Temporal and Spatial Changes of Proarrhythmic Substrate in Premature Ventricular Contraction-Induced Cardiomyopathy

Abstract

Background: The changes in proarrhythmic substrates and malignant ventricular arrhythmia mechanisms caused by premature ventricular contraction-induced cardiomyopathy (PVCCM) remain unclear.

Objectives: The goal of this study was to establish the electrophysiological mechanism of how high-load PVC causes malignant arrhythmia.

Methods: Thirteen swine were exposed to 50% paced PVC from the right ventricular apex for 12 weeks (PVCCM, n = 6) and no pacing for 12 weeks (control, n = 7). Cardiac function was quantified biweekly with echocardiography. Computed tomography scans and electrophysiological examinations were performed monthly to dynamically evaluate the changes in the cardiac structure and the arrhythmogenic substrate.

Results: The decreases in the cardiac function and ventricular enlargement in the PVCCM group were significant after 12 weeks of PVC stimulation compared with the control group (P < 0.001). Electrophysiological examination found that the ventricular effective refractory period dispersion (0.071 ± 0.008), area of the low-voltage zone (9.41 ± 1.55 cm²), and malignant ventricular arrhythmia inducibility (33.3%) of the PVCCM group increased significantly at week 8 after pacing (P < 0.001 vs the control group); these changes slowed down after 8 weeks. Moreover, the distribution of the low-voltage zone presented obvious spatial heterogeneity, especially in the anterior wall of the right ventricle, accompanied by delayed activation in the sinus rhythm (67 ± 13 milliseconds). Consistently, the proportion of ventricular fibrosis- and expression-related proteins were significantly increased in the PVCCM group (P < 0.001), especially in the right ventricle. Moreover, proteomic analysis confirmed the spatial profile of these fibrotic changes in the PVCCM group.

Conclusions: High-burden PVC can cause significant temporal and spatial heterogeneity changes in proarrhythmic substrates, which are potentially related to the upregulation of calcium signaling caused by asynchronous activation.

Keywords: fibrosis; malignant ventricular arrhythmia; premature ventricular contraction–induced cardiomyopathy; temporal and spatial heterogeneity changes.