Intramyocardial injection of hypoxia-conditioned extracellular vesicles increases myocardial perfusion in a swine model of chronic coronary diseaseCentral MessagePerspective
Dwight D. Harris, MD,
Sharif A. Sabe, MD,
Mark Broadwin, MD,
Christopher Stone, MD,
Cynthia Xu, MD,
Meghamsh Kanuparthy, MD,
Akshay Malhotra,
M. Ruhul Abid, MD, PhD,
Frank W. Sellke, MD, FACS
Affiliations
Dwight D. Harris, MD
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI
Sharif A. Sabe, MD
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI
Mark Broadwin, MD
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI
Christopher Stone, MD
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI
Cynthia Xu, MD
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI
Meghamsh Kanuparthy, MD
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI
Akshay Malhotra
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI
M. Ruhul Abid, MD, PhD
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI
Frank W. Sellke, MD, FACS
Address for reprints: Frank W. Sellke, MD, FACS, Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, 2 Dudley St, MOC 360, Providence, RI 02905.; Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI
Objective: Coronary artery disease remains a leading cause of morbidity and mortality worldwide. Patients with advanced coronary artery disease who are not eligible for endovascular or surgical revascularization have limited options. Extracellular vesicles have shown potential to improve myocardial function in preclinical models. Extracellular vesicles can be conditioned to modify their components. Hypoxia-conditioned extracellular vesicles have demonstrated the ability to reduce infarct size and apoptosis in small animals. Our objective is to assess the potential benefits of hypoxia-conditioned extracellular vesicles in a large animal model of coronary artery disease. Methods: Coronary artery disease was induced in 14 Yorkshire swine by ameroid constriction of the left circumflex coronary artery. Two weeks postsurgery, swine underwent a repeat left thoracotomy for injections of hypoxia-conditioned extracellular vesicles (n = 7) or saline (control, n = 7). Five weeks later, all animals underwent terminal harvest for perfusion measurements and myocardial sectioning. Results: Myocardial perfusion analysis demonstrated a trend toward increase at rest and a significant increase during rapid pacing (P = .09, P < .001). There were significant increases in activated phosphorylated endothelial nitric oxide synthase, endothelial nitric oxide synthase, phosphatidylinositol 3-kinase, phosphorylated protein kinase B, and the phosphorylated protein kinase B/protein kinase B ratio in the hypoxia-conditioned extracellular vesicles group compared with the control group (all P < .05). Additionally, there was a significant decrease in the antiangiogenic proteins collagen 18 and angiostatin (P = .01, P = .01) in the hypoxia-conditioned extracellular vesicles group. Conclusions: Intramyocardial injection of hypoxia-conditioned extracellular vesicles results in increased myocardial perfusion without a corresponding change in vessel density. Therefore, this improvement in perfusion is possibly due to changes in nitric oxide signaling. Hypoxia-conditioned extracellular vesicles represent a potential therapeutic strategy to increase myocardial perfusion in patients with advanced coronary artery disease.
