The Central Hypothesis is treatment regimes that protect vascular integrity early after reperfusion will reduce infarct expansion, final infarct size, and adverse cardiac remodeling in hearts with myocardial infarction. A no re-flow phenomenon is commonly observed in experimental animals with myocardium subjected to ischemia followed by reperfusion and in patients with acute myocardial infarction (MI). No re-flow refers to compromised distal myocardial perfusion despite restoration of patency in proximal macroscopic vessels. The extent of no re-flow is a determinant of infarct expansion. No re-flow may result from destruction of microscopic vessels, which we have termed vascular rhexis, or from other factors such as microemboli, inflammation, release of toxic cellular metabolites, and oxidative stress that cause endothelial cell dysfunction and induce microvascular leaks. This proposal is based on the concept that treatments designed to improve blood supply by preventing vascular rhexis associated with ischemia and reperfusion will reduce no re-flow and diminish infarct size, adverse ventricular remodeling and dysfunction after MI.
SPECIFIC AIMS : 1. Determine whether treatment with HGF/IgG complexes at the time of reperfusion can promote vascular integrity and reduce infarct expansion in a large animal model of MI. 2. Identify signaling pathway(s) activated by HGF/IgG complexes that confer enhanced vaso- protection after MI. 3. Determine whether sustained treatment with HGF/IgG complexes after MI provides long- term improvement in cardiac function by increasing cardiac perfusion and reducing infarct expansion, final infarct size, and/or adverse ventricular remodeling.

Public Health Relevance

Intra-myocardial or vascular administration of adult stem/progenitor cells after myocardial infarction (MI) has been shown to result in low levels of engrafted cells and modest improvements in cardiac function. The results support a 'paracrine hypothesis' whereby injured cardiac tissue benefits from the transient paracrine action of various proteins and peptides secreted by short-lived administered cells. Epicardial cells that constitute the cover of the heart are known to support myogenesis and angiogenesis during cardiac development and also to contribute reparative cells after cardiac injury. We developed methods to generate large quantities of human epicardially-derived cells (EPDC) from right atrial biopsies of cardiac bypass patients. We used the EPDCs to generate concentrated conditioned medium (EPDC CM) to treat acute MI. Our preliminary data indicate that treatment with EPDC CM or defined HGF/IgG complexes (identified from EPDC CM) may preserve vascular integrity after reperfusion, thereby improving cardiac perfusion and outcome in patients undergoing mechanical reperfusion for acute MI.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Gene and Drug Delivery Systems Study Section (GDD)
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Schwartz, Lisa
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University of Vermont & St Agric College
Internal Medicine/Medicine
Schools of Medicine
United States
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Iso, Yoshitaka; Usui, Sayaka; Toyoda, Masashi et al. (2018) Bone marrow-derived mesenchymal stem cells inhibit vascular smooth muscle cell proliferation and neointimal hyperplasia after arterial injury in rats. Biochem Biophys Rep 16:79-87
Rao, Krithika S; Spees, Jeffrey L (2017) Harnessing Epicardial Progenitor Cells and Their Derivatives for Rescue and Repair of Cardiac Tissue After Myocardial Infarction. Curr Mol Biol Rep 3:149-158
Spees, Jeffrey L; Lee, Ryang Hwa; Gregory, Carl A (2016) Mechanisms of mesenchymal stem/stromal cell function. Stem Cell Res Ther 7:125