Reproducing extracellular matrix adverse remodelling of non-ST myocardial infarction in a large animal model

Abstract

The rising incidence of non-ST-segment elevation myocardial infarction (NSTEMI) and associated long-term high mortality constitutes an urgent clinical issue. Unfortunately, the study of possible interventions to treat this pathology lacks a reproducible pre-clinical model. Indeed, currently adopted small and large animal models of MI mimic only full-thickness, ST-segment-elevation (STEMI) infarcts, and hence cater only for an investigation into therapeutics and interventions directed at this subset of MI. Thus, we develop an ovine model of NSTEMI by ligating the myocardial muscle at precise intervals parallel to the left anterior descending coronary artery. Upon histological and functional investigation to validate the proposed model and comparison with STEMI full ligation model, RNA-seq and proteomics show the distinctive features of post-NSTEMI tissue remodelling. Transcriptome and proteome-derived pathway analyses at acute (7 days) and late (28 days) post-NSTEMI pinpoint specific alterations in cardiac post-ischaemic extracellular matrix. Together with the rise of well-known markers of inflammation and fibrosis, NSTEMI ischaemic regions show distinctive patterns of complex galactosylated and sialylated N-glycans in cellular membranes and extracellular matrix. Identifying such changes in molecular moieties accessible to infusible and intra-myocardial injectable drugs sheds light on developing targeted pharmacological solutions to contrast adverse fibrotic remodelling.

From multi-omics approaches to personalized medicine in myocardial infarction

“…Furthermore, a recent study that integrated transcriptomics and proteomics has unveiled tissue remodeling signatures specific to NSTEMI. In conjunction with the elevation of inflammation and fibrosis markers, the ischemic regions of NSTEMI displayed unique patterns of complex galactosylated and sialylated N-glycans within cellular membranes and the ECM ( 325 ). These findings offer valuable insights into potential drug therapies aimed at addressing fibrous remodeling in NSTEMI, presenting novel perspectives for future therapeutic strategies.…”

Multi‐omic analyses and network biology in cardiovascular disease

“…used multi‐omic profiling of scRNA‐seq, snRNA‐seq, snATAC‐seq, and spatial transcriptomics data from eight anatomical regions of the adult human heart to identify distinct cellular niches within the microanatomical structures of the heart [158]. A recent preclinical study monitored the molecular changes associated with post‐ischemic remodeling at the transcript, protein, and glycan level with distinct profiles in the non‐ST‐segment elevation MI heart [159]. Moreover, Aboumsallem et al.…”