Injury minimization after myocardial infarction: focus on extracellular vesicles

Abstract

Despite improvements in clinical outcomes following acute myocardial infarction, mortality remains high, especially in patients with severely reduced left ventricular ejection fraction (LVEF <30%), emphasizing the need for effective cardioprotective strategies adjunctive to recanalization. Traditional cell therapy has shown equivocal success, shifting the focus to innovative cardioactive biologicals and cell mimetic therapies, particularly extracellular vesicles (EVs). EVs, as carriers of non-coding RNAs and other essential biomolecules, influence neighbouring and remote cell function in a paracrine manner. Compared to cell therapy, EVs possess several clinically advantageous traits, including stability, ease of storage (enabling off-the-shelf clinical readiness), and decreased immunogenicity. Allogeneic EVs from mesenchymal and/or cardiac stromal progenitor cells demonstrate safety and potential efficacy in preclinical settings. This review delves into the translational potential of EV-based therapeutic approaches, specifically highlighting findings from large-animal studies, and offers a synopsis of ongoing early-stage clinical trials in this domain.

Keywords: Acute myocardial infarction; Exosomes; Extracellular vesicles; Large-animal studies.

Graphical Abstract

Inflammation plays a significant role in acute myocardial infarction, affecting both the early phase following the clinical presentation of acute coronary syndrome and the subsequent chronic phase. During the acute phase, various inflammatory cell types, such as T-cells, granulocytes, monocytes, and B-cells, are attracted to the infarcted area to remove necrotic tissue and promote scar tissue formation. Initially, pro-inflammatory cells like polymorphonuclear neutrophils and M1 pro-inflammatory macrophages are predominant. Within 24–48 h, these M1 macrophages transition into an anti-inflammatory M2 state, contributing to the healing process. T-cells, including CD8+ and CD4+ types, are activated within lymph nodes connected to the heart and play a role in the healing process. Experiments conducted in small and large animals suggest a potential therapeutic role for exogenous extracellular vesicles (EVs) as an adjunctive therapy to percutaneous coronary intervention. EV-mediated modulation of the immune response facilitates a transition from an inflammatory state to a resolving phase after ischaemic damage. Abbreviations: DAMPS, damage-associated molecular pattern molecules; GM-CSF, granulocyte-macrophage colony stimulating factor; IL, Interleukin; IL-1ra, interleukin-1 receptor antagonist; Ly-6C, lymphocyte antigen; M1, inflammatory monocytes/macrophages; M2, reparative monocytes/macrophages; TGFB, transforming growth factor beta; Th2, T-helper cells; TNF-α, tumour necrosis factor alpha.