Circulation. Arrhythmia and electrophysiology最新文献

Background: Patients with arrhythmogenic cardiomyopathy due to pathogenic variants in PKP2, the gene for the desmosomal protein plakophilin-2, are being enrolled in gene therapy trials designed to replace the defective allele via adeno-associated viral transduction of cardiac myocytes. Evidence from experimental systems and patients indicates that ventricular myocytes in PKP2 arrhythmogenic cardiomyopathy have greatly reduced electrical coupling at gap junctions and reduced Na⁺ current density. In previous adeno-associated viral gene therapy trials, <50% of ventricular myocytes have generally been transduced.

Methods: We used established computational models of ventricular cell electrophysiology to define the effects of varying levels of successful gene therapy on conduction in patients with PKP2 arrhythmogenic cardiomyopathy. Conduction velocity and development of conduction block were analyzed in tissue constructs composed of cells with levels of electrical coupling and Na⁺ current density observed in experimental studies.

Results: We observed a nonlinear relationship between conduction velocity and the proportion of transduced cells. Conduction velocity increased only modestly when up to 40% of myocytes were transduced. Conduction block did not occur in tissue constructs with moderate levels of uncoupling (0.10 or 0.15 of normal) as this degree of coupling was sufficient to allow electrotonic current to pass through diseased cells. Thus, low levels of transduction, likely to occur in phase 1 clinical trials, do not seem to pose a major safety concern. However, our models did not incorporate the potential effects of fibrosis and inflammation, both of which are presumably present in PKP2 arrhythmogenic cardiomyopathy patients undergoing gene therapy and could impact arrhythmogenesis.

Conclusions: The extent of successful ventricular myocyte transduction anticipated to be achieved in PKP2 adeno-associated viral gene therapy trials will likely not restore conduction velocity to levels sufficient to decrease the risk of reentrant arrhythmias. Transduction efficiency of 60% to 80% would be required to restore conduction velocity to 50% of normal.

Background: The CommandEP system v2 (Sentiar, St. Louis, MO) utilizes an augmented reality headset (Magic Leap, Plantation, FL) to display a real-time 3-dimensional electroanatomic map, catheter locations, and ablation catheter contact force data to the electrophysiologist using a hands-free interface. In the intra-PARADIGM study (Procedural Augmented Reality Assessment in a 3-Dimensional Image Guided Modality), the impact of the CommandEP system on the electrophysiologist's ability to navigate accurately, intraprocedural communications, and system usability were studied.

Methods: CommandEP was used prospectively in patients undergoing electrophysiologist studies at 2 sites with 8 users. The electrophysiologist's ability to navigate accurately was calculated as catheter tip displacement from the target using CommandEP versus the electroanatomic mapping system. Physician-mapper interactions were quantified and classified as high- versus low-quality communications (high quality directly impacted navigation, medical decision-making, or patient care). Usability was assessed via survey.

Results: A total of 102 patients completed the study with the following diagnoses: AF (n=78/102, 76%), AFL (8/102, 8%), AT/SVT (n=9/102, 9%), PVC (n=6/102, 6%), and cardiac neuroablation (1/102, 1%). The physician's ability to navigate was more accurate when using the CommandEP system with an average distance of 2.98±2 mm versus electroanatomic mapping system 3.27±2 mm (P=0.02); 21% of points navigated using CommandEP versus 28% of points navigated using electroanatomic mapping system were >4 mm from the target (P=0.03). In all, 393 communications during study tasks were counted with 30 events when using CommandEP versus 363 events when using electroanatomic mapping system. Subanalysis showed no difference in accuracy pre- versus postcontact force (p=ns) and a slight reduction in both low- and high-quality communications (p=ns). Notably, 94% agreed/strongly agreed that they felt comfortable using the system, and 72% agreed/strongly agreed they would be comfortable using the CommandEP system in most/all EPS.

Conclusions: The CommandEP system improved physicians' ability to navigate accuracy, reduced the number of communications, increased the quality of communications, and had high usability.

Background: Early identification of out-of-hospital high-risk sudden cardiac death (SCD) after acute myocardial infarction is crucial for timely therapeutic interventions. However, left ventricular ejection fraction as a standalone clinical stratification tool has major limitations, necessitating improved risk stratification strategies.

Methods: Mass spectrometry measured 6592 peptides and 522 proteins, from which targeted proteomics identified the optimal protein combination to assess out-of-hospital SCD risk. ELISA validated its predictive value by comparing it with a clinical stratification tool (left ventricular ejection fraction ≤35%) and 2 reported models (risk score and out-of-hospital cardiac arrest score) in 3 case-control cohorts nested within diverse contemporary postinfarction populations.

Results: In the discovery cohort (105 SCD cases and 105 survivors), mass spectrometry discovered 44 differential proteins associated with SCD, unveiling early circulating features characterized by inflammatory response and complement activation in out-of-hospital SCD cases. Targeted proteomics identified the optimal SCD-warning 3-protein combination, including coronin-1A, haptoglobin, and CFD (complement factor D), to assess out-of-hospital SCD risk. An ELISA-based SCD-warning 3-protein combination model significantly outperformed left ventricular ejection fraction alone (C statistic: 0.752 versus 0.548; P<0.001) and improved their performance (ΔC statistic, 0.281; categorical net reclassification improvement, 0.095; continuous net reclassification improvement, 0.952; integrated discrimination improvement, 0.291). Similar incremental discrimination metrics were observed in 2 reported stratification models (risk score and out-of-hospital cardiac arrest score), particularly within the left ventricular ejection fraction-preserved population. These findings were repeatably validated in 2 independent cohorts (n=234 and 48, respectively). CFD inhibition protection for mortality and pro-malignant arrhythmias in acute myocardial infarction mice supported the biological plausibility of the critical protein in SCD-warning 3-protein combination.

Conclusions: In high-risk individuals for out-of-hospital SCD, the SCD-warning 3-protein combination may contribute to enhanced early identification for timely intensive management. These findings suggest pivotal proteins for improving understanding SCD pathophysiology.

Background: A dual-chamber leadless pacemaker can provide bradycardia therapy to most patients with pacemaker indications without the complications associated with a lead or pulse generator. We sought to confirm whether previously reported 3-month safety and performance outcomes were sustained through 12 months by determining whether 12-month complication-free and performance success rates exceeded their prespecified performance goals.

Methods: Patients were enrolled in the prospective, single-group Aveir DR i2i Study if they had a standard indication for dual-chamber pacing. Enrolled patients were implanted with an Aveir DR dual-chamber leadless pacemaker system, which comprised 2 communicating leadless pacemakers (1 in the right atrium and 1 in the right ventricle). The primary safety outcome evaluated whether freedom from serious device- or procedure-related events through 365 days exceeded the predetermined performance goal of 76.5%. The primary performance outcome determined whether the composite of atrial capture threshold (≤3.0 V at 0.4 ms) and sensing amplitude (P-wave ≥1.0 mV) at the 12-month visit exceeded the predetermined performance goal of 80.0%.

Results: Sites attempted implantation in 300 subjects, where 63.3% had sinus-node dysfunction and 33.3% had atrioventricular block as their primary pacing indication. The primary safety end point was achieved, with a Kaplan-Meier 12-month complication-free rate of 88.6% (95% CI, 84.5-91.8; P<0.001). The primary performance end point was achieved in 92.8% of patients (95% CI, 89.7-95.8; P<0.001).

Conclusions: Both primary safety and performance end points were met after 1 year, demonstrating consistency with previously reported 3-month outcomes of a dual-chamber leadless pacemaker.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05252702.