Myocardial Infarction: Cardioprotection by Erythropoietin - Tissue-Protective Cytokines: Methods and Protocols - page 256

from ischemic damage had been published in 2003. Since then,
numerous successful studies in different experimental models had
been reported and summarized in several review papers ( 1-6 ).
Now, almost a decade and several phase I and II clinical trials later,
we still failed to translate these highly promising experimental
findings into clinical advances. In this review we reassess the wells
of experimental data and outcomes of clinical trials and attempt to
analyze the reason of a chasm between them. Should we write off
the decade of intensive experimental work as yet another example
of biological differences between species or is there another, cur-
rently overlooked, reason for the negative outcomes of clinical tri-
als? To this effect we systematically review all available in vivo
experimental studies, conducted in two major experimental mod-
els, MI induced by a permanent ligation of a coronary artery or by
an ischemia-reperfusion method. We put an emphasis of this review
on the experimental details such as effective doses and therapeutic
window. Then, in the light of these experimental details, we reas-
sess the design and clinical outcomes of reported clinical trials.

Animal experiments in the model of permanent occlusion of a
coronary artery are summarized in the Table 1 . The first experi-
ment had been published in 2003 ( 7 ). Rats were subjected to a
surgical occlusion of the left descending coronary artery and were
treated either with intraperitoneal injection of 5,000 IU/kg of
erythropoietin (type is not reported) or with saline. After 60 min
of occlusion rats were sacrificed and apoptosis was assessed in the
area at risk via TUNEL staining. The number of TUNEL positive
nuclei in the AAR were dramatically reduced ( p < 0.0001) in
EPO-treated rats.
Two more studies were published at the same time. In one ( 8 )
rats were treated with a single systemic (intraperitoneal) injection
of Epoetin-alfa (3,000 IU/kg) immediately following a permanent
occlusion of an anterior descending coronary artery. Apoptosis in
the area at risk (peri-infarct area) was assessed in the subgroup of
rats 24 h after coronary occlusion and was found to be reduced by
50%. The rest of the animals were followed up with serial echocar-
diography during 8 weeks. Experiment was concluded by a histo-
logical evaluation of the heart. At the end of experiment left
ventricular (LV) volumes were significantly smaller and EF was
significantly higher in the EPO treated group comparing with con-
trol, untreated animals. Moreover, histologically measured MI size
was fourfold smaller in the EPO-treated animals. Interestingly,
hematocrit level measured during the first 3 weeks after surgery
was not elevated in the EPO-treated group. Results of this first
study had been consistently reproduced by the same group later on
in 2005, 2006, and 2011 in different experiments in which a single
injection of 3,000 IU/kg of EPO immediately after coronary
occlusion served to elicit a standard effect to compare with other
types of interventions ( 9-12 ).

1.1 Review
of published studies

1.1.1 Permanent
occlusion of a coronary
artery model