Circulation. Arrhythmia and electrophysiology最新文献

Background: Hemolysis is a recognized side effect of pulsed field ablation (PFA). Severe hemolysis can lead to acute kidney injury, affecting the morbidity of patients undergoing PFA for atrial fibrillation. Here, we aimed to characterize the degree of hemolysis across different PFA technologies.

Methods: This is a retrospective cohort study of 552 PFA procedures performed in our center, where Hp (haptoglobin) was measured both at baseline and on postoperative day 1. The PFA catheters used were Farawave (59%), Sphere-9 (19%), Pulseselect (16%), and Varipulse (5.8%).

Results: Hemolysis (ie, reduction in Hp >10 mg/dL) was observed in the majority of cases (95%), with the lowest incidence observed in patients undergoing PFA with Sphere-9 (88%) compared with Farawave (97%), Varipulse (97%), and Pulseselect (100%). Significant and severe hemolysis (ie, Hp-postoperative day 1 ≤25 mg/mL and Hp-postoperative day 1 ≤10 mg/mL) occurred in 34% and 13%, with a different distribution across catheter types: Farawave 46% and 21%, Varipulse 29% and 9.7%, Pulseselect 23% and 1.2%, and Sphere-9 5.5% and 0%. Hp decreased by a mean of 76±40 mg/dL from baseline, with a significantly greater degree of reduction seen with Farawave (94±40 mg/dL) and Varipulse (85±32 mg/dL) compared with Pulseselect (62±25 mg/dL) or Sphere-9 (39±23 mg/dL). There is a linear relationship between Hp reduction and number of PFA applications, with a decrease of Hp per application of 0.47 mg/dL (95% CI, 0.22-0.71 mg/dL) for Farawave, 0.40 mg/dL (95% CI, 0.09-0.73 mg/dL) for Pulseselect, and 0.10 mg/dL (95% CI, 0.02-0.19 mg/dL) for Sphere-9.

Conclusions: PFA-induced hemolysis is common, with different PFA technologies exhibiting variable degrees of hemolysis, lower with the focal PFA catheter Sphere-9 when compared with single-shot PFA catheters.

Background: Retrograde ethanolization of the vein of Marshall (VOM) has been identified as an adjunct technique in the treatment of persistent atrial fibrillation (AF) and left atrial tachycardia, as stated in the last consensus statement on ablation of AF. However, there is a lack of high-volume data on the technique.

Methods: Through the collection of data from worldwide centers, we performed this international survey that aims to analyze the safety and procedural characteristics of VOM ethanolization in patients referred for treatment of AF or left atrial tachycardia.

Results: We included 5579 patients (66 years; range, 20-93) from 26 centers, who underwent VOM ethanolization between 2008 and 2024 for persistent AF (81%), paroxysmal AF (9%), or left atrial tachycardia (10%) under deep sedation (53%) or general anesthesia (47%). A concomitant mitral isthmus line was attempted in 79% of the cases, achieving mitral isthmus block in 98% of patients. There were 0.92% of periprocedural serious adverse events, including 0.09% of peri-procedural death (5 patients). Three patients developed hemodynamic collapse immediately after VOM ethanolization, causing the death of 1 due to anaphylactic shock. One patient died following surgical drainage of pericardial effusion 3 weeks after the procedure. The 3 other deaths were not directly related to VOM ethanolization. Pericardial effusion was observed in 123 patients (2.2%) at the time of or immediately after the procedure, requiring drainage in 20 patients (0.36%) and later in 32 additional patients (0.57%), including 5 (0.09%) requiring drainage. Pacemaker implantation was required in 2 patients (0.04%), 1 for high-grade atrioventricular block and 1 for sinus node dysfunction.

Conclusions: This international survey shows that VOM ethanolization is predominantly performed in patients with persistent AF. It is associated with rare but potentially life-threatening adverse events. Mitral isthmus line ablation results in a very high rate of block when performed concomitantly.

Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, characterized by atrial fibrosis, a crucial substrate facilitating its initiation and persistence. CKAP4 (cytoskeleton-associated protein 4) has been associated with fibroblast activation; however, its involvement in atrial remodeling and AF susceptibility remains unclear.

Methods: We measured serum CKAP4 by ELISA in 189 patients with drug-refractory AF and 79 controls and then correlated these levels with left atrial scar burden assessed by 3-dimensional electroanatomic mapping. CKAP4 cell-type specificity and AF-associated regulation were evaluated in human single-cell/single-nucleus RNA-seq data sets (GSE238242 and GSE224959). CKAP4 regulation and function were examined in mice subjected to transverse aortic constriction or Ang II (angiotensin II) infusion and in neonatal rat atrial fibroblasts stimulated with Ang II using CKAP4 knockdown/overexpression. AF inducibility was tested by transesophageal burst pacing. Mechanistic studies assessed CKAP4 interactions with wingless/INT signaling pathway (WNT) 3A/WNT5A (co-immunoprecipitation and proximity ligation) and perturbed β-catenin signaling with an agonist (Wnt/β-catenin pathway agonist) or inhibitor (β-catenin/TCF pathway inhibitor) in vitro and in vivo.

Results: Serum CKAP4 was higher in AF than controls (P<0.001) and correlated with regional and total scar burden (r=0.16-0.29; all P<0.05). CKAP4 was enriched in fibroblasts and upregulated in AF in both human data sets. Transverse aortic constriction and Ang II increased atrial CKAP4 in vivo. In atrial fibroblasts, CKAP4 knockdown reduced α-Smooth Muscle Actin (α-SMA), collagen I/III, vimentin, and migration, whereas overexpression produced opposite effects. In mice, CKAP4 knockdown attenuated left atrial fibrosis and reduced AF inducibility. CKAP4 interacted with WNT3A and WNT5A and activated β-catenin signaling; SKL2001 rescued the antifibrotic/antiarrhythmic effects of CKAP4 knockdown, while β-catenin/TCF pathway inhibitor blunted CKAP4-overexpression-induced collagen synthesis and migration.

Conclusions: CKAP4 promotes atrial fibrosis and increases AF vulnerability through the WNT/β-catenin signaling pathway, highlighting the CKAP4-WNT/β-catenin axis as a promising therapeutic target to attenuate atrial structural remodeling in AF.

Background: Inappropriate sinus tachycardia (IST) is an arrhythmia characterized by rapid sinus rates of over 100 bpm at rest. The mechanisms underlying this often-debilitating condition are not fully understood. The differential diagnosis for this persistent observation is broad, including medication side effects or serendipitous use of chronotropic stimulating drugs. Genetic causes of IST are seldom considered. Only 2 mutations have been linked to this condition, both of which affect the gene encoding HCN4 channels, which play an important role in generating pacemaker activity of the sinoatrial node.

Methods: Standard clinical genetic testing was performed on a child with IST, her affected mother, and 2 healthy siblings. A novel HCN4 channel variant identified in the family was studied by whole-cell patch clamp analysis. Three-dimensional protein structures of mutant and wild-type HCN4 channels were generated and subjected to 200 ns of unrestricted molecular dynamics simulation.

Results: A heterozygous, missense variant was identified in the HCN4 gene (p.N299S) in the affected child and mother, while absent in 2 healthy siblings of the child. Patch clamp analysis revealed significantly increased HCN4 current density and a rightward-shifted activation curve in cells expressing p.N299S-HCN4 versus wild-type channels, suggesting constitutive activity of the mutant HCN4 channel. In molecular dynamics simulations, the voltage sensor of p.N299S-HCN4 channels adopted a resting conformation mimicking that of cAMP-bound wild-type HCN4, providing a structural basis for the functional observations. Ivabradine application returned the gain-of-function properties of mutant channels to baseline levels.

Conclusions: We identified a gain-of-function HCN4 variant in a family with IST that displays constitutive activity and structurally mimics the effects of cAMP activation. This study furthers our understanding of the mechanisms underlying IST and provides data supporting the efficacious effect of ivabradine in genetically based IST.

Background: BMP10 (bone morphogenetic protein 10) is a ligand of the TGF (transforming growth factor) β superfamily secreted mainly by atrial cardiomyocytes. Elevated BMP10 blood concentrations predict atrial fibrillation (AF), AF recurrence after ablation, and AF-related cardiovascular complications like stroke. The conditions increasing BMP10 secretion and the downstream effects of BMP10 in cardiomyocytes are poorly understood. We assessed BMP10 secretion dynamics and BMP10 effects in a human 3-dimensional model of atrial and ventricular engineered heart tissue (EHT).

Methods: Cardiomyocytes (atrial and ventricular) differentiated from human induced pluripotent stem cells were cast into a fibrin-matrix to generate EHT. Atrial EHTs were optogenetically paced (3-5 Hz) or maintained at intrinsic beating rate for 24 hours up to 15 days. Release of BMP10 and other cardiac biomarkers from EHT was quantified. BMP10 plasma concentrations were compared between 1370 patients with different atrial rhythms at blood draw. Additionally, ventricular EHTs were exposed to BMP10 for 10 days.

Results: Atrial but not ventricular EHT released BMP10 within 48 hours of culture. High-rate optogenetic pacing increased atrial EHT BMP10 release by ≈3-fold after a latency of at least 24 hours post initiation of pacing. BMP10 plasma concentrations were elevated in patients with documented AF compared with sinus rhythm and even higher in patients with current AF. BMP10 induced upregulation of TGFβ pathway transcripts, increased expression of genes related to AF and heart failure, including PITX2 and NPPB, and increased relative contraction times in ventricular EHTs.

Conclusions: High atrial rates elevate BMP10 expression and release, and higher plasma concentrations of BMP10 are observed in patients with active AF. BMP10 exposure induces transcriptomic changes linked to AF and heart failure in ventricular EHT. These findings support BMP10 as a biomarker and potential mediator of AF-related remodeling and tachycardiomyopathy.

Background: Recurrence of atrial arrhythmias remains a significant challenge following catheter ablation for atrial fibrillation. The potential role of semaglutide in reducing atrial arrhythmia recurrence postablation is unclear.

Methods: A consecutive sample of 437 patients with a body mass index ≥24 kg/m² and type 2 diabetes who underwent their first atrial fibrillation ablation procedure between January 2022 and March 2024 were enrolled. Participants were divided into a semaglutide group and a control group based on patient preference. The primary outcome was the freedom from atrial arrhythmia recurrence during the 12-month follow-up period after the 3-month blanking period postablation.

Results: Of the 437 enrolled patients, 158 opted for semaglutide therapy and 279 declined. At baseline, the semaglutide group had higher body mass index (27.5 [2.2] versus 27.0 [2.4]; P=0.038) and glycated hemoglobin levels (8.0 [1.0] versus 7.6 [1.1]; P<0.001) compared with controls. During the 12-month follow-up, the semaglutide group showed a higher event-free rate for recurrent atrial arrhythmias (hazard ratio, 0.68 [95% CI, 0.49-0.95]; P=0.030), greater weight loss (-8.2% [3.2] versus -4.6% [2.9]; P<0.001), and larger reductions in glycated hemoglobin (-1.3% [0.8] versus -0.6% [0.8]; P<0.001).

Conclusions: Semaglutide treatment following catheter ablation for atrial fibrillation is associated with a lower rate of atrial arrhythmia recurrence over 12 months and may lead to improvements in weight and glycated hemoglobin levels.

Background: Radiofrequency catheter ablation (RFCA) of ventricular tachycardia (VT) in arrhythmogenic right ventricular cardiomyopathy is safe and reduces ventricular arrhythmia burden. Previous studies included adult patients, and data on pediatric patients are scarce. The objective of our study was to report on the safety and efficacy of RFCA in pediatric arrhythmogenic right ventricular cardiomyopathy.

Methods: Fifteen patients who fulfilled the 2010 arrhythmogenic right ventricular cardiomyopathy task force criteria, clinically presented before the age of 18, and underwent VT RFCA procedures at ≤21 years old were included. Baseline characteristics, genotypic and phenotypic data, and ablation outcomes were collected.

Results: The mean age at symptom onset was 15.5±1.6 years, and at the index procedure was 18.1±2 years, with 73% of the patients being male. Pathogenic mutation in desmosomal genes was detected in 87%. First presentation symptoms included palpitations (33%), syncope (27%), sustained VT (27%), and sudden cardiac arrest (13%). ECG repolarization abnormalities were present in 93% and 40% were reported to be athletes. In the index RFCA procedure, sustained monomorphic VT was induced in 60%. Electroanatomic mapping showed 100% basal RV epicardial substrate and 54% endocardial low voltage/scar. Repeat VT ablation was required in 80% over a mean follow-up of 16.4 months. The median number of procedures was 2 (interquartile range, 2-4), with sustained VT-free survival of 73% over a mean follow-up duration of 21.4 months. No acute periprocedural complications occurred. Bilateral cardiac sympathetic denervation due to recurrent ventricular arrhythmia was performed in 27%. Eventually, 2 patients (13%) developed advanced heart failure and underwent heart transplantation.

Conclusions: Pediatric arrhythmogenic right ventricular cardiomyopathy RFCA is safe, but early recurrences are common, requiring repeat ablations and sometimes bilateral cardiac sympathetic denervation. The substrate is mostly epicardial with preserved endocardial voltage. VT free survival is 73% after multiple procedures. Progressive heart failure requiring transplantation occurred in 13% within 2 decades of initial presentation.