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Original Articles: Adult Cardiac

Granulocyte Colony-Stimulating Factor Prevents Reperfusion Injury After Heart Preservation

^a Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
^b Division of Cardiovascular Surgery, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

Accepted for publication December 18, 2007.

^_* Address correspondence to Dr Sawa, Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine, Suita Osaka 565-0871, Japan (Email: sawa{at}surg1.med.osaka-u.ac.jp).

Background: Heart transplantation is an accepted method of treatment for selected patients with end-stage heart disease. Making prolonged heart preservation safer will benefit patients awaiting heart transplantation. Granulocyte colony-stimulating factor (G-CSF) exhibited protective effects against myocardial ischemia–reperfusion injury mediated through the Janus kinase (Jak)/(signal transducer and activator of transcription (Stat) pathway. We examined whether pharmacologic preconditioning with G-CSF improves cardiac function after heart preservation.

Methods: Male rats were divided into four groups: group A, saline injection; group B, G-CSF, 10 µg/kg; group C, G-CSF, 100 µg/kg; and group D, G-CSF, 100 µg/kg plus AG490 (a selective Jak2 inhibitor), 1 mg/kg. The G-CSF and AG490 were given intravenously for 3 consecutive days. Four hours after the final treatment, isolated rat hearts underwent 12 hours of hypothermic (4°C) preservation, followed by 60 minutes of normothermic reperfusion.

Results: Stat3 phosphorylation was observed in the heart at 15 minutes after G-CSF treatment in group C, but this was attenuated by additional treatment with AG 490 in group D. Compared with group A, group C exhibited significant recovery of left ventricular pressure, maximum positive rate of left ventricular developed pressure (Max dP/dt), and coronary flow (p < 0.05, respectively), as well as lower creatine phosphokinase leakage during reperfusion (p < 0.05). Group B and group D did not show significant hemodynamic recovery during reperfusion. In group C, increased Bcl-xL and decreased Bax expressions as well as decreased terminal deoxynucleotide transferase-mediated deoxy uridine triphosphate nick-end labeling (TUNEL)-positive cardiomyocytes were observed after reperfusion. Immunohistochemical examination showed significantly increased capillary density before hypothermic preservation in group C, but not in other groups.

Conclusions: Pharmacologic preconditioning with G-CSF protected hearts from prolonged hypothermic ischemia–reperfusion injury.