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(Circulation. 2004;109:1379-1385.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

Elevated Levels of Activin A in Heart Failure

Potential Role in Myocardial Remodeling

Arne Yndestad, MSc; Thor Ueland, BSc; Erik Øie, MD, PhD; Geir Florholmen, MSc; Bente Halvorsen, PhD; Håvard Attramadal, MD, PhD; Svein Simonsen, MD, PhD; Stig S. Frøland, MD, PhD; Lars Gullestad, MD, PhD; Geir Christensen, MD, PhD; Jan Kristian Damås, MD, PhD; Pål Aukrust, MD, PhD

From the Research Institute for Internal Medicine (A.Y., T.U., B.H., S.S.F., J.K.D., P.A.), Section of Endocrinology (T.U.), Institute for Surgical Research (E.Ø., H.A.), MSD Cardiovascular Research Centre (E.Ø., H.A.), Department of Cardiology (S.S., J.K.D.), and Section of Clinical Immunology and Infectious Diseases (S.S.F., P.A.), Rikshospitalet University Hospital, Oslo; Institute for Experimental Medical Research, Ullevål University Hospital, Oslo (G.F., G.C.); and Department of Medicine, Bærum Hospital, Sandvika (L.G.), Norway.

Correspondence to Arne Yndestad, MSc, Research Institute for Internal Medicine, Rikshospitalet University Hospital, University of Oslo, N-0027 Oslo, Norway. E-mail arne.yndestad{at}klinmed.uio.no

Received March 28, 2003; de novo received September 5, 2003; revision received November 14, 2003; accepted December 22, 2003.

Background— Although modulation of inflammatory processes has been suggested as a new treatment modality in heart failure (HF), our knowledge about abnormalities in the cytokine network during HF is still limited. On the basis of a previous cDNA array study examining peripheral blood mononuclear cells from HF patients, we hypothesized a role for activin A, a member of the transforming growth factor (TGF)-ß superfamily, in the pathogenesis of HF.

Methods and Results— This study had 4 main and novel findings. First, serum levels of activin A were significantly elevated in patients with HF (n=86) compared with healthy control subjects (n=20), with increasing levels according to disease severity as assessed by clinical, hemodynamic, and neurohormonal parameters. Second, compared with control subjects, HF patients, as determined by real-time quantitative reverse transcriptase polymer chain reaction, also had markedly increased gene expression of the activin A subunit activin ß_A in T cells but not in monocytes. Third, in a rat model of HF, we demonstrated a concerted induction of the gene expression of activin ß_A and activin receptors IA, IB, IIA, and IIB after myocardial infarction. Immunohistochemical analysis localized activin A solely to cardiomyocytes. Finally, activin A markedly increased gene expression of mediators involved in infarction healing and myocardial remodeling (ie, atrial natriuretic peptide, brain natriuretic peptide, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, transforming growth factor-ß₁, and monocyte chemoattractant protein-1) in neonatal rat cardiomyocytes.

Conclusions— Together with our demonstration of activin A–induced gene expression in neonatal cardiomyocytes of mediators related to myocardial remodeling, the expression pattern of activin A during clinical and experimental HF suggests an involvement of this cytokine in the pathogenesis of HF.

Key Words: heart failure • inflammation • leukocytes • myocardium

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