BACKGROUND: Radiofrequency ablation of the mitral isthmus (MI) is unreliable. Vein of Marshall (VOM) ethanol infusion can improve MI ablation success and eliminate local MI autonomic innervation. The role of pulsed field ablation (PFA) in MI ablation and its autonomic effect is unclear. We evaluated the transmurality of endocardial PFA at the MI and its autonomic effects, using real-time epicardial VOM electrograms and VOM high-frequency stimulation. METHODS: Patients undergoing atrial fibrillation ablation (n=71) were prospectively enrolled. MI ablation (endocardial to VOM) was delivered using FaraPulse (N=31), PulseSelect (N=9), or Affera (N=31) while monitoring VOM epicardial electrograms to assess transmurality, defined as VOM signal elimination after 20 minutes. MI block was assessed using differential pacing from the left atrial appendage and VOM. High-frequency stimulation from the VOM was performed before and after PFA. VOM ethanol infusion was administered when MI ablation was incomplete. RESULTS: Endocardial PFA led to durable epicardial electrogram attenuation in 52.1% (FaraPulse in 38.7%, PulseSelect in 44.4%, and Affera in 67.7%; P <0.05). Myocardial capture with VOM pacing persisted in 43.7% (FaraPulse in 45.2%, PulseSelect in 100%, and Affera in 25.8%; P <0.05). Pseudoblock (epicardial-only MI conduction and MI delays) was present in 38%. MI block was achieved with PFA alone in 45% (32/71) of patients; VOM ethanol infusion achieved MI block in an additional 38% (27/71) of patients for a cumulative 83% (59/71); and coronary sinus ablation was required in the remaining 17% (12/71). After PFA, VOM high-frequency stimulation elicited intact parasympathetic responses evidenced as atrioventricular block. CONCLUSIONS: Across all 3 PFA platforms, endocardial ablation of the MI is not reliably transmural and does not ablate VOM parasympathetic innervation. VOM ethanol infusion can complete transmurality and denervation of the MI.
BACKGROUND:Left atrial appendage closure (LAAC) is an alternative to oral anticoagulation (OAC) for stroke prevention in patients with atrial fibrillation, but randomized controlled trials have primarily focused on composite end points, potentially obscuring differences in individual clinical outcomes. We compared the efficacy and safety of LAAC versus OAC with an emphasis on individual clinical outcomes. METHODS:A systematic review and meta-analysis of randomized controlled trials comparing LAAC with OAC in adults with atrial fibrillation was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Databases were searched from January 2000 to March 2026. The primary efficacy end point was any stroke, and the primary safety end point was major bleeding. Risk ratios (RRs) with 95% CIs were pooled using a random-effects model. RESULTS:Six randomized controlled trials comprising 7004 patients (3681 LAAC; 3323 OAC) were included. LAAC was associated with a higher risk of ischemic stroke (RR, 1.41 [95% CI, 1.04-1.91]; P=0.03; 3.2% versus 2.1%), without a significant difference in any stroke (RR, 1.08 [95% CI, 0.82-1.42]; P=0.60) or the composite of stroke, systemic embolism, or death (RR, 0.99 [95% CI, 0.77-1.29]; P=0.96). Cardiovascular mortality (RR, 0.88; P=0.40) and all-cause mortality (RR, 0.92; P=0.36) were similar between groups. Major bleeding, including procedural events, did not differ significantly (RR, 0.93; P=0.40), although LAAC was associated with a significantly lower risk of nonprocedural major bleeding (RR, 0.57 [95% CI, 0.43-0.77]; P<0.01; 6.2% versus 10.7%). CONCLUSIONS:In patients with atrial fibrillation, LAAC is associated with a higher risk of ischemic stroke, but lower risk of nonprocedural major bleeding compared with OAC, with no significant differences in composite thromboembolic outcomes or mortality, underscoring the importance of individualized risk-benefit assessment in stroke prevention strategies.
BACKGROUND: Pulsed field ablation therapies need to be optimized to maximize lesion depth while mitigating heat and musculoskeletal stimulation. We describe the adjustment of biphasic pulsed field ablation parameters for an irrigated tip catheter. METHODS: Experimental models all used an 8F, flexible-tip, irrigated ablation catheter. Computer simulation models were designed to assess the effects of bipolar versus monopolar applications. A vegetal (potato) model was used to assess the effects of voltage, pulse width, and number of pulses per burst on lesion depth. In-vitro testing on bovine cardiac muscle was performed with temperature sensors at the surface and 3 and 7 mm beneath the surface to measure temperature rises. Finally, an in vivo canine model was used to assess for musculoskeletal stimulation caused by the pulsed field ablation therapies established with the vegetal/in vitro testing. RESULTS: Monopolar delivery consistently delivered more tissue depth than bipolar configurations. Adjustments from n to n+1.0 µs and increasing pulses per burst from 50 to 250 increased lesion depth but also increased musculoskeletal stimulation. The optimized burst count was 5 R-wave-gated bursts over 4 to 9 seconds. The optimized therapy had a minimal observed depth of >5 mm and minimized musculoskeletal stimulation. Final selected therapies did create temperature rises, which were completely offset by irrigation rates of 7 to 13 mL/min. CONCLUSIONS: Pulse width and number of pulses per burst are important contributors to lesion depth, musculoskeletal stimulation, and incident heating. Even small adjustments in these parameters can alter lesion depth, muscle stimulation, and thermal effects, which will differentiate optimal from suboptimal pulsed field ablation.
BACKGROUND:Isthmus conduction velocity (CV) predicts ventricular tachycardia risk in tetralogy of Fallot and traditionally is calculated using electrogram-based methods (electrogram CV index [EGM-CVi]). Isochronal activation mapping approximates CV in adults with ischemic and nonischemic cardiomyopathy but has never been tested in congenital heart disease populations. Our objectives were to (1) investigate the diagnostic performance of isochronal CV index (ISO-CVi) in predicting inducible ventricular tachycardia and (2) compare it to traditional EGM-CVi in a population of patients with repaired tetralogy of Fallot undergoing electrophysiology study before transcatheter pulmonary valve replacement. METHODS:Retrospective cohort subanalysis of the CATAPULT-TOF registry (Catheter Ablation of Ventricular Tachycardia Before Transcatheter Pulmonary Valve Replacement in Repaired Tetralogy of Fallot). The primary outcome was inducible monomorphic ventricular tachycardia (MMVT) at electrophysiology study. Predictor variables were ISO-CVi and EGM-CVi. Electroanatomic activation maps profiling anatomic isthmus 3 were centrally adjudicated to measure anatomic isthmus 3 ISO-CVi; real-world anatomic isthmus 3 EGM-CVi values reported by contributing centers per the parent registry protocol were used as the comparator. Multivariable logistic regression and receiver operating characteristic analyses quantified associations between predictors and outcomes. RESULTS:Seventy patients with tetralogy of Fallot underwent pretranscatheter pulmonary valve replacement electrophysiology study at a median age of 40 (interquartile range, 24.8-51) years. Inducible MMVT was observed in 24 (34%). Median ISO-CVi was lower in those with versus without MMVT (0.17 versus 0.30 m/s; P<0.001). Median EGM-CVi did not differ between groups (0.43 versus 0.70 m/s; P=0.055). Coefficients of variation were higher for EGM-CVi (79%) than ISO-CVi (45%). On multivariable analysis, ISO-CVi was associated with MMVT (odds ratio, 0.14 [95% CI, 0.04-0.40]; P=0.0009) with a sensitivity and specificity of 88% and 70%, respectively, at a threshold of 0.22 m/s. CONCLUSIONS:ISO-CVi strongly associates with inducible MMVT and is measured with less variability than legacy EGM-CVi methods in a real-world sample. If external validity is confirmed, ISO-CVi may represent a more standardized method of isthmus CV estimation that could be broadly implemented across centers.
BACKGROUND:Peritricuspid, or cavotricuspid isthmus-dependent, atrial flutter is the most common arrhythmia in patients with dextro-transposition of the great arteries treated with atrial switch surgery, but its underlying mechanisms remain poorly understood. METHODS:Twenty consecutive patients with prior atrial switch surgery referred for atrial flutter ablation were included. All underwent transbaffle puncture and high-density mapping. Anatomic barriers, activation patterns, conduction velocities, and low-voltage areas were assessed. RESULTS:In all cases of peritricuspid atrial flutter, surgical incisions defined the posterior boundary of the circuit. The narrowest segment of the reentry was consistently located within a septal corridor bounded posteriorly by the baffle incision and anteriorly by the tricuspid annulus. Slow conduction (<30 cm/s) was identified in this septal corridor in 92% of peritricuspid flutters and in 85% of patients during sinus or paced rhythm. Low-voltage areas were limited and frequently colocalized with regions of slow conduction. No patient exhibited slow conduction or low voltage at the cavotricuspid isthmus. The septal corridor was also involved in 60% of nonperitricuspid reentrant atrial tachycardias. Programmed atrial stimulation with S2 mapping accentuated conduction delay in this region, with demonstration of functional block and induction of atrial flutter. CONCLUSIONS:In patients with dextro-transposition of the great arteries corrected by atrial switch, surgical incisions define posterior boundaries and create a narrow septal corridor, or baffle-tricuspid isthmus, characterized by slow conduction and a propensity for functional block. These anatomic and electrophysiological features likely underlie the high prevalence of peritricuspid reentry in this population, representing a ubiquitous critical substrate for arrhythmia initiation and maintenance. Systematic cavotricuspid isthmus ablation should, therefore, be considered in these patients.
BACKGROUND:Conventional activation mapping of atrial fibrillation (AF) during clinical procedures is limited by low-amplitude, fractionated electrograms and cycle length variability. The Tau20-RETROmapping stimulator-recorder system (TauRhythm Therapies, United Kingdom) is an investigational device used to identify nonpulmonary vein AF drivers by real-time, high-density activation mapping of uniform wavefronts during AF. We validated the accuracy of the system and applied it to left atrial mapping for evidence of AF drivers. METHODS:Left atrial geometry was acquired using a 3-dimensional electroanatomic mapping system with high-density mapping catheters (CARTO 3 with Optrell, or EnSite X with HD Grid). Electrograms were recorded for 30 seconds at multiple left atrial sites. The Tau20-RETROmapping system generates activation maps of organized wavefronts. System performance was manually validated against randomly sampled local electrograms using a grid sweep of thresholds to identify Pareto-optimal parameters in sinus rhythm, atrial pacing, atrial tachycardia (AT), and AF. The system was then applied to identify putative driver activation patterns during persistent AF. RESULTS:We studied 24 patients undergoing pulmonary vein isolation for AF. Six patients presented in sinus rhythm or AT, in whom the system demonstrated a sensitivity of 100.0% (95% CI, 80.5%-100.0%) and a specificity of 100.0% (85.2%-100.0%). Eighteen patients were mapped in AF: the system had a sensitivity of 94.4% (86.2%-98.4%) and a specificity of 97.1% (89.9%-99.6%) when identifying organized AF wavefronts, and accurately identified the earliest activation in 89.6% (79.7%-95.7%) of waves. Stable propagation originating from the left atrial appendage (LAA) was observed in 3/18 patients, while 8/18 demonstrated competing propagation toward and away from the LAA. Conduction away from the LAA was detected along the anterior (8/18 patients), lateral (8/18 patients), and posterior (7/18 patients) walls. No propagation near the LAA was observed in 6/18 patients. CONCLUSIONS:The Tau20-RETROmapping system enables real-time activation mapping of AF, with the most convincing driver-like areas being identified around the LAA.
BACKGROUND:Exercise training improves contractile function and can reduce arrhythmia burden after a myocardial infarction (MI). How exercise modifies the proarrhythmic status is uncertain. METHODS: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. RESULTS: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. CONCLUSIONS: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.
BACKGROUND: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. METHODS: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. RESULTS: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. CONCLUSIONS: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.
BACKGROUND: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. METHODS: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. RESULTS:Cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 mouse 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 density, 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 density compared with isogenic control human-induced pluripotent stem cell-derived-cardiomyocytes, which were both prevented by parthenolide and EpoY. CONCLUSIONS: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.
BACKGROUND: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. METHODS: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. RESULTS: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 (protein kinase C)-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. CONCLUSIONS: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.
BACKGROUND:The origins of left ventricular outflow tract premature ventricular contractions (PVCs) differ in depth and may involve preferential pathways, potentially requiring complex ablation. However, a noninvasive method to preprocedurally estimate ablation complexity has not been established. METHODS:Sixteen patients with idiopathic left ventricular outflow tract PVCs (V2 transition ratio ≥0.6) underwent 2-dimensional speckle-tracking echocardiography during monomorphic PVCs. Endocardial peak systolic strain timing in 18 left ventricular segments was displayed on a bull's-eye map using 8 color-coded intervals (0-800 ms). Patients were classified as localized (n=6) when the earliest interval appeared in 1 segment and nonlocalized (n=10) when it involved ≥2 segments. Ablation outcomes were compared according to whether a simple ablation approach (PVC elimination within 30 s at a single site) was achieved. RESULTS:Baseline electrocardiographic characteristics were comparable between the groups. Ablation-related parameters, including contact force, power output, and impedance drop at the initial ablation site, were also similar. However, the nonlocalized group required statistically significantly greater total radiofrequency energy to eliminate the targeted PVCs (median, 22 206 versus 10 409 J; P=0.031) and demonstrated a statistically significantly lower rate of successful simple ablation approach compared with the localized group (20.0% versus 83.3%; P=0.035). Nonlocalized patterns may reflect conduction from deeper origins with preferential pathways, thereby requiring more complex ablation strategies. CONCLUSIONS:A localized earliest-strain pattern was associated with successful PVC elimination using a simple ablation approach, whereas a nonlocalized pattern indicated the need for more complex ablation. This simple, noninvasive metric may aid preprocedural planning for left ventricular outflow tract PVC ablation.
BACKGROUND:Arrhythmogenic cardiomyopathy (ACM) is a major cause of sudden cardiac death (SCD) in competitive athletes. We aimed to evaluate the prevalence and characteristics of ACM with the increased awareness of the disease at preparticipation screening after the introduction of the 1994 and 2010 diagnostic criteria. METHODS:The North-East Italy registry of juvenile SCD (≤40 years old) was searched for competitive athletes dying due to ACM in the time interval from 1985 to 2024. Cases referred from other regions were also included. Clinical and pathology data were analyzed according to guidelines. RESULTS:ACM was the cause of SCD in 29% of athletes. The incidence rate of SCD in athletes was 0.43 (0.27-0.65) versus 0.14 (0.05-0.33) per 100 000/y before and after 2010, respectively. Fifty-one athletes with ACM (50 men, 25±6.4 years) were enrolled. The pattern was right ventricular/biventricular in 74.5% and left ventricular in 25.5% (41% after 2010). Fibrofatty replacement was transmural in 63% of right ventricular/biventricular ACM and exclusively subepicardial-midmural in left ventricular ACM. First-line preparticipation screening revealed abnormalities in 62.7% (83.3% before 1994 and 40.9% after 2010). Twelve-lead ECG abnormalities were present in 50.9% (60.5% in right ventricular/biventricular ACM and 23% in left ventricular ACM), with negative T waves in 39.2% and low QRS voltage in 25.5%. Premature ventricular complexes/nonsustained ventricular tachycardia with left bundle-branch block or multiple morphologies were present on basal or limited exercise ECG in 35.3%. Maximal stress test, Holter, and 2-dimensional echocardiography were positive in 55%, 45.4%, and 5.8% of cases, respectively. In the only case who underwent contrast-enhanced cardiac magnetic resonance, late gadolinium enhancement was detected. CONCLUSIONS:ACM-related SCD incidence appeared lower in the post-2010 period. A phenotypic shift toward the left ventricular variant is observed, with ECG changes in a minority of cases and usually normal 2-dimensional echocardiography. If the index of suspicion is high, contrast-enhanced cardiac magnetic resonance is crucial for early identification and SCD prevention.
BACKGROUND: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.METHODS: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.RESULTS: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.CONCLUSIONS: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.
BACKGROUND:Evidence supporting the Micra AV leadless pacing system has largely derived from highly experienced centers, potentially limiting generalizability to routine clinical practice. METHODS:The AV-CESAR study (French Cohort Evaluating the Effectiveness of Atrioventricular Synchrony by the micRa AV) is a nationwide retrospective cohort, including the first 1000 patients implanted with a Medtronic Micra AV leadless pacemaker in France (2020-2024). Mean follow-up was 13.4±10.6 months. Primary end points were early (in-hospital) and late (postdischarge) device-related major complications; pacemaker syndrome and need for implantation of a new pacing system were centrally adjudicated. RESULTS:Among 1003 patients, device implantation was successful in 1000 (99.7%). Mean age was 72.0±15 years; 62.8% were men, 44.0% had ≥2 comorbidities, and 62.4% were unsuitable for transvenous pacemakers. The primary indication was permanent complete atrioventricular block with preserved sinus rhythm (78.0%). Early major complications occurred in 2.4%, including pericardial effusion (0.8%; 3 requiring surgery), access-site complications (0.8%), and thromboembolism (0.3%). Late major complications included pacemaker syndrome (2.5%), pacing-induced cardiomyopathy (1.2%), high thresholds (>4 V/0.24ms, 0.3%), and premature battery depletion (0.2%). No device infections or dislodgements were observed. Overall, 2.5% of patients required implantation of a new pacing system (pacing-induced cardiomyopathy n=11; pacemaker syndrome n=7; high threshold n=3; battery/software failure n=3; tricuspid regurgitation n=1) and 12.7% were permanently reprogrammed to ventricular paced/sensed, inhibited (VVI) mode. In pacing-dependent patients with ambulatory Holter monitoring (>3.4 million paced cycles), mean atrioventricular synchrony was 67.6±17.3% and correlated with device-reported AM-VP (74.8±17.1%; R2=0.92; P<0.001). Atrioventricular synchrony declined at heart rates >90 beats per minute (5.6% of monitored time). All-cause mortality was 13.8%, with 0.2% directly device-related; 41.7% of deaths were cardiovascular. CONCLUSIONS:The Micra AV system is primarily used as an alternative when dual-chamber conventional pacemakers are not feasible. It demonstrated acceptable safety and clinical performance in a high-risk population. The marked reduction in atrioventricular synchrony at higher heart rates may suggest limited clinical benefit in patients with higher exertional heart rates. REGISTRATION:URL: https://clinicaltrials.gov/study/NCT05953558; Unique identifier: NCT05953558.
