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PRE-CLINICAL RESEARCH

Improvement in Cardiac Function With Small Intestine Extracellular Matrix Is Associated With Recruitment of C-Kit Cells, Myofibroblasts, and Macrophages After Myocardial Infarction

Zhi-Qing Zhao, MD, PhD^_*,_*, John D. Puskas, MD, Di Xu, MD, Ning-Ping Wang, MD^_*, Mario Mosunjac, MD, Robert A. Guyton, MD, Jakob Vinten-Johansen, PhD and Robert Matheny, MD

^_* Cardiovascular Research Laboratory, Mercer University School of Medicine, Savannah, Georgia
Cardiothoracic Research Laboratory, Department of Pathology, Carlyle Fraser Heart Center/Crawford Long Hospital, Emory University, Atlanta, Georgia
CorMatrix Cardiovascular, Inc., Atlanta, Georgia

Manuscript received June 18, 2009; revised manuscript received September 29, 2009, accepted October 5, 2009.

^_* Reprint requests and correspondence: Dr. Zhi-Qing Zhao, Department of Basic Biomedical Sciences, Mercer University School of Medicine, 4700 Waters Avenue, Savannah, Georgia 31404 (Email: zhao_z{at}mercer.edu).

This study was presented at the American College of Cardiology Annual Scientific Sessions, Chicago, Illinois, 2008.

Objectives: This study tested the hypothesis that modulation of angiogenesis and cardiac function by injecting small intestine extracellular matrix emulsion (EMU) into myocardium is associated with recruitment of c-kit cells, myofibroblasts, and macrophages after myocardial infarction.

Background: Degradation of native extracellular matrix has been associated with adverse cardiac remodeling after infarction.

Methods: Sixty-four rats were subjected to 45 min ischemia followed by 3, 7, 21, and 42 days of reperfusion, respectively. Saline or EMU (30 to 50 µl) was injected into the area at risk myocardium after reperfusion. Histological examination was performed by immunohistochemical staining, and cardiac function was analyzed using echocardiography.

Results: The population of c-kit–positive cells in infarcted myocardium with the EMU injection increased significantly relative to the saline control at 7 days of reperfusion. Along with this change, alpha-smooth muscle actin expressing myofibroblasts and macrophages accumulated to a significant extent compared with the saline control. Increased vascular endothelial growth factor protein level and strong immunoreactivity of vascular endothelial growth factor expression were observed. Angiogenesis in the EMU area was significantly enhanced relative to the saline control, evidenced by increased density of -smooth muscle actin positive vessels. Furthermore, echocardiography showed significant improvements in fractional shortening, ejection fraction, and stroke volume in the EMU group. The wall thickness of the infarcted middle anterior septum in the EMU group was significantly increased relative to the saline control.

Conclusions: We show for the first time that injection of EMU into the infarcted myocardium increases neovascularization and preserves cardiac function, potentially mediated by enhanced recruitment of c-kit–positive cells, myofibroblasts, and macrophages.

Key Words: angiogenesis • cardiac remodeling • extracellular matrix emulsion

Abbreviations and Acronyms   ECM = extracellular matrix   EDV = end-diastolic volume   EF = ejection fraction   EMU = extracellular matrix emulsion   ESV = end-systolic volume   IgG = immunoglobulin G   LCA = left coronary artery   LV = left ventricle   LVDD = left ventricular diastolic dimension   LVSD = left ventricular systolic dimension   SCF = stem cell factor   SMA = smooth muscle actin   VEGF = vascular endothelial growth factor

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