine benzoate (vehicle), or from vehicle plus menthol, WS-3, or WS-23, at increasing concentrations throughout exposure. Telemetry-derived electrocardiograms were analyzed for changes in heart rate, heart rate variability, morphology, and ventricular premature beat arrhythmias. Human induced pluripotent stem cell-derived cardiomyocytes were evaluated for the effects of serially increasing coolant concentrations on beat rate, electric field potential duration, and rate-corrected field potential duration from a newly validated formula, in the absence and presence of norepinephrine to simulate basal physiology and nicotine-evoked sympathoexcitation. Upon e-cig aerosol inhalation, all coolants acutely enhanced vehicle-induced autonomic imbalance, but only the synthetic coolants, WS-3 and WS-23, potentiated ventricular arrhythmogenesis. Ventricular premature beats during e-cig exposures correlated with sympathetic dominance and transient delays in ventricular repolarization measured by heart rate variability and rate-corrected QT interval, respectively; however, correlations were strongest for WS-23 despite no significant impact of coolants on nicotine intake. Conversely, in human induced pluripotent stem cell-derived cardiomyocytes, coolants did not affect basal physiology but slowed beat rate and shortened rate-corrected field potential duration during norepinephrine stimulation. Together, these data indicate that coolants dose-dependently enhance the arrhythmogenicity of e-cigs, likely through acute alterations in autonomic modulation and repolarization. Pending confirmation by human studies, these common non-nicotine additives may exacerbate e-cig cardiotoxicity and pose unique cardiovascular risks, particularly in those with arrhythmogenic susceptibility to sympathetic stimulation or slowed ventricular repolarization.
Combining radiofrequency (RF) and pulsed-field (PF) applications in various combinations, or repeating PF applications, has been reported to augment lesion size and depth. We compared lesion dimensions using single, double, and combined applications of PF and RF for the large-footprint lattice-tip catheter. Sixteen swine underwent endocardial ablation using the lattice-tip catheter. Four-second PF and 5-second, saline-irrigated, temperature-controlled RF energy were delivered in the ventricles using 1 of 5 different settings: single applications of PF (PF1-only), single RF (RF1-only), and 3 sequential settings: PF1-PF2 (2 consecutive PF applications at the same location), PF1-RF1 (PF followed by RF), and RF1-PF1 (RF followed by PF). A total of 102 lesions (69 left and 33 right ventricles) were analyzed. Mean lesion depths were 6.8±0.3 mm (PF1-PF2), 6.6±0.3 mm (RF1-PF1), 5.7±0.2 mm (PF1-only), 5.0±0.3 mm (PF1-RF1), and 5.1±0.2 mm (RF1-only). Mean lesion depths did not differ significantly between PF1-PF2 and either PF1-only or RF1-PF1 (P=0.114 and P=0.986, respectively). However, the variability in depth was significantly smaller in the PF1-PF2 group compared with both PF1-only and RF1-PF1 (P=0.017 and P=0.013, respectively). Only the PF1-PF2 setting produced significantly deeper lesions compared with the RF1-only and PF1-RF1 settings (P=0.015 and P=0.012, respectively). RF lesions exhibited a prominent dark hemorrhagic core and a thin pale rim; PF lesions appeared uniformly pale; and combination lesions demonstrated a central dark zone surrounded by a pale rim of variable thickness. Repeating PF twice created the optimal combination of greatest depth and least variation compared with all other strategies. RF1-PF1 resulted in similar depth, but required toggling between settings and risked thermal adverse events.
Catheter ablation has been shown to improve prognosis in patients with heart failure (HF) and atrial fibrillation (AF); however, the optimal ablation strategy remains undefined. In this multicenter, randomized controlled trial, 300 patients with persistent AF and HF, including both HF with reduced ejection fraction (ejection fraction ≤40%) and HF with preserved ejection fraction (ejection fraction >40%, including mid-range ejection fraction [ejection fraction 41% to 50%]), were enrolled and randomized equally to the anatomic-guided ablation, electrogram-guided ablation, and extensive electrogram-anatomic-guided ablation groups, with 100 patients in each group. The coprimary end points were: (1) the composite of cardiovascular death or HF-related hospitalization/urgent visit within 36 months; and (2) maintenance of sinus rhythm at 36 months. Secondary end points included AF burden <1%, New York Heart Association class improvement (≥1 grade), 6-minute walk test change, NT-proBNP (N-terminal pro-B-type natriuretic peptide) reduction, and procedure-related complications. Subgroup analyses were performed for HF with reduced ejection fraction and HF with preserved ejection fraction. At 36 months, the extensive electro-anatomic-guided ablation group demonstrated the lowest incidence of the composite end point (17.0%) compared with the electrogram-guided ablation (29.0%) and anatomic-guided ablation (36.0%; overall P=0.010) groups, and the highest rate of sinus rhythm maintenance (62.0%) compared with the electrogram-guided ablation (53.0%) and anatomic-guided ablation (44.0%; P=0.039) groups. Consistent improvements were observed for AF burden <1%, New York Heart Association class, 6-minute walk test, and NT-proBNP. Major complications were low and similar across all groups. These trends were consistent in both the HF with reduced ejection fraction and HF with preserved ejection fraction subgroups. Electrogram-anatomic ablation provides superior long-term rhythm control, reduces cardiovascular events, and improves symptoms in patients with persistent AF and HF, regardless of ejection fraction. URL: https://www.clinicaltrials.gov; Unique identifier: NCT07153718.
Atrial cardiopathy often precedes atrial fibrillation (AF) and has emerged as an independent risk factor for cardiovascular outcomes. However, previous studies have been limited in size and have overlooked the right atrium. In 51 693 UK Biobank participants without prevalent AF, we assessed biatrial volumes and emptying fraction from cardiac magnetic resonance imaging using deep learning segmentation. We evaluated associations with new-onset AF, ischemic stroke, heart failure, and dementia, conducted a genome-wide association study, and evaluated causal associations using Mendelian randomization. Among 51 693 adults, the mean (SD) age was 65 (7.7) years, and 24 584 (48%) were male. During the 4-year follow-up, 964 (1.9%) developed AF, 266 (0.5%) developed ischemic stroke, 365 (0.7%) developed heart failure, and 72 (0.1%) developed dementia. After adjustment for clinical risk factors, both left and right atrial measures were associated with new-onset AF (left atrial minimal volume; hazard ratio, 1.55 [95% CI, 1.48-1.62]), ischemic stroke, and heart failure, with stronger associations in women. Left atrial minimal volume was also associated with dementia. Our genome-wide association study identified 51 (27 novel) genetic associations with atrial measures, many of which do not overlap with established AF loci. Genetic correlations revealed that each atrium had varying correlations with cardiometabolic risk factors, and Mendelian randomization demonstrated that left atrial measures had direct causal effects on AF and stroke risk. However, the stroke associations were attenuated after accounting for AF variants. In this largest assessment of biatrial structure and function to date, both left and right atrial cardiopathies were independently associated with increased risk of adverse cardiovascular events. We identified several novel genetic loci for atrial traits and observed unique genetic correlations between left and right atrial traits and cardiovascular phenotypes, providing insight into chamber-specific remodeling. Several of these measures are likely to be causal determinants of cardiovascular complications previously attributed to AF.
Atrial fibrillation (AF) is associated with substantial morbidity and mortality. We sought to investigate the predictive value of serum metabolomics for 5-year incident AF in the context of clinical and polygenic risk score (PRS) stratification tools. We studied a cohort of 240 628 patients UK Biobank participants with proton nuclear magnetic resonance spectroscopy measurements of 170 serum metabolites at enrollment. Five-year incidence of AF was assessed using Cox proportional hazards models. Cohorts for Heart and Aging Research in Genomic Epidemiology-AF (CHARGE-AF) and AF polygenic risk score (AF-PRS) scores were used as benchmark risk models for comparison. Models were trained on 80% of the cohort, and performances were validated on the remaining 20% cohort. Performance of clinical, AF-PRS, and combined metabolomics models was evaluated using time-dependent area under the receiver operating characteristic curve, net reclassification improvement, and relative integrated discrimination improvement analysis. During follow-up, 4174 (1.7%) participants developed AF. After training a model on the full metabolomics panel in addition to Cohorts for Heart and Aging Research in Genomic Epidemiology-AF and AF-PRS, the final model retained 8 metabolites. Creatinine level was associated with increased risk (hazard ratio, 1.01 per 1 SD log-transformed value [95% CI, 1.00-1.03]) while linoleic acid level (hazard ratio, 0.985 [0.979-0.994]) was associated with decreased risk of AF. The addition of metabolomics to the CHARGE-AF+AF-PRS model improved risk prediction (5-year time-dependent area under the receiver operating characteristic curve, 0.789 [0.776-0.802] versus 0.755 [0.738-0.772]; P<0.05) and stratification on the validation set (NRIcases: 11.1%, NRIcontrols: 3.1%, IDIrelative: 11.6%). A model using only age, sex, metabolomics, and AF-PRS had fair risk prediction on the validation set (5-year time-dependent area under the receiver operating characteristic curve, 0.787 [0.773-0.801]). The addition of metabolomics to clinical and genomic risk scores improves the prediction of 5-year incident AF. A risk stratification tool using age, sex, and serum metabolomics and AF-PRS provides excellent AF risk prediction. Mechanisms by which specific metabolites reflect AF risk require further exploration.
Exercise training improves contractile function and can reduce arrhythmia burden after a myocardial infarction (MI). How exercise modifies the proarrhythmic status is uncertain. In this study, rats 6 weeks post-MI were randomized to an 8-week high-intensity exercise program (MI-EX) or to a sedentary control group (MI-SED) and compared with a sedentary sham group (Sham-SED). After the exercise program, in vivo and ex vivo programmed electrical stimulation was performed on the rat hearts. Subsequently, optical mapping was conducted to electrophysiologically characterize the MI hearts. Exercise significantly improved maximal oxygen uptake (VO2max; MI-EX, 67 mL·min-1·kg-0.75 versus MI-SED, 47 mL·min-1·kg-0.75). In vivo cardiac stimulation protocols indicated reduced inducibility of ventricular arrhythmias in MI-EX compared with MI-SED. This anti-arrhythmic effect was retained ex vivo in Langendorff-perfused hearts. Optical mapping of the noninfarcted left ventricle indicated a prolonged average action potential (AP) duration at 4.5 Hz pacing frequency in both MI groups compared with Sham-SED. As pacing frequency increased (6.5 Hz and ≈8 Hz), AP duration remained significantly longer in the MI-SED group but decreased in the MI-EX group, demonstrating a negative frequency dependency. Spatial heterogeneity of AP duration in the noninfarcted left ventricle area was increased post-MI but was significantly reduced following exercise. Optical AP recorded from the remnant myocardium within the scar showed similar AP duration characteristics at low stimulation frequencies, but AP upstroke time was shorter in the MI-EX group compared with MI-SED. Post-MI exercise was associated with electrophysiological changes in both the noninfarcted region and the remnant myocardium within the scar. These changes suggest a mechanism for the anti-arrhythmic effects of exercise following MI.
Alterations in microtubule dynamics have been shown to affect cardiomyocyte membrane stiffness and modulate ion channels, including the cardiac sodium channel. While conditions, such as heart failure and Duchenne muscular dystrophy, are associated with increased detyrosination of microtubules and reduced sodium current, a potential role for microtubule detyrosination in arrhythmogenic cardiomyopathy has not been explored. We here investigated the impact of microtubule detyrosination on membrane stiffness, cardiac sodium channel distribution, and function in mouse and human models of arrhythmogenic cardiomyopathy. Isolated ventricular cardiomyocytes from mice with cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 (plakophilin-2), as well as PKP2-c.2013delC, and isogenic control human-induced pluripotent stem cell-derived-cardiomyocytes were incubated for 2 to 4 hours with compounds known to decrease microtubule detyrosination (parthenolide, 10 µmol/L; EpoY, 20 µmol/L) or vehicle (dimethyl sulfoxide). Immunocytochemistry, mechano-scanning ion conductance microscopy, patch-clamp analysis, and stochastic optical reconstruction microscopy were performed. Cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 cardiomyocytes displayed increased microtubule detyrosination and membrane stiffness, which were both attenuated by parthenolide treatment. Parthenolide significantly increased whole-cell sodium current density in cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 mouse cardiomyocytes, with macropatch measurements demonstrating that this increase occurred both at the intercalated disc and lateral membrane. Stochastic optical reconstruction microscopy analysis revealed that parthenolide increased cardiac sodium channel cluster density at the intercalated disc of cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 mouse cardiomyocytes. In contrast, parthenolide had no effect on sodium current, cardiac sodium channel cluster size, or density in cardiomyocytes from control mice. PKP2-c.2013delC human-induced pluripotent stem cell-derived-cardiomyocytes displayed increased microtubule detyrosination and reduced sodium current compared with isogenic control human-induced pluripotent stem cell-derived-cardiomyocytes, which were both prevented by parthenolide and EpoY. Increased microtubule detyrosination secondary to loss of PKP2 impacts cardiomyocyte (dys)function beyond the desmosome, contributing to both electrical and mechanical alterations in the setting of arrhythmogenic cardiomyopathy. Our findings identify microtubule detyrosination as a novel therapeutic target in pathophysiological conditions, such as arrhythmogenic cardiomyopathy, aimed at improving both contractile and electrical function.
Spontaneous automaticity of sinoatrial node cells (SANCs) is driven by a system that couples ion channels, membrane clock and Ca2+clock, the sarcoplasmic reticulum generated LCRs (local subsarcolemmal Ca2+releases). Although LCRs are critically dependent on high basal cAMP and both PKA (protein kinase A)- and CaMKII (Ca2+/calmodulin dependent protein kinase II)-dependent protein phosphorylation, the link between cAMP and CaMKII remains unclear. Here, we tested a hypothesis that high cAMP activates EPAC (exchange protein directly activated by cAMP) which increases basal CaMKII activity, reinforcing the coupled clock pacemaker system, to boost LCRs and accelerate spontaneous SANC firing. Real-time quantitative polymerase chain reaction, Western blot, immunostaining, whole-cell patch clamp, and line-scan confocal microscopy were employed to study EPAC-dependent regulation of rabbit SANC firing. Both EPAC isoforms were expressed and active in SANC. Selective inhibition of EPAC1 (CE3F4) or EPAC2 (HJC0350) similarly suppressed basal CaMKII activity, CaMKII-dependent phosphorylation of Ca2+-cycling proteins (PLB [phospholamban] and RyR [ryanodine receptors]) and reduced the amplitude of L-type Ca2+current. EPAC1 and EPAC2 inhibitors significantly decreased LCR number, size, and prolonged the LCR period (interval between prior AP-induced Ca2+transient and LCR) reducing spontaneous SANC firing by ≈30%. In contrast, EPAC activator (8-pCPT) increased LCR number and size, shortened the LCR period and accelerated spontaneous firing by≈18%. EPAC-mediated effects were implemented in PKC-dependent manner via EPAC-PLC-PKC-CaMKII signaling pathway, since PKC inhibitor reproduced effects of EPAC inhibition on CaMKII activity, CaMKII-dependent phosphorylation of Ca2+-cycling proteins, LCR parameters, and spontaneous SANC firing. EPAC is an essential component of basal cardiac pacemaker function, which accelerates spontaneous automaticity of SANC via an increase in basal CaMKII-dependent phosphorylation of Ca2+-cycling proteins (PLB, RyR, L-type Ca2+channels, and likely others), leading to amplification of LCR parameters, shortening of LCR timing and resultant spontaneous cycle length. Consequently, EPAC might represent a novel therapeutic target to regulate resting heart rate and treat sinoatrial node dysfunction.
Early repolarization syndrome (ERS) is diagnosed in survivors of unexplained cardiac arrest (UCA) who exhibit a distinct ECG pattern of early repolarization (ER), defined as J-point elevation ≥0.1 mV in ≥2 contiguous inferolateral leads. UCA survivors without ER or another identifiable cause are classified as idiopathic ventricular fibrillation (IVF). This study evaluated long-term outcomes in ERS compared with IVF. This retrospective cohort study analyzed patients from the CASPER (Cardiac Arrest Survivors with Preserved Ejection Fraction Registry) who survived UCA and had structurally normal hearts with an Implantable Cardioverter Defibrillator. Of 709 patients, 186 with explanatory diagnoses and no ER pattern were excluded. The remaining 523 were categorized as ERS (n=48), IVF (n=463), or UCA with ER plus an additional diagnosis (Dx+ER, n=12). Patients were followed for the primary outcome of appropriate Implantable Cardioverter Defibrillator therapy, and logistic regression identified predictors of arrhythmia recurrence. Corrected QT interval intervals were significantly shorter in ERS than in IVF (412±25 ms versus 431±41 ms; P<0.01). Over a median follow-up of 5.6 years, appropriate Implantable Cardioverter Defibrillator interventions occurred in 23% of ERS and 13% of IVF patients (P=0.09), with incidence rates of 3.0 and 1.5 per 100 person-years, respectively. Four deaths occurred (0.8%), with no significant difference between groups (P=0.39). In Dx+ER, appropriate Implantable Cardioverter Defibrillator therapies occurred in 42% of patients (incidence rate, 4.5 per 100 person-years). Arrhythmia-free survival was lower in ERS than in IVF (P=0.03). After adjusting for age, sex, and ethnicity, ER was an independent predictor of arrhythmia recurrence (odds ratio, 2.59 [95% CI, 1.33-4.85]; P=0.004). ERS is associated with shorter corrected QT interval intervals and reduced arrhythmia-free survival compared with IVF, with an incidence rate of 3.0 per 100 person-years. These findings underscore the importance of careful ECG review in patients with apparent UCA, to detect ER and undertake individualized risk assessment in affected individuals.
Integration of catheter-tissue contact force with pulsed field ablation (PFA) dosing is essential for achieving safe and durable lesion formation with contact force sensing catheters in ventricular models. However, data on the use of these catheters for atrial ablation remain limited. This study evaluated the procedural safety and 30-day lesion characteristics of atrial PFA delivered with the OMNYPULSE ablation catheter in a porcine model. Twelve pigs were randomized to receive either 6 (×6 or Group A) or 12 (×12 or group B) PFA applications per ablation. Following 3-dimensional electroanatomic mapping, PFA was delivered to the right superior and inferior pulmonary veins, cavotricuspid isthmus, right atrial posterior wall, left atrial roof, and mitral annulus. Procedural safety was assessed acutely, and lesion characteristics were evaluated on 30-day histology. Maximum transmurality extent (MTE) was defined as >80% of the lesion span exhibiting continuous endocardial-to-epicardial fibrosis within representative histological sections. Adequate catheter-tissue contact was achieved during PFA delivery (contact force, 28±15 g). No acute procedural complications were observed. At 30 days, PVs and right atrial sites (ie, cavotricuspid isthmus and right atrial posterior wall) demonstrated near-complete MTE regardless of PFA dosing. In contrast, MTE was significantly lower at the mitral annulus and LA roof compared with other sites (44±30% and 21±26%, respectively; P<0.001). Increasing the number of PFA applications (×12) resulted in a remarkable improvement in MTE at these locations, with MTE increases of up to 68% compared with ×6 dosing at these sites. Atrial PFA using the OMNYPULSE catheter was feasible and safe in a porcine model. However, lesion transmurality varied by atrial location and was dose-dependent at select sites, underscoring the need for site-specific PFA dosing strategies. Further studies are warranted to define optimal PFA parameters for consistent atrial lesion formation.
Intracardiac echocardiography (ICE) is increasingly used to guide left atrial appendage occlusion as an alternative to transesophageal echocardiography (TEE), particularly in elderly patients for whom general anesthesia may pose additional risks. Real-world comparative safety data in older adults remain limited, with prior studies including only small ICE cohorts. We aimed to compare short- and long-term outcomes of ICE- versus TEE-guided left atrial appendage occlusion in adults aged ≥80 years. We queried the TriNetX US Collaborative Network to identify patients aged ≥80 years with atrial fibrillation who underwent percutaneous left atrial appendage occlusion from 2015 to 2025. Patients were stratified by imaging modality: ICE- versus TEE-guided approach. Propensity score matching (1:1) was performed across demographics and comorbidities, yielding 2913 patients per group. Outcomes were assessed from the index procedure through 7 days, 90 days, and 1 year using Cox proportional hazards models to generate hazard ratios with 95% CIs. Outcomes included mortality, stroke, device thrombosis, pericardial effusion, pericardiocentesis, tamponade, and device leak. Baseline characteristics were well balanced after matching, with a mean age of 83 years and 44% women. At 90 days, ICE and TEE demonstrated no significant differences in mortality (hazard ratio, 1.18 [95% CI, 0.81-1.73]), stroke, device thrombosis, pericardial effusion, pericardiocentesis, tamponade, or device leak. At 1-year follow-up, mortality (hazard ratio, 0.93 [95% CI, 0.76-1.13]), stroke, and device thrombosis remained similar between groups. However, ICE was associated with a higher incidence of device leak compared with TEE (hazard ratio, 1.81 [95% CI, 1.11-2.97]). In this large propensity-matched cohort of very elderly patients undergoing left atrial appendage occlusion, ICE and TEE demonstrated comparable rates of mortality, stroke, and device thrombosis at 90 days and 1 year. ICE was associated with a higher rate of device leak at 1 year, warranting careful procedural technique and follow-up surveillance. Prospective studies are needed to define optimal intraprocedural imaging strategies in this high-risk population.
Premature atrial contractions (PACs) are independently associated with atrial fibrillation, stroke, and heart failure, yet no pharmacological therapy is approved for PAC suppression. Experimental studies have identified a functional cardiac glutamatergic system in which N-methyl-D-aspartate receptors regulate atrial electrophysiology. Preclinical studies show that pharmacological antagonism of N-methyl-D-aspartate receptors with memantine suppresses atrial arrhythmias. We conducted an investigator-initiated, phase 2, multicenter, randomized, double-blind, placebo-controlled trial. Symptomatic adults with frequent PACs (≥1000/24 h) were randomly assigned to receive memantine or placebo for 6 weeks. The primary end point was the percentage change in mean 24-hour PAC count from baseline to the end of treatment. The primary analysis was performed in the intention-to-treat population. Prespecified secondary end points included the responder rate (≥50% PAC reduction), percentage change in nonsustained atrial tachycardia burden, and cumulative incidence of new-onset atrial fibrillation. Among 241 patients included in the efficacy analysis, memantine resulted in a greater reduction in PAC count than placebo (between-group difference, 47.1 percentage points; P=0.0045). The responder rate was higher with memantine than with placebo (52.4% versus 23.1%; P<0.0001). Memantine also reduced nonsustained atrial tachycardia burden (between-group difference, 30.98 percentage points; P=0.0043) and was associated with a lower cumulative incidence of new-onset atrial fibrillation (4.8% versus 23.9%; P<0.0001). No clinically meaningful differences were observed in electrocardiographic intervals or left ventricular function, and no drug-related serious adverse events occurred. In patients with frequent symptomatic PACs, memantine reduced atrial ectopy and atrial tachyarrhythmia burden and demonstrated a favorable safety profile. These findings provide proof of concept for a novel, non-ion channel-based therapeutic strategy targeting the cardiac glutamatergic system. URL: https://www.clinicaltrials.gov; Unique identifier: NCT06501638.
The cingulo-insular region is crucial for modulating cardiac activity. However, the distinct roles of its anatomic subdivisions in modulating sympathetic-parasympathetic balance remain poorly defined. We aimed to explore the distinct contributions of subdivisions within the cingulo-insular region to modulating cardio-autonomic balance. In this prospective observational study, patients with drug-resistant epilepsy undergoing stereo-electroencephalography with electrical cortical stimulation of the cingulo-insular region were enrolled. Stereo-electroencephalography and ECG signals were synchronously recorded during electrical cortical stimulation of the cingulo-insular region. Heart rate variability and R-R interval analyses were conducted to assess cardiac sympathetic-parasympathetic balance. The correlation coefficient between heart rate variability and the strength of phase-amplitude coupling in stereo-electroencephalography was calculated before and after stimulation. Data from 33 patients (70 electrode contacts, 287 trials) were analyzed. Stimulation of the anterior cingulate gyrus enhanced parasympathetic activity, correlated with increased local phase-amplitude coupling strength. The left anterior cingulate gyrus stimulation increased pNN50 (median difference, -5.00% [95% CI, -17.99 to -0.16]; P=0.044); right anterior cingulate gyrus stimulation increased the SD of all normal-to-normal intervals (median difference, -14.22 ms [95% CI, -26.68 to -1.63]; P=0.019) and SD2 (median difference, -19.49 ms [95% CI, -33.26 to -3.22]; P=0.013). Meanwhile, stimulation of the posterior insula significantly reduced the parasympathetic component of heart rate variability and short-term R-R interval. The left posterior insula decreased the SD1/SD2 ratio (median difference, 0.08 [95% CI, 0.03-0.15]; P=0.005); right posterior insula decreased power in the high-frequency range (median difference, 25.30 ms2 [95% CI, 3.98-49.35]; P=0.013) and the approximate entropy (median difference, 0.15 [95% CI, 0.04-0.29]; P=0.004). Within the cingulo-insular region, the anterior cingulate gyrus is associated with a relative cardio-parasympathetic dominance, while the posterior insula is linked to a relative cardio-sympathetic dominance. These findings provide a deeper understanding of the neural modulation of cardio-autonomic balance, and may have implications for the prevention and treatment of cardio-autonomic dysfunction in neurological disorders.
Although emerging evidence supports 3-dimensional myocardial activation during atrial fibrillation (AF), human studies remain limited. We thus characterized the endocardial and epicardial left atrial posterior wall (LAPW) in humans to assess the prevalence of asynchronous endocardial-epicardial LAPW conduction during AF. Patients with symptomatic nonparoxysmal AF who had unsuccessful antiarrhythmic or catheter ablation therapy referred for hybrid epicardial-endocardial AF ablation and left atrial appendage ligation underwent high-density mapping of LAPW with Grid catheters, including simultaneous endocardial-epicardial mapping. Twenty-seven patients (19 men, median 69 years, 55% long-standing persistent AF) were included. There was significantly greater epicardial compared with endocardial LAPW bipolar voltages during AF. In areas of low endocardial bipolar voltage, normal endocardial unipolar voltage corresponded to normal epicardial bipolar voltage. Asynchronous endocardial-epicardial LAPW AF activation during simultaneous endocardial-epicardial mapping was universal. Furthermore, more rapid epicardial compared with endocardial LAPW AF activity was observed during simultaneous endocardial-epicardial mapping in AF. Conduction block between the endocardial and epicardial LAPW surfaces was also common during organized AF, with instances of isolated or multiple blocked beats, Wenckebach conduction, and sustained endocardial LAPW entrance block with ongoing epicardial AF observed. Epicardial-to-endocardial entrance block was also infrequently observed during sinus rhythm. At 12-month follow-up, freedom from atrial arrhythmias was 68%. Endocardial-epicardial LAPW asynchrony may be observed during human persistent AF and is characterized by: (1) greater epicardial compared with endocardial bipolar voltages, (2) more frequent epicardial-to-endocardial activation gradients during AF, and (3) conduction block commonly seen between the epicardial and endocardial surfaces during AF. Although the study was predominantly descriptive in nature, the observations suggest a dynamic 3-dimensional arrhythmogenicity of the LAPW and the potential importance of the epicardial layer, with implications for ablation therapies. Future prospective studies are required to determine the significance of these findings to clinical ablation outcomes.
Current guidelines recommend regular screening for first-degree relatives of gene-elusive arrhythmogenic right ventricular cardiomyopathy (ARVC) patients using a similar regimen as for genotype-positive/phenotype-negative relatives. However, the multifactorial nature of gene-elusive ARVC may necessitate a different approach. This study aimed to determine the yield of cardiac screening in first-degree relatives of ARVC probands without a validated genetic cause. We included all first-degree relatives of probands who (1) met the 2010 Task Force Criteria, (2) underwent next-generation sequencing that included all genes with at least moderate evidence for ARVC causation per Clinical Genome Resource appraisal (validated ARVC genes), and (3) had no pathogenic/likely pathogenic (P/LP) variants identified in these genes. The primary and secondary end points were definite ARVC by the 2010 Task Force Criteria and ventricular arrhythmia, respectively. We included 44 relatives (39.0 [22.3-45.8] years; 36% male) from 24 families. In 4 (17%) families, a P/LP variant was identified in a different cardiomyopathy/arrhythmia gene (SCN5A, LMNA, CDH2, FLNC). Overall, 10 (23%) relatives had definite ARVC at baseline evaluation. Of the 20 relatives without definite ARVC who had follow-up available, 8/20 (40%) relatives progressed to definite ARVC during 9.0 (5.8-14.4) years of follow-up. No statistical difference in the yield of baseline screening or serial evaluation between relatives from families with a P/LP variant and relatives from families without a P/LP variant was observed. Of the 27 relatives who had follow-up available, ventricular arrhythmia was observed in 2/27 (7%) relatives and occurred 6.3 and 13.8 years after definite ARVC diagnosis. Both of those relatives were from families without a P/LP variant. These findings highlight the importance of managing first-degree relatives of ARVC probands without a validated genetic cause similarly to genotype-positive ARVC relatives. Furthermore, using a broad cardiomyopathy and arrhythmia gene panel in ARVC probands, rather than limiting testing to validated ARVC genes alone, is warranted.
The mechanisms behind endocardial entanglement and resultant delamination during left bundle branch area pacing, as well as potential solutions, have not been fully demonstrated in the human heart. Active fixation of a lumenless screw-in lead into the right ventricular septum was attempted with or without delivery system support using donor human hearts rejected for transplant. Delivery sheath support was ensured through firm catheter support maintained by a fixed clip. Endocardial entanglement, endocardial delamination after unscrewing, and lead penetration were evaluated using both macroscopic and microscopic analyses. Each of 10 lead deployments with or without support was attempted using 4 donor human hearts. There was a higher incidence of endocardial entanglement and resultant helix-only penetration in the nonsupport group than the support group (70% versus 0%). Unscrewing after the endocardial entanglement consistently revealed extensively delaminated endocardium entwined around the helix. The median endocardial delamination area was larger in the entanglement group than in the nonentanglement group (25.0 mm2 versus 0.9 mm2, P<0.001). In the regions with endocardial entanglement, histological analysis confirmed extensive endocardial delamination with minimal myocardial injury. On the other hand, localized endocardial delamination and deep intramural penetration were observed in the regions without entanglement. Screw-in procedures reattempted into the regions with extensive endocardial delamination following entanglement achieved deep penetration even without delivery system support. Endocardial entanglement and delamination were confirmed in donor human hearts. Adequate delivery system support, particularly its coaxiality and counterforce effect, is likely to prevent endocardial entanglement and facilitate effective penetration of a lumenless screw-in lead into the human ventricular septum.
Mapping of heart rhythms is influenced by the size and configuration of the mapping electrodes. Whether a recorded electrogram represents near (local) or remote activity influences diagnosis and treatment, yet is affected by mapping characteristics that are often undefined. We developed biophysical computational models to predict interactions between the recording tool and cardiac tissue in coherent and disorganized rhythms, which we validated in clinical recordings. Biophysical computational models demonstrated the ability to quantify and visualize the recording antennae for different electrode configurations. Our results show that unipolar electrograms reflected a recording antenna within 3-dimensional ellipsoids of radius 8 mm across-tissue and 2.7 mm transmurally. Bipolar electrogram antennae align with propagation direction in ellipsoids of long axis radius 1.7, 5.7, and 8.3 mm for 2, 5, and 10 mm spacing, respectively, and often extend beyond the physical extent of electrodes. Notably, omnipolar electrograms, constructed from orthogonal bipoles in a triangular configuration, retained some directional preferences of bipolar electrograms, with a complex relationship between electrode orientation and wave direction. When tested clinically on high-resolution, narrow field (grid) catheters and moderate-to-low resolution, global (basket) catheters, antennae varied more with electrode type (correlation coefficient of 0.43 unipolar, 0.05 bipolar, and 0.26 omnipolar; P<0.001) and spacing (correlation coefficient of 0.36 versus 0.42; P=0.002) than the precise electrode size. This novel computational-clinical system approach enabled us to systematically compare electrode configurations. This work may help interpret signals in complex biological rhythms, such as atrial fibrillation, and may influence the design of novel catheter configurations and signal processing approaches to identify local tissue signals.
The subcutaneous implantable cardioverter defibrillator (S-ICD) offers protection from sudden cardiac death without transvenous leads. Although contemporary techniques and programming have reduced inappropriate shocks, high rates persist in certain populations. The objective of this study was to evaluate the impact of a novel quantitative vector screening (QVS) protocol on the incidence of sensing-related complications and inappropriate shocks in patients undergoing S-ICD implantation. We analyzed 223 consecutive patients who underwent S-ICD implantation at the Hospital of the University of Pennsylvania from December 2018 to July 2025. Traditional vector screening was used before 2023. In 2023, we implemented QVS, which incorporated quantitative sensing scores for each candidate and raised the threshold for S-ICD implantation. The primary end point was time to first inappropriate shock or under-sensed ventricular arrhythmia. Secondary outcomes included SMART Pass deactivation and need for device revision. Outcomes were reported as survival analyses. During preimplant screening, the QVS protocol reduced patient eligibility from 96% to 83%. The median follow-up after implant was 42 months (interquartile range, 48) in the traditional vector screening arm and 18 months (interquartile range, 15) in the QVS arm. The primary end point of time to first inappropriate shock or under-sensed ventricular arrhythmia was longer in the QVS arm (log-rank, P=0.02). There were 23 primary end point events among 145 patients in the traditional vector screening arm (5.2 per 100 patient-years [95% CI, 3.1-7.4]) and 2 primary end point events among 78 patients in the QVS arm (1.8 per 100 patient-years [95% CI, 0.01-4.38]). Implementation of a novel S-ICD screening protocol with stricter eligibility thresholds reduced sensing-related complications, particularly inappropriate shocks.
Catheter ablation for atrial fibrillation is a widely used rhythm-control strategy, yet its role in reducing thromboembolic risk and enabling oral anticoagulation (OAC) discontinuation remains uncertain. This meta-analysis aims to comprehensively synthesize and evaluate randomized controlled trial evidence supporting long-term antithrombotic strategies in patients with atrial fibrillation undergoing catheter ablation. A systematic literature search was performed in MEDLINE/PubMed, Embase, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials evaluating antithrombotic strategies after catheter ablation for atrial fibrillation. The primary outcome was ischemic stroke. A frequentist network meta-analysis comparing reported treatment arms, along with a pooled incidence meta-analysis for outcomes of interest, was conducted. Four randomized controlled trials, including 3924 patients, met the inclusion criteria. Three trials compared long-term OAC continuation versus OAC discontinuation, and 1 compared OAC continuation with left atrial appendage occlusion after catheter ablation. No significant differences in stroke incidence were observed when comparing OAC or left atrial appendage occlusion with no antithrombotic therapy (incidence rate ratio, 0.90 [95% CI, 0.02-33.85]; P=0.95; incidence rate ratio, 0.79 [95% CI, 0.00-241.01]; P=0.94, respectively). Among patients who discontinued antithrombotic therapy without undergoing left atrial appendage occlusion (n=1161), with 2864 cumulative person-years of follow-up, the pooled incidence of stroke was 0.23 events per 100 person-years (95% CI, 0.02-2.43; I2=0%). This analysis reinforces that, across randomized data, the incidence of thromboembolic events in patients who discontinued OAC after successful ablation remained low. However, the evaluation of net clinical benefit is limited by the low number of events across all treatment arms, underscoring the need for larger studies with prolonged follow-up to further validate the safety of this strategy, particularly in higher-risk populations.