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(Circulation. 2009;120:526-532.)
© 2009 American Heart Association, Inc.

Vascular Medicine

Circulating Transforming Growth Factor-β in Marfan Syndrome

Peter Matt, MD; Florian Schoenhoff, MD; Jennifer Habashi, MD; Tammy Holm, MD; Christel Van Erp, PhD; David Loch, PhD; Olga D. Carlson, PhD; Benjamin F. Griswold, BSc; Qin Fu, PhD; Julie De Backer, MD, PhD; Bart Loeys, MD, PhD; David L. Huso, DVM, PhD; Nazli B. McDonnell, MD, PhD; Jennifer E. Van Eyk, PhD; Harry C. Dietz, MD; the GenTAC Consortium

From the Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Md (P.M., F.S., J.H., T.H., C.V.E., D.L., H.C.D.); Division of Cardiac Surgery, University Hospital, Basel/Berne, Switzerland (P.M.); Department of Cardiovascular Surgery, University of Berne, Switzerland (F.S.); Johns Hopkins Proteomics Center, Baltimore, Md (P.M., F.S., Q.F., J.E.V.E.); Laboratory of Clinical Investigation, National Institute on Aging, Bethesda, Md (O.D.C., B.F.G.); Centre for Medical Genetics, Ghent University, Ghent, Belgium (J.D.B., B.L.); Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Md (D.L.H.); and Clinical Research Branch, National Institute on Aging, Bethesda, Md (N.B.M.).

Correspondence to Jennifer Van Eyk, PhD, 602 Mason F. Lord Bldg, Center Tower, Johns Hopkins University, Baltimore, MD 21239 (e-mail jvaneyk1{at}jhmi.edu) or Peter Matt, MD, Division of Cardiac Surgery, University Hospital, CH-4031 Basel, Switzerland (e-mail pmatt@uhbs.ch).

Received December 7, 2008; accepted June 1, 2009.

Background— Marfan syndrome (MFS) is caused by mutations in the fibrillin-1 gene and dysregulation of transforming growth factor-β (TGF-β). Recent evidence suggests that losartan, an angiotensin II type 1 blocker that blunts TGF-β activation, may be an effective treatment for MFS. We hypothesized that dysregulation of TGF-β might be mirrored in circulating TGF-β concentrations.

Methods and Results— Serum obtained from MFS mutant mice (Fbn1^C1039G/+) treated with losartan was analyzed for circulating TGF-β1 concentrations and compared with those from placebo-treated and wild-type mice. Aortic root size was measured by echocardiography. Data were validated in patients with MFS and healthy individuals. In mice, circulating total TGF-β1 concentrations increased with age and were elevated in older untreated Fbn1^C1039G/+ mice compared with wild-type mice (P=0.01; n=16; mean±SEM, 115±8 ng/mL versus n=17; mean±SEM, 92±4 ng/mL). Losartan-treated Fbn1^C1039G/+ mice had lower total TGF-β1 concentrations compared with age-matched Fbn1^C1039G/+ mice treated with placebo (P=0.01; n=18; 90±5 ng/mL), and circulating total TGF-β1 levels were indistinguishable from those of age-matched wild-type mice (P=0.8). Correlation was observed between circulating TGF-β1 levels and aortic root diameters in Fbn1^C1039G/+ and wild-type mice (P=0.002). In humans, circulating total TGF-β1 concentrations were elevated in patients with MFS compared with control individuals (P<0.0001; n=53; 15±1.7 ng/mL versus n=74; 2.5±0.4 ng/mL). MFS patients treated with losartan (n=55) or β-blocker (n=80) showed significantly lower total TGF-β1 concentrations compared with untreated MFS patients (P0.05).

Conclusions— Circulating TGF-β1 concentrations are elevated in MFS and decrease after administration of losartan, β-blocker therapy, or both and therefore might serve as a prognostic and therapeutic marker in MFS.

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