Abstract 1403: Post-infarct Treatment with Erythropoietin Gelatin Hydrogel Sheet Improves Cardiac Function and Remodeling through Activation of Cell-surviving Signals, Anti-fibrotic and Pro-angiogenic Effects
Purpose: Erythropoietin (EPO) reportedly protects the ischemic myocardium, but the effective dose is too high to be clinically useful. We hypothesized that an EPO-gelatin hydrogel sheet applied directly to the heart would be beneficial following myocardial infarction.
Methods: Rabbits underwent 30 min of coronary occlusion and 14 days of reperfusion. Beginning immediately after the start of reperfusion, saline (Control group) or 1500 IU/kg EPO (EPO group) was injected subcutaneously once per day for 5 days. In the EPO-DDS group, a gelatin hydrogel patch containing 1500 IU/kg EPO to be released continuously over 14 days was applied to the myocardial surface of the risk area. Left ventricular (LV) function was then measured using echocardiography; infarct size and fibrotic area were determined by TTC and Sirius Red staining; numbers of CD31-positive microvessels were determined immunohistochemically; and expression of erythropoietin receptor (EPO-R) and activation of Akt, Bcl-2, Bax and MMP-1 were assessed by Western blotting.
Results: Ejection fraction and fractional shortening were significantly greater in the EPO-DDS group (68.9±3.8%, 35.8±2.8%) than the EPO (64.0±2.8%, 32.0±1.9%) or Control (57.8±2.8%, 28.2±1.9%) groups. Conversely, LV systolic and diastolic dimensions, infarct size and fibrotic area were significantly smaller in the EPO-DDS group (7.8±0.5 mm,12.1±0.4 mm, 13.2±1.9%,11.3±1.4%) than the EPO (9.1±0.6 mm,13.3±0.8 mm, 24.7±1.7%, 30.7±2.0%) or Control (7.8±0.5 mm,15.4±0.5 mm, 23.1±2.9%, 38.4±4.0%) groups. Hematocrit was significantly increased in the EPO group (44.0±2.3%) but not in the EPO-DDS group (37.8±1.4%). The number of CD31-positive microvessels was significantly higher in the EPO-DDS group (319.5±3.2/HPF) than in the EPO (260.3±16.1/HPF) or Control groups (269.5±11.8/HPF). Expression of EPO-R, p-Akt and MMP-1, Bcl-2 was markedly higher in the EPO-DDS group than in the EPO or Control groups.
Conclusions: The EPO-gelatin hydrogel patch, but not systemic injection of EPO, accelerates the healing process, reduces myocardial infarct size and improves LV function and remodeling with no side effects (e.g., erythropoiesis). The mechanism involves activation of EPO-R, Akt, Bcl-2, MMP-1 and angiogenesis.