Cytokine Combination Therapy with Erythropoietin a

Authors: Franca S Angeli Nicolas Amabile Mia Shapiro Rachel Mirsky Lauren Bartlett Yan Zhang Renu Virmani Kanu Chatterjee Andrew Boyle William Grossman Yerem Yeghiazarians

Publish Date: 2010/09/01

Volume: 24, Issue: 5-6, Pages: 409-420

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Abstract

Erythropoietin EPO and granulocyte colony stimulating factor GCSF have generated interest as novel therapies after myocardial infarction MI but the effect of combination therapy has not been studied in the large animal model We investigated the impact of prolonged combination therapy with EPO and GCSF on cardiac function infarct size and vascular density after MI in a porcine modelMI was induced in pigs by a 90 min balloon occlusion of the left anterior descending coronary artery 16 animals were treated with EPO+GCSF or saline control group Cardiac function was assessed by echocardiography and pressurevolume measurements at baseline 1 and 6 weeks postMI Histopathology was performed 6 weeks postMIAt week 6 EPO+GCSF therapy stabilized left ventricular ejection fraction 41 ± 1 vs 33 ± 1 p  001 and improved diastolic function compared to the control group Histopathology revealed increased areas of viable myocardium and vascular density in the EPO+GCSF therapy compared to the control Despite these encouraging results in a historical analysis comparing combination therapy with monotherapy with EPO or GCSF there were no significant additive benefits in the LVEF and volumes overtime using the combination therapyMyocardial infarction MI is a leading cause of morbidity and mortality in Western countries 1 Despite advances in the management of MI the number of patients with congestive heart failure continues to grow and remains associated with increased risk of death 1 Novel therapeutic approaches targeted to repairing myocardial damage have been the focus of intense research over the recent years 2 3 4 5Recently granulocyte colony stimulating factor GCSF and Erythropoietin EPO have emerged as promising candidates for treatment of acute ischemic heart disease Despite promising preclinical data using GCSF 6 7 human clinical trials in acute MI patients while generally reassuring in terms of safety have been disappointing from the standpoint of clinical benefit raising questions about the adequacy of GCSF monotherapy Nevertheless we have recently shown that GCSF therapy mobilizes bone marrow cells enhances neovascularization and prevents further deterioration of LV function in a porcine model of MI with lower LVEF 8 In line with our results a recent metaanalysis suggests that GCSF may be potentially beneficial in patients with larger infarcts who have a lower LVEF 50 9EPO has been shown to improve myocardial contractility 10 reduce cellular damage and apoptosis 11 and increase neovascularization leading to reduced infarct size and improved cardiac function in rodent models of MI 12 13 14 For the first time our group has recently shown that in a large animal MI model prolonged therapy 4 weeks with EPO decreases infarct size mobilizes bone marrow cells enhances neovascularization and results in improvements in ventricular remodeling and function in a porcine model of acute MI 15Given the diversity of cytokines and their overlapping functions 16 17 18 and the beneficial effects of EPO and GCSF therapy post MI we hypothesized that combination therapy with EPO and GCSF would enhance angiogenesis and decrease infarct size and therefore would result in concomitant improvements in ventricular remodeling and function in a porcine model of acute MI with reperfusion The current manuscript builds on the previous work and examines whether the combination of EPO and GCSF would be safe and effective in improving the cardiac function postMI To our knowledge no prior study has examined the effect of EPO+GCSF combination therapy after MI in the large animal model Of note since limited funding was secured for completion of this combination cytokine study the current results were compared to historical and previously published EPO and GCSF monotherapy arms 8 15 by our group To keep this comparison appropriate all aspects of the study amongst the groups were performed similarly and by the same operators

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