Integrated Proteomics and Metabolomics Analyses Reveal Molecular Mechanism of Cardiac Resynchronization Therapy Against Cardiac Fibrosis and Ventricular Arrhythmias.

Abstract

It is widely accepted that cardiac resynchronization therapy (CRT) implantation has anti-arrhythmias effect, though few studies observed a pro-arrhythmias effect in non-responders. Left ventricular reverse remodeling (LVRR) is associated with the inhibitory effect of CRT on ventricular arrhythmias (VAs). Cardiac fibrosis is an important factor that influences LVRR. This study aimed to determine the effects of CRT on VAs, LVRR and cardiac fibrosis, and uncover the underlying mechanism. Eleven dogs underwent rapid right ventricular pacing (RVP) for 4 weeks to develop heart failure, and then were randomly divided into a RVP group (n = 5; RVP for another 4 weeks) and a CRT group (n = 6; biventricular pacing for 4 weeks). Another five dogs were in the control group. Compared with the RVP group, CRT prevented the deterioration in systolic dysfunction and cardiac fibrosis. Ventricular fibrillation threshold was decreased by RVP, which was reversed by CRT, indicating an anti-arrhythmic effect of CRT. Proteomics analysis of myocardia from the dogs showed significant alterations in fibrosis-related signaling pathways by CRT. Metabolomics analysis revealed a metabolic reprogramming of the failure heart conferred by CRT. Integrated analysis of the proteomics and metabolomics identified eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1) as the key mediator of CRT. 4EBP1 was downregulated in myocardia from the dogs in the RVP group, which was rescued by CRT. Moreover, overexpression of 4EBP1 diminished transform growth factor (TGF)-β1-induced human CFBs proliferation and synthesis of collagens. CRT regulates fibrosis-related signaling pathways and induces metabolic reprogramming to against cardiac fibrosis and subsequent VAs, potentially through the upregulation of 4EBP1.