This Article Full Text Full Text (PDF) All Versions of this Article: 109/11/1379    most recent 01.CIR.0000120704.97934.41v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yndestad, A. Articles by Aukrust, P. Search for Related Content PubMed PubMed Citation Articles by Yndestad, A. Articles by Aukrust, P. Related Collections Other heart failure Gene expression Growth factors/cytokines Heart failure - basic studies Clinical Studies

(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

This article has been cited by other articles:

				G. Ertl and T. Thum New Insight Into Healing Mechanisms of the Infarcted Heart J. Am. Coll. Cardiol., January 12, 2010; 55(2): 144 - 146. [Full Text] [PDF]

				Y. Oshima, N. Ouchi, M. Shimano, D. R. Pimentel, K. N. Papanicolaou, K. D. Panse, K. Tsuchida, E. Lara-Pezzi, S.-J. Lee, and K. Walsh Activin A and Follistatin-Like 3 Determine the Susceptibility of Heart to Ischemic Injury Circulation, October 20, 2009; 120(16): 1606 - 1615. [Abstract] [Full Text] [PDF]

				A. Yndestad, K.-O. Larsen, E. Oie, T. Ueland, C. Smith, B. Halvorsen, I. Sjaastad, O. H. Skjonsberg, T. M. Pedersen, O.-G. Anfinsen, et al. Elevated levels of activin A in clinical and experimental pulmonary hypertension J Appl Physiol, April 1, 2009; 106(4): 1356 - 1364. [Abstract] [Full Text] [PDF]

				J. L. Bjornstad, N. O. Neverdal, O. A. Vengen, C. W. Knudsen, T. Husebye, J. Pepper, M. Lie, G. Christensen, and T. Tonnessen Alterations in circulating activin A, GDF-15, TGF-{beta}3 and MMP-2, -3, and -9 during one year of left ventricular reverse remodelling in patients operated for severe aortic stenosis Eur J Heart Fail, December 1, 2008; 10(12): 1201 - 1207. [Abstract] [Full Text] [PDF]

				E. Lara-Pezzi, L. E. Felkin, E. J. Birks, P. Sarathchandra, K. D. Panse, R. George, J. L. Hall, M. H. Yacoub, N. Rosenthal, and P. J. R. Barton Expression of Follistatin-Related Genes Is Altered in Heart Failure Endocrinology, November 1, 2008; 149(11): 5822 - 5827. [Abstract] [Full Text] [PDF]

				K. L. Hamilton, L. Lin, Y. Wang, and A. A. Knowlton Effect of ovariectomy on cardiac gene expression: inflammation and changes in SOCS gene expression Physiol Genomics, January 17, 2008; 32(2): 254 - 263. [Abstract] [Full Text] [PDF]

				Q. Yu, K. Horak, and D. F. Larson Role of T Lymphocytes in Hypertension-Induced Cardiac Extracellular Matrix Remodeling Hypertension, July 1, 2006; 48(1): 98 - 104. [Abstract] [Full Text] [PDF]

				G. Euler-Taimor and J. Heger The complex pattern of SMAD signaling in the cardiovascular system Cardiovasc Res, January 1, 2006; 69(1): 15 - 25. [Abstract] [Full Text] [PDF]

				U. C. Sharma, S. Pokharel, T. J. van Brakel, J. H. van Berlo, J. P.M. Cleutjens, B. Schroen, S. Andre, H. J.G.M. Crijns, H.-J. Gabius, J. Maessen, et al. Galectin-3 Marks Activated Macrophages in Failure-Prone Hypertrophied Hearts and Contributes to Cardiac Dysfunction Circulation, November 9, 2004; 110(19): 3121 - 3128. [Abstract] [Full Text] [PDF]