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Reduction in Hemoglobin–Oxygen Affinity Results in the Improvement of Exercise Capacity in Mice With Chronic Heart Failure

Tetsuya Watanabe, MD, PhD^_*, Toshihiro Takeda, MD, PhD^_*, Shigemiki Omiya, MD^_*, Shungo Hikoso, MD, PhD^_*, Osamu Yamaguchi, MD, PhD^_*, Yuko Nakano, DDS, Yoshiharu Higuchi, MD, PhD^_*, Atsuko Nakai, PhD^_*, Yusuke Abe, MS, Yayoi Aki-Jin, PhD, Masayuki Taniike, MD, PhD^_*, Isamu Mizote, MD^_*, Yasushi Matsumura, MD, PhD^||, Takahiko Shimizu, PhD, Kazuhiko Nishida, MD, PhD^_*, Kiyohiro Imai, PhD, Masatsugu Hori, MD, PhD, FACC^_*, Takuji Shirasawa, MD, PhD and Kinya Otsu, MD, PhD^_*,_*

^_* Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
First Department of Oral and Maxillo-Facial Surgery, Osaka University Graduate School of Dentistry, Osaka, Japan
Department of Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
Department of Frontier Bioscience, Faculty of Engineering and Micro-Nano Technology Research Center, Hosei University, Tokyo, Japan
^|| Department of Medical Information Science, Osaka University Graduate School of Medicine, Osaka, Japan.

Manuscript received October 29, 2007; revised manuscript received April 29, 2008, accepted June 3, 2008.

^_* Reprint requests and correspondence: Dr. Kinya Otsu, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. (Email: kotsu{at}medone.med.osaka-u.ac.jp).

Objectives: This study examined whether a reduction in hemoglobin–oxygen affinity improves exercise capacity in mice with heart failure.

Background: Exercise intolerance is a major determinant of quality of life in patients with chronic heart failure. One of the major goals of the treatment for chronic heart failure is to improve quality of life.

Methods: Four weeks after left coronary ligation, we transplanted bone marrow cells isolated from the transgenic mice expressing a hemoglobin variant with low oxygen affinity, Presbyterian, into the lethally irradiated mice with heart failure or administered a synthetic allosteric modifier of hemoglobin. The mice were then exercised on a treadmill.

Results: Four weeks after the left coronary artery ligation, mice showed cardiac dysfunction and chamber dilation, which were characteristics of heart failure. The transplantation led to a reduction in hemoglobin–oxygen affinity and an increase in oxygen supply for skeletal muscle without changes in muscle properties. The transplanted mice showed improved running performance on a treadmill despite impaired cardiac contractility. Furthermore, administration of the synthetic allosteric modifier of hemoglobin showed a similar effect.

Conclusions: Allosteric modification of hemoglobin represents a therapeutic option for improving exercise capacity in patients with chronic heart failure. One mechanism of improvement in exercise capacity is enhanced oxygen delivery in the skeletal muscle.

Key Words: hemoglobin • heart failure • oxygen • muscles

Abbreviations and Acronyms   BMC = bone marrow cell   BMT = bone marrow cell transplantation   CHF = chronic heart failure   Hb = hemoglobin   HbPres = hemoglobin Presbyterian   LCA = left coronary artery   MI = myocardial infarct/infarction   SDH = succinate dehydrogenase   WT = wild type