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(Circulation. 2005;112:2940-2945.)
© 2005 American Heart Association, Inc.

Heart Failure

Mineralocorticoid Receptor Antagonism Ameliorates Left Ventricular Diastolic Dysfunction and Myocardial Fibrosis in Mildly Symptomatic Patients With Idiopathic Dilated Cardiomyopathy

A Pilot Study

Hideo Izawa, MD, PhD; Toyoaki Murohara, MD, PhD; Kohzo Nagata, MD, PhD; Satoshi Isobe, MD, PhD; Hiroyuki Asano, MD; Tetsuya Amano, MD, PhD; Sahoko Ichihara, MD, PhD; Tomoko Kato, MD, PhD; Satoru Ohshima, MD; Yosuke Murase, MD; Shigeo Iino, MD, PhD; Koji Obata, PhD; Akiko Noda, PhD; Kenji Okumura, MD, PhD; Mitsuhiro Yokota, MD, PhD

From the Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya (H.I., T.M., S. Isobe, H.A., T.K., S.O., Y.M., S. Iino, K. Okumura); Nagoya University School of Health Sciences, Nagoya (K.N., A.N.); Department of Cardiovascular Genome Science, Nagoya University School of Medicine, Nagoya (K. Obata, M.Y.); and Department of Human Functional Genomics, Life Science Research Center, Mie University, Tsu (S. Ichihara), Japan.

Correspondence to Hideo Izawa, MD, PhD, Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466–8550, Japan. E-mail izawa{at}med.nagoya-u.ac.jp

Received September 27, 2004; de novo received June 27, 2005; revision received August 9, 2005; accepted August 22, 2005.

Background— Mineralocorticoid receptor antagonism reduces mortality associated with heart failure by mechanisms that remain unclear. The effects of the mineralocorticoid receptor antagonist spironolactone on left ventricular (LV) function and chamber stiffness associated with myocardial fibrosis were investigated in mildly symptomatic patients with idiopathic dilated cardiomyopathy (DCM).

Methods and Results— Twenty-five DCM patients with a New York Heart Association functional class of I or II were examined before and after treatment with spironolactone for 12 months. LV pressures and volumes were measured simultaneously, and LV endomyocardial biopsy specimens were obtained. Serum concentrations of the carboxyl-terminal propeptide (PIP) and carboxyl-terminal telopeptide (CITP) of collagen type I were measured. The patients were divided into 2 groups on the basis of the serum PIP/CITP ratio (35, group A, n=12; >35, group B, n=13), an index of myocardial collagen accumulation. LV diastolic chamber stiffness, the collagen volume fraction, and abundance of collagen type I and III mRNAs in biopsy tissue were greater and the LV early diastolic strain rate (tissue Doppler echocardiography) was smaller in group B than in group A at baseline. These differences and the difference in PIP/CITP were greatly reduced after treatment of patients in group B with spironolactone, with treatment having no effect on these parameters in group A. The collagen volume fraction was significantly correlated with PIP/CITP, LV early diastolic strain rate, and LV diastolic chamber stiffness for all patients before and after treatment with spironolactone.

Conclusions— Spironolactone ameliorated LV diastolic dysfunction and reduced chamber stiffness in association with regression of myocardial fibrosis in mildly symptomatic patients with DCM. These effects appeared limited, however, to patients with increased myocardial collagen accumulation.

Key Words: biopsy • cardiomyopathy • collagen • drugs • heart failure

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