Repeated low-dose of erythropoietin is associated with improved left ventricular function in rat acute myocardial infarction model.
OBJECTIVE
To evaluate the potential protective affects of Epo on left ventricular (LV) function and remodeling after acute myocardial infarction (MI).


METHODS
Epo was injected into the peritoneum of male Wistar rats (250 g) during 6 weeks post induction of MI. Rats were divided into five groups: MI treated with single high dose (MT1, 5,000 U/kg, n=10), single high dose (5,000 U/kg) and repeated high doses (MTHi, 1,000 U/kg twice a week; n=8), or single high dose (5,000 U/kg) and repeated low doses (MTLo, 750 U/kg once a week, n=10), MI non-treated (MNT, n=10), sham (S, n=5). Echocardiography was performed 3.6+/-1.5 days and 43.7+/-2.3 days post MI. Collagen deposition and infarct size were measured on histological sections using computerized image analysis. Apoptosis was assessed by ApopTag staining.


RESULTS
Baseline fractional shortening (FS) was similar between groups. Six weeks after MI the FS of MTLo (26.9%) was significantly higher compared to MNT (17.8%), MT1 (19.5%) and MTH (22.3%) (p=0.01). However, remodeling indices (end diastolic and end systolic areas, LV circumference) did not improve in the Epo groups, and even worsened in the MTHi group. There was significantly less collagen staining in non-infarct areas in MT1 and MTHi groups compared to MNT and MTLo (0.38+/-0.3%, 0.49+/-0.34%, vs 0.89+/-0.41%, 0.95+/-0.33%, respectively, p<0.001). The number of ApopTag positive nucleus was significantly higher in the MNT group compared to the MT1, MTHi, MTLo groups (14.4+/-8, 7.6+/-4, 5.8+/-7, 4.8+/-5, respectively, p=0.01 for trend).


CONCLUSIONS
Repeated low doses of Epo after MI improved LV function, but the role of Epo on remodeling is not clear. It did not reduce left ventricular indices, but reduces fibrosis and apoptosis. High Epo doses reduced LV function and aggravated remodeling.
Ben-Dor
Itsik
I
Department of Cardiology, Rabin Medical Center, Beilinson Campus, 39 Jabotinsky Street, Petah Tikva, 49100, Israel.
Hardy
Britta
B
Fuchs
Shmuel
S
Kaganovsky
Ella
E
Kadmon
Ehud
E
Sagie
Alex
A
Coleman
Raymond
R
Mansur
Mali
M
Politi
Boaz
B
Fraser
Abigail
A
Harell
Daniela
D
Okon
Elimelech
E
Battler
Alexander
A
Haim
Moti
M
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002097:C-Reactive Protein / Q000032:analysis / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004562:Electrocardiography; D004921:Erythropoietin / Q000008:administration & dosage*; D006454:Hemoglobins / Q000032:analysis; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D015996:Survival Rate; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects
D006454:Hemoglobins; D004921:Erythropoietin; D002097:C-Reactive Protein