Circulation. Arrhythmia and electrophysiology最新文献

Background: Although hyperthyroidism is known to increase the risk of atrial fibrillation (AF), subclinical hypothyroidism (SH) is an often-underreported condition characterized by elevated thyroid-stimulating hormone (TSH) levels and normal free triiodothyronine/free thyroxine (fT₃/fT₄) levels. This study aimed to clarify the association between SH and AF and to identify potential direct electrophysiological effects of TSH.

Methods: We retrospectively included 2311 patients diagnosed with SH between 2007 and 2020 who had an ECG within 7 days of diagnosis. Logistic regression analysis identified factors independently associated with AF in patients with SH. Effects of different TSH doses on ion channel mRNA and protein levels were analyzed in HL-1 and neonatal rat cardiomyocytes. Video analysis with MYOCYTER, patch-clamp, optical mapping, and computational modeling were used to study automaticity and action potential characteristics after TSH application.

Results: AF was documented more often with higher TSH levels (4-10 mU/L TSH: 32.1% versus >10 mU/L TSH: 44.6%; P<0.0001). Multivariable regression identified elevated TSH levels as an independent risk factor for AF. TSHR (TSH receptors) were confirmed in cardiomyocytes, and exposure to TSH led to changes in ion channel expression levels that promoted action potential prolongation. TSH also increased the beating rate in neonatal rat cardiomyocytes. We identified a TSHR-mediated cascade involving cAMP, PKA (protein kinase A), and CREB (cAMP-responsive element-binding protein) as a potential regulator of cardiomyocyte electrical remodeling leading to the proarrhythmic effects that promote the development of AF.

Conclusions: Individuals with SH exhibit an increased prevalence of AF, which is likely in part due to a direct effect of TSH on ion channel expression in cardiomyocytes via the TSHR/cAMP/PKA pathway.

Background: Cavotricuspid isthmus (CTI) ablation is frequently performed either as a standalone procedure or in combination with pulmonary vein isolation. With the rapid adoption of pulsed field ablation for atrial fibrillation, it is essential to delineate the utility of this modality in treating CTI-dependent atrial flutter (AFL). This study aims to evaluate the procedural and clinical outcomes of CTI ablation using pulsed field energy.

Methods: We conducted a retrospective analysis of consecutive patients who underwent pulsed field ablation for CTI-dependent AFL between January 2024 and March 2025. The primary end points were acute procedural success, periprocedural complications, and CTI-dependent AFL recurrence during follow-up.

Results: A total of 132 patients underwent CTI nonthermal ablation. The median age was 69.5 years, and 27.3% were female. The Farawave catheter was used in 93.9% of cases, PulseSelect in 4.5%, and Sphere-9 in 1.5%. Acute block was achieved in 99.2% of patients, although 8 required adjunctive radiofrequency ablation to complete the line. Periprocedural complications included transient ST-segment elevation in 2 patients and transient conduction disturbances in 3. During a median follow-up of 114 days (n=131), 5 patients (3.8%) experienced recurrence of typical AFL. The 6-month typical AFL-free survival estimate was 93.6%.

Conclusions: Pulsed field ablation appears to be a feasible and effective strategy for CTI-dependent AFL. However, anatomic variability may limit its universal applicability with current catheter designs. Although acute procedural success is high, the long-term durability of the CTI block and its comparative efficacy versus conventional thermal ablation remain areas requiring further investigation.

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.