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(Circulation. 2009;120:1585-1597.)
© 2009 American Heart Association, Inc.

Heart Failure

Absence of Thrombospondin-2 Causes Age-Related Dilated Cardiomyopathy

Melissa Swinnen, MS^*; Davy Vanhoutte, PhD^*; Geert C. Van Almen, MS; Nazha Hamdani, PhD; Mark W.M. Schellings, PhD; Jan D'hooge, PhD; Jolanda Van der Velden, PhD; Matthew S. Weaver, PhD; E. Helene Sage, PhD; Paul Bornstein, MD; Fons K. Verheyen, PhD; Thierry VandenDriessche, PhD; Marinee K. Chuah, PhD; Dirk Westermann, MD; Walter J. Paulus, MD, PhD; Frans Van de Werf, MD, PhD; Blanche Schroen, PhD; Peter Carmeliet, MD, PhD; Yigal M. Pinto, MD, PhD; Stephane Heymans, MD, PhD

From the Center for Heart Failure Research (M.S., G.C.V.A., M.W.M.S., B.S., S.H.) and Department of Molecular Cell Biology (F.K.V.), CARIM, Maastricht University, Maastricht, the Netherlands; Vesalius Research Center, K.U. Leuven and VIB, Leuven, Belgium (M.S., D.V., T.V., M.K.C., P.C.); Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands (N.H., J.V.d.V., W.J.P.); Department of Cardiovascular Diseases, K.U. Leuven, Leuven, Belgium (D.V., J.D., F.V.d.W.); Hope Heart Program, Benaroya Research Institute at Virginia Mason, Seattle, Wash (M.S.W., E.H.S.); Departments of Biochemistry and Medicine, Washington University, Seattle (P.B.); Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany (D.W.); and Heart Failure Research Center, University of Amsterdam, Amsterdam, the Netherlands (Y.M.P.).

Correspondence to Stephane Heymans, MD, PhD, Center for Heart Failure Research, CARIM, Department of Cardiology, Maastricht University Medical Center, PO BOX 5800, 6202 AZ Maastricht, the Netherlands. E-mail s.heymans{at}cardio.unimaas.nl

Received March 13, 2009; accepted August 17, 2009.

Background— The progressive shift from a young to an aged heart is characterized by alterations in the cardiac matrix. The present study investigated whether the matricellular protein thrombospondin-2 (TSP-2) may affect cardiac dimensions and function with physiological aging of the heart.

Methods and Results— TSP-2 knockout (KO) and wild-type mice were followed up to an age of 60 weeks. Survival rate, cardiac function, and morphology did not differ at a young age in TSP-2 KO compared with wild-type mice. However, >55% of the TSP-2 KO mice died between 24 and 60 weeks of age, whereas <10% of the wild-type mice died. In the absence of TSP-2, older mice displayed a severe dilated cardiomyopathy with impaired systolic function, increased cardiac dilatation, and fibrosis. Ultrastructural analysis revealed progressive myocyte stress and death, accompanied by an inflammatory response and replacement fibrosis, in aging TSP-2 KO animals, whereas capillary or coronary morphology or density was not affected. Importantly, adeno-associated virus-9 gene–mediated transfer of TSP-2 in 7-week-old TSP-2 KO mice normalized their survival and prevented dilated cardiomyopathy. In TSP-2 KO animals, age-related cardiomyopathy was accompanied by increased matrix metalloproteinase-2 and decreased tissue transglutaminase-2 activity, together with impaired collagen cross-linking. At the cardiomyocyte level, TSP-2 deficiency in vivo and its knockdown in vitro decreased the activation of the Akt survival pathway in cardiomyocytes.

Conclusion— TSP-2 expression in the heart protects against age-dependent dilated cardiomyopathy.

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Circulation 2009 120: 1553-1554. [Extract] [Full Text]