Erythropoietin Induces Neovascularization and Improves Cardiac Function in Rats With Heart Failure After Myocardial Infarction
Peter van der Meer, MD*, ,*,
Erik Lipsic, MD*,,
Robert H. Henning, MD, PhD,
Kristien Boddeus, BSc,
Jolanda van der Velden, PhD ,
Adriaan A. Voors, MD, PhD*,
Dirk J. van Veldhuisen, MD, PhD, FACC*,
Wiek H. van Gilst, PhD*, and
Regien G. Schoemaker, PhD
* Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands
Department of Clinical Pharmacology, University Medical Center Groningen, Groningen, the Netherlands
Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands
Manuscript received January 6, 2005;
revised manuscript received February 10, 2005,
accepted March 15, 2005.
* Reprint requests and correspondence: Dr. Peter van der Meer, Department of Cardiology, University Hospital Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands (Email: p.van.der.meer{at}thorax.azg.nl).
OBJECTIVES: We assessed the effects of erythropoietin (EPO) treatment in a rat model of post-myocardial infarction (MI) heart failure.
BACKGROUND: Erythropoietin, traditionally known as a hematopoietic hormone, has been linked to neovascularization. Whereas administration of EPO acutely after MI reduces infarct size and improves cardiac function, its role in the failing heart is unknown.
METHODS: Rats underwent coronary ligation or sham surgery. Rats with MI were randomly assigned to: untreated (MI), a single bolus of EPO immediately after MI induction (MI-EPO-early), EPO treatment immediately after MI and once every three weeks (MI-EPO-early+late), and EPO treatment starting three weeks after induction of MI, once every three weeks (MI-EPO-late). After nine weeks, hemodynamics, infarct size, myosin heavy chain (MHC) isoforms, myocyte hypertrophy, and capillary density were measured.
RESULTS: Erythropoietin treatment started immediately after MI (MI-EPO-early and MI-EPO-early+late) resulted in a 23% to 30% reduction in infarct size (p < 0.01) and, accordingly, hemodynamic improvement. Erythropoietin treatment, started three weeks after MI (MI-EPO-late), did not affect infarct size, but resulted in an improved cardiac performance, reflected by a 34% reduction in left ventricular end-diastolic pressure (p < 0.01), and 46% decrease in atrial natriuretic peptide levels (p < 0.05). The improved cardiac function was accompanied by an increased capillary density (p < 0.01), an increased capillary-to-myocyte ratio (p < 0.05), and a partial reversal of beta-MHC (p < 0.05) in all treated groups.
CONCLUSIONS: In addition to its effect on infarct size reduction, EPO treatment improves cardiac function in a rat model of post-MI heart failure. This observation may be explained by neovascularization, associated with an increased alpha-MHC expression.
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Abbreviations and Acronyms
| | CHF = chronic heart failure | | dLVP = developed left ventricular pressure | | EPO = erythropoietin | | LV = left ventricle/ventricular | | LVEDP = left ventricular end-diastolic pressure | | LVSP = left ventricular systolic pressure | | MHC = myosin heavy chain | | MI = myocardial infarction | | N-ANP = N-terminal atrial natiuretic peptide |
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