JACC. Clinical electrophysiology最新文献

Background: Pathogenic variants in DSP cause arrhythmogenic cardiomyopathies with variable inheritance pattern. Recessive mutations underlie syndromic forms such as Carvajal syndrome, whereas dominant variants cause DSP cardiomyopathy, a left-dominant arrhythmogenic cardiomyopathy characterized by early electrical instability, inflammation, and fibrosis. The mechanisms driving these phenotypes remain poorly defined.

Objectives: The authors sought to create a clinically relevant platform to investigate disease mechanisms in Desmoplakin Cardiomyopathy.

Methods: We generated a knock-in mouse carrying the Dsp^S311A mutation, orthologous to the human pathogenic hotspot S299R. Heterozygous and homozygous mice (n ≥6/group) were longitudinally phenotyped by echocardiography, electrocardiographic telemetry, histology, and ultrastructural and molecular analyses. Moderate treadmill exercise was used as a physiological stressor. Outcomes included cardiac function, arrhythmias, fibrosis, apoptosis, inflammation, and desmosomal integrity.

Results: Homozygous Dsp^S311A/S311A mice developed early biventricular dysfunction with subepicardial necrosis, replacement fibrosis, myocardial inflammation, spontaneous arrhythmias, and cutaneous defects, recapitulating Carvajal syndrome. Heterozygous Dsp^WT/S311A mice exhibited hallmarks of dominant DSP cardiomyopathy: patchy left ventricular fibrosis, apoptosis, inflammation, and electrical instability preceding systolic impairment. Desmosomal remodeling occurred in both genotypes, with connexin-43 mislocalization evident from 1 month, whereas β-catenin nuclear translocation and reduced DSP/DSG2 protein were restricted to homozygotes. Of note, spontaneous arrhythmias and electrical instability were already present in both genotypes, temporally preceding structural remodeling. Exercise accelerated apoptosis, fibrosis, arrhythmias, and premature death.

Conclusions: This Dsp^S311A knock-in model captures key aspects of recessive and dominant DSP cardiomyopathies, uniquely combining spontaneous arrhythmias, inflammation, and extracardiac features. This model provides a unique in vivo platform to dissect DSP-related arrhythmogenic mechanisms and to test therapies aimed at preventing sudden cardiac death.

Background: A protected, slow-conducting diastolic pathway (isthmus) is the electrophysiological hallmark of post-myocardial infarction (MI) re-entrant ventricular tachycardia (VT). Contemporary evaluations of the histologic composition promoting slow, protected conduction during VT are lacking.

Objectives: The goal of this study was to compare the histologic characteristics of confirmed VT isthmuses (VTIs) and non-isthmus scar (NIS) in a chronic MI swine model.

Methods: One month after non-reperfused anterior MI, nine Landrace X Large White pigs with inducible VT underwent high-density activation mapping to define the diastolic corridor. Radiofrequency lesions were created to guide the ex vivo VTI localization. Tissue transverse samples from the labeled VTI and NIS were obtained for further histologic, immunohistochemical, and RNA-sequencing expression analyses.

Results: Compared with NIS, VTI showed significantly higher fatty infiltration (P = 0.012) and lower levels of collagen I (P = 0.053), collagen III (P = 0.043), and collagen volume fraction (P = 0.027); there were no differences in overall fibrotic deposition. VTI exhibited greater vascular density compared with NIS (P = 0.018), with arteries and veins primarily surrounded by preserved cardiomyocytes. Compared with NIS, viable cardiomyocytes and fibroblasts in VTI displayed higher densities of connexin 43 and connexin 40 (P = 0.022 and P = 0.004, respectively), despite no differences in cardiac troponin I, sarcoplasmic/endoplasmic reticulum Ca2⁺-ATPase 2, or vimentin expression. Thirty-six genes, involving pathways related to extracellular matrix remodeling, inflammation, and immune response modulation, were differentially expressed between VTI and NIS.

Conclusions: The VTI exhibits a distinct histologic composition and differential gene expression compared with the surrounding NIS. Mid-diastolic activation sites showed increased adipocytic deposition, vascularization, and connexin expression, along with lower levels of collagen I, collagen III, and collagen volume fraction.

Background: Intramural premature ventricular contraction (PVC) mapping is limited by the ability of unipolar and bipolar electrograms (EGMs) to discriminate near from far-field activity.

Objectives: In this study, the authors hypothesized that multipolar EGMs with improved far-field rejection would provide superior source detection.

Methods: A Langendorff perfused healthy swine heart model was utilized in which a left ventricular free wall PVC was generated using a variable depth plunge needle. EGMs were recorded from the ventricular surface using either a customized array (n = 5) or the OPTRELL catheter in CARTO (n = 6). A comparison of unipolar vs multipolar EGM morphology, amplitude, width, and timing was performed for the predictive accuracy of source location. In silico modeling of outflow tract PVCs assessed localization with dual surface mapping.

Results: Multipolar EGMs produced a smaller percentage of QS morphology on the array compared with unipolar EGMs irrespective of depth (6 mm: 9 ± 5 vs 49 ± 10; 5 mm: 6 ± 5 vs 56 ± 20; 4 mm: 9 ± 7 vs 61 ± 20; 3 mm: 7 ± 2 vs 50 ± 25; P < 0.001). A multipole QS had a positive likelihood ratio of 8.0% (95% CI: 5.5%-11.7%) of being adjacent to the source and a non-QS EGM had a 95% (95% CI: 94%-96%) specificity of being remote to the source. Local activation annotation with multipolar EGMs produced maps with a single early focus, in contrast to unipolar maps, which showed a diffuse breakout pattern with multiple early areas.

Conclusions: Multipolar EGMs are superior to unipolar EGMs in predicting the location of a PVC, reflected by a smaller area of QS morphology and narrowing down the diffuse breakout of early activation.