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PRECLINICAL STUDIES: CLINICAL RESEARCH

Macrophage Colony-Stimulating Factor Treatment After Myocardial Infarction Attenuates Left Ventricular Dysfunction by Accelerating Infarct Repair

Toshiyuki Yano, MD^_*, Tetsuji Miura, MD, PhD, FACC^_*,_*, Peter Whittaker, PhD, Takayuki Miki, MD, PhD^_*, Jun Sakamoto, MD, PhD^_*, Yuichi Nakamura, MD^_*, Yoshihiko Ichikawa, MD, PhD^_*, Yoshihiro Ikeda, MD^_*, Hironori Kobayashi, MD^_*, Katsuhiko Ohori, MD^_* and Kazuaki Shimamoto, MD, PhD^_*

^_* Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
Departments of Emergency Medicine and Anesthesiology, University of Massachusetts Medical School, Worcester, Massachusetts

Manuscript received July 1, 2005; revised manuscript received August 29, 2005, accepted September 8, 2005.

^_* Reprint requests and correspondence: Dr. Tetsuji Miura, Second Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo 060-8543, Japan (Email: miura{at}sapmed.ac.jp).

OBJECTIVES: We aimed to determine the effects of macrophage colony-stimulating factor (M-CSF) and granulocyte colony-stimulating factor (G-CSF) treatment on both the repair process and ventricular function after myocardial infarction (MI).

BACKGROUND: The M-CSF and G-CSF have multiple potential effects on cells involved in wound repair.

METHODS: Myocardial infarction was induced by 45- or 90-min coronary occlusion and reperfusion in rats with or without subsequent injection of M-CSF (10⁶ IU/kg/day) or G-CSF (50 µg/kg/day) for five days. We examined histology and messenger ribonucleic acid (mRNA), and assessed left ventricular function in situ using a conductance catheter.

RESULTS: Five days after MI, M-CSF increased the number of ED-1–positive cells, mRNA levels of transforming growth factor-ß-1, collagen I and III, and collagen fibers within the infarct. Fourteen days after MI, induced by 45-min ischemia, left ventricular end-systolic elastance (Ees) was reduced (1,191 ± 87 mm Hg/ml vs. 1,812 ± 150 mm Hg/ml) and both isovolumic relaxation time constant () (11.9 ± 0.9 ms vs. 8.5 ± 0.4 ms) and left ventricular end-diastolic volume (LVEDV) (0.225 ± 0.014 ml vs. 0.172 ± 0.011 ml) increased versus sham-operated rats. These alterations after MI were attenuated by M-CSF (Ees = 1,650 ± 146, = 9.7 ± 0.7, LVEDV = 0.199 ± 0.012) but not by G-CSF. This beneficial effect of M-CSF on Ees was also detected in hearts with MI induced by 90-min ischemia. Furthermore, M-CSF increased collagen content within infarcts and reduced the proportion of thin collagen fibers 14 days after MI. The Ees significantly correlated with infarct collagen content. Nevertheless, neither M-CSF nor G-CSF modified infarct size.

CONCLUSIONS: The M-CSF treatment attenuates deterioration of left ventricular function after MI by accelerating infarct repair.

Abbreviations and Acronyms   ANOVA = analysis of variance   Ees = left ventricular end-systolic elastance   ESPVR = end-systolic pressure volume relation   GAPDH = glyceraldehydes 3-phosphate dehydrogenase   G-CSF = granulocyte colony-stimulating factor   HE = hematoxylin and eosin   LVEDP = left ventricular end-diastolic pressure   LVEDV = left ventricular end-diastolic volume   M-CSF = macrophage colony-stimulating factor   MI = myocardial infarction   mRNA = messenger ribonucleic acid   PSR = picrosirius red   TGF = transforming growth factor

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