Integrated multi-omic response to heart failure reverse remodeling with left ventricular assist device

Abstract Introduction The left ventricular assist device (LVAD) has emerged as a standard therapeutic intervention for advanced heart failure (HF), patients who received LVAD support showed remarkable cardiac structural and functional improvement, a phenomenon termed reverse remodeling. However, the key molecular mechanisms associated with reverse remodeling, promising predictive biological process and LVAD combination therapeutic are not fully understood. Methods We employed 91 human LV myocardial tissue samples from patients with HF undergoing LVAD implantation (n=65), LVAD bridging to transplantation or recovery (n=11), and nonfailing donors (n=15). To comprehensively characterize the molecular landscape of Chinese HF patients and myocardial recovery, we conducted an integrated multi-omics analysis encompassing genomics, transcriptomics, proteomics, phosphoproteomics, and radiomics. This approach elucidated the connections and discrepancies among multi-omics layers and identified alterations in biological pathways and key signaling networks. Patients were prospectively monitored through echocardiography to characterize their myocardial structure and function. Furthermore, we measured proteins in human LV tissue via immunofluorescence and western blot. Results Protein-mRNA correlation analysis revealed that transcriptional levels do not accurately reflect protein abundance, especially for ribosome and mRNA metabolism-related processes. Comparative analysis between HF and nonfailing controls (NC) identified five hallmarks of HF: (1) upregulation of extracellular matrix (ECM) and complement activation, and (2) downregulation of mitochondrial, ribosome, and muscle contraction. Pre-LVAD differential and weighted correlation network analysis (WGCNA) analyses demonstrated that ribosome proteins (e.g., RPL19, RPS15) are associated with better prognosis (p0.01). Immunofluorescence and western blot validation confirmed a progressive decline in RPL15 expression across NC, reverse-remodeled (RR), and non-recovered (U) groups. Intriguingly, RR patients exhibited significant restoration of ribosome and RNA metabolism after LVAD implantation, suggesting that enhanced cardiac translation may promote reverse remodeling. Conclusions Our study presents the largest and most comprehensive multi-omics resource to date for deciphering human myocardial reverse remodeling. We identified ribosome as both a predictive biomarker for LVAD responsiveness and a tractable therapeutic target to potentiate cardiac recovery. This resource not only advances the understanding of the molecular mechanisms underlying reverse remodeling but also holds significant potential for guiding clinical decision-making and personalized therapeutic strategies.