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(Hypertension. 2004;43:739.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Hypertensive Myocardial Fibrosis and Diastolic Dysfunction

Another Model of Inflammation?

Fumitaka Kuwahara; Hisashi Kai; Keisuke Tokuda; Motohiro Takeya; Akira Takeshita; Kensuke Egashira; Tsutomu Imaizumi

From Internal Medicine III and Cardiovascular Research Institute (F.K., H.K., K.T., T.I.), Kurume University School of Medicine, Kurume; Pathology II (M.T.), Kumamoto University School of Medicine, Kumamoto; and Cardiovascular Medicine (A.T., K.E.), Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.

Correspondence to Dr Hisashi Kai, Internal Medicine III and Cardiovascular Research Institute, Kurume University School of Medicine, 67 Asahimachi, Kurume 830-0011, Japan. E-mail naikai{at}med.kurume-u.ac.jp

Excessive myocardial fibrosis deteriorates diastolic function in hypertensive hearts. Involvement of macrophages is suggested in fibrotic process in various diseased situations. We sought to examine the role of macrophages in myocardial remodeling and cardiac dysfunction in pressure-overloaded hearts. In Wistar rats with suprarenal aortic constriction, pressure overload induced perivascular macrophage accumulation and fibroblast proliferation with a peak at day 3, decreasing to lower levels by day 28. Myocyte chemoattractant protein (MCP)-1 mRNA was upregulated after day 1, peaking at day 3 and returning to insignificant levels by day 28, whereas transforming growth factor (TGF)-ß induction was observed after day 3, with a peak at day 7, and remained relatively elevated at day 28. After day 7, concentric left ventricular (LV) hypertrophy developed, associated with reactive fibrosis and myocyte hypertrophy. At day 28, echocardiography showed normal LV fractional shortening but decreased ratio of early to late filling wave of transmitral Doppler velocity, and hemodynamic studies revealed elevated LV end-diastolic pressure, suggesting normal systolic but impaired diastolic function. Chronic treatment with an anti-MCP-1 monoclonal neutralizing antibody inhibited not only macrophage accumulation but also fibroblast proliferation and TGF-ß induction. Furthermore, the neutralizing antibody attenuated myocardial fibrosis, but not myocyte hypertrophy, and ameliorated diastolic dysfunction without affecting blood pressure and systolic function. In conclusion, roles of MCP-1-mediated macrophage accumulation are suggested in myocardial fibrosis in pressure-overloaded hearts through TGF-ß-mediated process. Inhibition of inflammation may be a new strategy to prevent myocardial fibrosis and resultant diastolic dysfunction in hypertensive hearts.

Key Words: macrophages • fibrosis • hypertension • diastole

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