Cardioprotection by recombinant human erythropoietin following acute experimental myocardial infarction: dose response and therapeutic window.
BACKGROUND
Recombinant human erythropoietin (rhEPO) protects tissue from ischemic damage, but translation of this finding into useful guidelines with respect to human trials for myocardial infarction (MI) requires a determination of the minimum effective rhEPO dose and the therapeutic window following MI.


RESULTS
Serial echocardiography revealed that during four weeks following MI, induced by a permanent coronary ligation in rats, the LV end-diastolic and end-systolic volumes in untreated rats expanded from 0.35 +/- 0.01 and 0.14 +/- 0.01 ml to 0.84 +/- 0.04 and 0.61 +/- 0.06 ml, respectively, and ejection fraction (EF) reduced by 50%. A single i.v. injection of rhEPO immediately following MI in a dose of 150 IU/kg was as effective as 3,000 IU/kg in causing a 2-fold reduction of the number of apoptotic nuclei in the AAR 24-h later, a 2-fold reduction of the MI size measured 4 weeks later, attenuation of progressive LV dilatation and fall in EF. A 3000 IU/kg dose had similar therapeutic effects when delayed by 4, 8, or 12 h following MI, but was not effective after a 24-h delay. A single dose of 150 IU/kg was effective within 4 h post-MI, but was without effect if administered after an 8-h delay.


CONCLUSIONS
Cell death, final MI size, myocardial remodeling and functional decline are significantly reduced in rats by a single injection of rhEPO in a dose as low as 150 IU/kg if administered during the first 4 h after the ischemic event. Higher doses extend the therapeutic window up to 12 h.
Moon
Chanil
C
Laboratory of Cardiovascular Sciences, Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, 21224, MD, USA.
Krawczyk
Melissa
M
Paik
Doojin
D
Lakatta
Edward G
EG
Talan
Mark I
MI
D000818:Animals; D017209:Apoptosis; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004452:Echocardiography; D004921:Erythropoietin / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins
D002316:Cardiotonic Agents; D011994:Recombinant Proteins; D004921:Erythropoietin