Published Online
on March 1, 2004

A more recent version of this article appeared on March 23, 2004

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Submitted on March 28, 2003
Revised on November 14, 2003
Accepted on December 22, 2003

Elevated Levels of Activin A in Heart Failure. Potential Role in Myocardial Remodeling

Arne Yndestad MSc^*, Thor Ueland BSc, Erik ie 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, and 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.., H.A.), MSD Cardiovascular Research Centre (E.., 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.

^* To whom correspondence should be addressed. E-mail: arne.yndestad{at}klinmed.uio.no.

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)- 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 _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 _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-₁, 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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