Circulation. Arrhythmia and electrophysiology最新文献

Background: Horses are one of the few animals that spontaneously develop atrial fibrillation (AF), making them a powerful model for studying AF mechanisms and treatment effects. Despite the initial effectiveness of treatment in horses and humans, AF-induced atrial remodeling compromises its long-term success. Observational studies have suggested that metformin may reduce the risk of AF, but its effects on progressive AF-induced atrial remodeling have yet to be evaluated in a high-fidelity large animal model.

Methods: Here, we used a longitudinal horse model of tachypacing-induced self-sustained AF to characterize the electrical, molecular, and metabolic atrial changes over 4 months of disease, with and without metformin treatment (30 mg/kg orally, twice daily; initiated before AF induction, N=24 horses). Electrophysiological and multiomic approaches were combined with histology, echocardiography, biochemical, and mitochondrial analyses to evaluate disease progression and treatment response.

Results: The horse model replicated critical aspects of AF-induced atrial remodeling observed in Humans, including electrical and structural changes. Despite upregulation of metabolic genes and proteins in AF, no significant ultrastructural mitochondrial changes were detected. Metformin plasma trough levels confirmed stable therapeutic exposure. Metformin-treated horses were protected against early AF stabilization and sustained a less complex AF substrate in the right atrium after 4 months of disease. These protective effects were associated with increased right atrial activity of the metabolic regulator, AMPK (AMP-activated protein kinase), changes in metabolic pathways, and modulation of ion-channel gene expression.

Conclusions: Metformin treatment conferred protection against early AF stabilization and selectively attenuated right atrial substrate complexity in a translationally relevant preclinical model. These findings support metformin as a lead molecule for AF prevention, warranting further mechanistic and clinical studies.

Background: In a previous study, on pulsed-field ablation (PFA) in the swine ventricle, we found that lesion depth was described (±1 mm accuracy) by a logarithmic function of contact force (CF) and the number of PFA pulses (PF-ablation index). This study was designed to validate prospectively whether the novel PF-ablation index would allow PFA lesions to be created at depths of 3.5, 4.5, 5.5, and 6.5 mm with high prediction accuracy in a swine-beating heart model.

Methods: A 7.5F catheter with a 3.5 mm ablation electrode and CF sensor (ThermoCool SmartTouch SF-Dual Energy) was connected to a PFA system (TRUPULSE 2). In 6 closed-chest swine, a biphasic PFA pulse was delivered between the ablation electrode and a skin patch at 123 separate ventricular sites at 5 different levels of CF (1) low (average CF: 4-15 g; median, 12 g; n=25), (2) moderate (16-30 g; median, 23 g; n=41); 3) high (31-45 g; median, 36 g; n=27), (4) very high (46-68 g; median, 52 g; n=18); or (5) no electrode contact, 1 to 2 mm from the endocardium (n=12). PFA application was terminated when the PF-ablation index reached a predicted lesion depth of 3.5 mm (27 sites), 4.5 mm (25 sites), 5.5 mm (29 sites), and 6.5 mm (30 sites). Swine were euthanized 2 hours after ablation. Lesion size was measured using triphenyl tetrazolium chloride staining.

Results: Predicted lesion depth by the PF-ablation index correlated well with actual lesion depthwith ±1.0 mm accuracy in 97/106 (92%) lesions and ±1.5 mm accuracy in all 106 lesions. There were no or poor relationships between intracardiac electrogram attenuation, impedance decrease, electrode temperature, and lesion size. No detectable lesions were created without electrode contact.

Conclusions: A novel PF-ablation index incorporating CF and the number of PFA pulses provides high accuracy in predicting lesion depth in real-time. Intracardiac electrogram attenuation, impedance decrease, and electrode temperature are poor predictors of PFA lesion size.

Background: Activation recovery interval (ARI), extracted from unipolar electrograms, serves as a practical surrogate for repolarization during experimental studies in vivo. Far-field signal contamination and low spatial resolution obscure regional repolarization gradients and duration alternans detection using unipolar ARI. We hypothesized that the attenuation of far-field contamination with the principal component-referenced unipole will allow for a more accurate assessment of true local repolarization gradients and spatially assess action potential duration alternans.

Methods: Unipolar ARI and the novel method, Repol^Loc, were validated for the detection of spatial and temporal repolarization changes using simultaneous optical and electrical mapping in a rabbit Langendorff model. Repolarization changes were created using global infusion of ibutilide or pinacidil, or topical application of lidocaine. Epicardial mapping was conducted in a porcine Langendorff model following the topical application of lidocaine to investigate the spatial resolution of each method. Generalized linear models of the two methods were used to compare with optical action potential duration (APD80).

Results: Following the infusion of antiarrhythmic drugs, the Repol^Loc method (slope=0.90) had a slightly higher correlation to optical APD80 than the ARI method (slope=0.79). Following regional application of lidocaine, Repol^Loc was better able to localize the site of drug administration with an average 26.12% reduction as compared with 18.66% reduction in unipolar ARI (P=0.0046). Additionally, temporal repolarization alternans and restitution changes assessed by Repol^Loc method tracked optical APD80 quantified time domain changes.

Conclusions: Repol^Loc has higher sensitivity to local spatiotemporal repolarization heterogeneities and alternans than traditional ARI. Although ARI only correlates with uniformly distributed changes in repolarization in the entire myocardium, Repol^Loc also provided accurate regional gradient assessment and duration alternans of repolarization. These findings suggest ARI has significant far-field contamination and Repol^Loc may provide a better clinical mapping tool for spatiotemporal repolarization gradient mapping.

Background: Long QT syndrome (LQTS) is primarily an inherited condition associated with the risk of sudden cardiac death. Due to variable phenotypic expression, a prolonged QT interval on a 12-lead ECG is not always present. LQTS may present in the fetus with persistent bradycardia, including sinus bradycardia or functional 2:1 atrioventricular block. We report our experience of persistent fetal bradycardia prompting parental assessment for congenital LQTS.

Methods: From January 1, 2018 to November 1, 2023, 20 parents (20 mothers; 20 fathers) of fetuses presenting with persistent bradycardia and suspected congenital LQTS were assessed. Autoimmune-mediated atrioventricular block, diagnosed in the presence of maternal anti-Ro/anti-La antibodies, and fetuses with ventricular tachycardia were excluded. Parental ECGs were acquired in the remainder, with comprehensive evaluation, including genomic testing, performed in 12 mothers and 11 fathers.

Results: Among 20 fetuses, 16 had sinus bradycardia and 4 had 2:1 atrioventricular block (intermittent=2; persistent=2). Pathogenic LQTS genetic variants were found in 11 fetuses (KCNQ1=8; KCNE1=1; KCNH2=1; CALM2 [calmodulin 2]=1), 9 mothers (KCNQ1=7; KCNE1=1; KCNH2=1) and 1 father (KCNQ1=1). Maternal corrected QT interval was higher in those with pathogenic variants compared with those who did not undergo genomic testing (456.9±11.6 versus 425.9±28.7 ms, P=0.009) but <400 ms in the paternal carrier. After review, 5 mothers with pathogenic variants were commenced on β-blockers (prepartum=4; postpartum=1). Provocation testing with a treadmill exercise test led to the initiation of β-blockade postnatally in one further case.

Conclusions: The first indication of parental LQTS may be persistent fetal bradycardia. This should prompt consideration of this diagnosis even with a normal maternal corrected QT interval and lead to the initiation of specific management strategies for pregnancy, delivery, and the postpartum period before the results of genomic testing are available.

Background: Cardiac resynchronization therapy (CRT) is an important therapeutic option in selected pediatric patients and patients with congenital heart disease with reduced systemic ventricular ejection fraction (SVEF). However, the identification of optimal responders is challenging. This study aimed to identify predictors of response to CRT in children and patients with congenital heart disease at 5 large quaternary referral centers.

Methods: Patients were aged <21 or had congenital heart disease and had SVEF <45%, symptomatic heart failure, and significant electrical dyssynchrony before CRT. Primary outcome was defined as an ordinal response at 6 or 12 months: (1) improved SVEF (≥5%), (2) unchanged SVEF, and (3) worse SVEF. Secondary outcome utilized a propensity score-matched control cohort. Response to CRT was defined using the longitudinal trajectory of SVEF up to the latest follow-up.

Results: In total, 167 eligible CRT recipients were identified across the 5 centers; 150 had comprehensive data at 6 or 12 months: 96 (64%) with improved SVEF, 26 (17%) unchanged, and 28 (19%) worsened. Mean increase in SVEF was 11% (interquartile range, 3%-21%). On univariable ordinal regression, lower SVEF (P=0.013), biventricular circulation (P=0.022), systemic left ventricle (P=0.021), and conduction delay to the lateral wall of the systemic ventricle (P=0.01) were associated with a positive response. For the assessment of the secondary outcome, 324 controls were identified. Median follow-up is 5.1 (interquartile range, 2.0-8.6) years. Almost all subgroups demonstrated improved SVEF trend with CRT, except those with systemic right ventricle (P=0.69) or without prior single-site pacemaker (P=0.20).

Conclusions: CRT in children and patients with congenital heart disease frequently results in an improvement in SVEF. Those with lower SVEF, conduction delay to the lateral wall of the systemic ventricle, and those with a systemic left ventricle are most likely to respond.