New agents for the treatment of infarcted myocardium.
Local delivery of angiogenic growth factors for the treatment of myocardial ischemia has been well documented in various animal models, and clinical trials are now in progress. Our strategy was radically different, based on selective protection of some of the growth factors naturally present within the injured tissue. This protection was obtained by applying a chemically defined substitute for Dextran called RGTA11 (for ReGeneraTing Agent). RGTA is a family of agents, which has properties mimicking those of heparan sulfates toward heparin-binding growth factors (HBGF) and which stimulate tissue repair and protection. Indeed, we have previously shown that RGTA prevents most of the damage resulting from acute skeletal muscle ischemia [FASEB J. (1999) 13, 761-766]. We now show that the same agent can be used for the treatment of myocardial infarction. Acute myocardial infarction was induced in pigs by ligation of the left circumflex artery. One hour later, a single injection of 10 mg of RGTA11 was made in the center of the infarcted area. Three weeks later we observed 1) recovery of 84% of the initial left ventricular ejection fraction (only 55% in saline-treated controls), 2) an almost 50% reduction in the infarct size, 3) a reduction in fibrotic tissue formation, 4) significant preservation of myocytes, and 5) an increase in the number of blood vessels. The treatment of ischemic heart disease with RGTA would have clear advantages over other therapies such as growth factor, gene, or cell transplants, based on a stable, simple, and easy-to-develop chemical product.
Yamauchi
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H
Centre de Recherches Chirurgicales, Association Claude Bernard, UPRESA-CNRS 7054, hopital Henri Mondor, 94010 Creteil, France.
Desgranges
P
P
Lecerf
L
L
Papy-Garcia
D
D
Tournaire
M C
MC
Moczar
M
M
Loisance
D
D
Barritault
D
D
D000199:Actins / Q000032:analysis; D000818:Animals; D003911:Dextrans / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D007150:Immunohistochemistry; D009130:Muscle, Smooth / Q000737:chemistry; D009203:Myocardial Infarction / Q000517:prevention & control*; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D013552:Swine; D014841:von Willebrand Factor / Q000032:analysis
D000199:Actins; D003911:Dextrans; C104129:RGTA11; D014841:von Willebrand Factor