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1 Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, United States
2 Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, United States
* To whom correspondence should be addressed. E-mail: fprunier{at}club-internet.fr.
Objectives: We examined the cardiac effects of chronic erythropoietin (EPO) therapy initiated seven days after myocardial infarction (MI) in rats. Background: A single high dose of EPO has been shown to reduce infarct size by preventing apoptosis when injected immediately after myocardial ischemia. The pro-angiogenic potential of EPO has also been reported, but the effects of chronic treatment with standard doses after MI are unknown. Methods: Rats underwent coronary occlusion followed by reperfusion, or a sham procedure. Infarcted rats were assigned to one of three treatment groups: 1) darbepoetin 0.75 µg/kg (MI+darb 0.75, n=12); 2) darbepoetin 1.5 µg/kg (MI+darb 1.5, n=12); 3) vehicle (MI+PBS, n=16), once a week from day 7 post-surgery. Sham rats received the vehicle alone (n=10). After eight weeks of treatment the animals underwent echocardiography, left ventricular pressure/volume measurements, and peripheral blood endothelial progenitor cell (EPC) counting. MI size and capillary density in the border zone and the area at risk (AAR) were measured post-mortem. Results: The AAR was similar in the three MI groups. Compared to MI+PBS, the MI+darb 1.5 group showed a reduction in the MI/AAR ratio (20.8% vs 38.7%, p<0.05), as well as significantly reduced left ventricle dilation and improved cardiac function. This reduction in post-MI remodeling was accompanied by increased capillary density (p<0.05) and by a higher number of EPC (p<0.05). Both darbopoeitin doses increased the hematocrit, while MI+darb 0.75 did not increase EPC numbers or capillary density and had no functional effect. Conclusion: Chronic EPO treatment reduces MI size and improves cardiac function only at a dose that induces EPC mobilization in blood and that increases capillary density in the infarct border zone.
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