Extracellular vesicles improve diastolic function and substructure in normal and high-fat diet models of chronic myocardial ischemia

Abstract

Objective: The burden of mortality and morbidity of cardiovascular disease is in part due to substantial fibrosis accelerated by coexisting risk factors. This study aims to evaluate the effect of extracellular vesicle therapy on diastolic function and myocardial fibrosis in the setting of chronic myocardial ischemia with and without a high-fat diet.

Methods: Forty male Yorkshire swine were administered a normal or high-fat diet. At 11 weeks of age, they underwent placement of an ameroid constrictor on their left circumflex coronary artery. Both dietary groups then received either intramyocardial injection of vehicle saline as controls or extracellular vesicles as treatment into the ischemic territory (normal diet control, n = 8; high-fat diet controls, n = 11) or extracellular vesicles (normal diet extracellular vesicles, n = 9; high-fat diet extracellular vesicles, n = 12). Five weeks later, hemodynamic parameters, histology, and selected protein expression were evaluated.

Results: Extracellular vesicles reduced end-diastolic pressure volume relationship (P = .002), perivascular collagen density (P = .031), calcium mineralization (P = .026), and cardiomyocyte diameter (P < .0001), and upregulated osteopontin (P = .0046) and mechanistic target of rapamycin (P = .021). An interaction between extracellular vesicles and diet was observed in the vimentin area (P = .044) and fraction of myofibroblast markers to total vimentin (P = .049). Significant changes across diet were found with reductions in muscle fiber area (P = .026), tumor necrosis factor α (P = .0002), NADPH oxidase 2 and 4 (P = .0036, P = .008), superoxide dismutase 1 (P = .034), and phosphorylated glycogen synthase kinase 3β (P = .020).

Conclusions: Extracellular vesicle therapy improved the myocardium's ability to relax and is likely due to structural improvements at the extracellular matrix and cellular levels.

Keywords: cardiovascular disease; extracellular vesicles; fibrosis; metabolic stress.