Aortic aneurysm and dissection are manifestations of Marfan syndrome (MFS), a disorder caused by mutations in the gene that encodes fibrillin-1. Selected manifestations of MFS reflect excessive signaling by the transforming growth factor-β (TGF-β) family of cytokines. We show that aortic aneurysm in a mouse model of MFS is associated with increased TGF-β signaling and can be prevented by TGF-β antagonists such as TGF-β-neutralizing antibody or the angiotensin II type 1 receptor (AT1) blocker, losartan. AT1 antagonism also partially reversed noncardiovascular manifestations of MFS, including impaired alveolar septation. These data suggest that losartan, a drug already in clinical use for hypertension, merits investigation as a therapeutic strategy for patients with MFS and has the potential to prevent the major life-threatening manifestation of this disorder.MFS is a systemic disorder of connective tissue caused by mutations in FBN1, the gene encoding fibrillin-1 (1). As a principal component of the extracellular matrix microfibril (2, 3), fibrillin-1 was initially thought to play primarily a structural role in connective tissue. Several lines of evidence support an additional role as a regulator of the cytokine TGF-β (4, 5). Mice homozygous for a hypomorphic Fbn1 allele have impaired pulmonary alveolar septation associated with increased TGF-β signaling that can be prevented by perinatal administration of a polyclonal TGF-β neutralizing antibody (NAb) (5). Similarly, myxomatous

Skeletal muscle has the ability to achieve rapid repair in response to injury or disease 1 . Many individuals with Marfan syndrome (MFS), caused by a deficiency of extracellular fibrillin-1, exhibit myopathy and often are unable to increase muscle mass despite physical exercise. Evidence suggests that selected manifestations of MFS reflect excessive signaling by transforming growth factor (TGF)-β (refs. 2,3). TGF-β is a known inhibitor of terminal differentiation of cultured myoblasts; however, the functional contribution of TGF-β signaling to disease pathogenesis in various inherited myopathic states in vivo remains unknown 4,5 . Here we show that increased TGF-β activity leads to failed muscle regeneration in fibrillin-1-deficient mice. Systemic antagonism of TGF-β through administration of TGF-β-neutralizing antibody or the

ConclusionsIn a small cohort study, the use of ARB therapy in patients with Marfan's syndrome significantly slowed the rate of progressive aortic-root dilation. These findings require confirmation in a randomized trial.

Transforming growth factor–β (TGFβ) signaling drives aneurysm progression in multiple disorders, including Marfan syndrome (MFS), and therapies that inhibit this signaling cascade are in clinical trials. TGFβ can stimulate multiple intracellular signaling pathways, but it is unclear which of these pathways drives aortic disease and, when inhibited, which result in disease amelioration. Here we show that extracellular signal–regulated kinase (ERK) 1 and 2 and Smad2 are activated in a mouse model of MFS, and both are inhibited by therapies directed against TGFβ. Whereas selective inhibition of ERK1/2 activation ameliorated aortic growth, Smad4 deficiency exacerbated aortic disease and caused premature death in MFS mice. Smad4-deficient MFS mice uniquely showed activation of Jun N-terminal kinase–1 (JNK1), and a JNK antagonist ameliorated aortic growth in MFS mice that lacked or retained full Smad4 expression. Thus, noncanonical (Smad-independent) TGFβ signaling is a prominent driver of aortic disease in MFS mice, and inhibition of the ERK1/2 or JNK1 pathways is a potential therapeutic strategy for the disease.

Angiotensin II (AngII) mediates progression of aortic aneurysm, but the relative contribution of its type 1 (AT1) and type 2 (AT2) receptors remains unknown. We show that loss of AT2 expression accelerates the aberrant growth and rupture of the aorta in a mouse model of Marfan syndrome (MFS). The selective AT1 receptor blocker (ARB) losartan abrogated aneurysm progression in the mice; full protection required intact AT2 signaling. The angiotensin-converting enzyme inhibitor (ACEi) enalapril, which limits signaling through both receptors, was less effective. Both drugs attenuated canonical transforming growth factor–β (TGFβ) signaling in the aorta, but losartan uniquely inhibited TGFβ-mediated activation of extracellular signal–regulated kinase (ERK), by allowing continued signaling through AT2. These data highlight the protective nature of AT2 signaling and potentially inform the choice of therapies in MFS and related disorders.

Loeys-Dietz syndrome (LDS) is a connective tissue disorder that is characterized by a high risk for aneurysmand dissection throughout the arterial tree and phenotypically resembles Marfan syndrome. LDS is caused by heterozygous missense mutations in either TGF-β receptor gene (TGFBR1 or TGFBR2), which are predicted to result in diminished TGF-β signaling; however, aortic surgical samples from patients show evidence of paradoxically increased TGF-β signaling. We generated 2 knockin mouse strains with LDS mutations in either Tgfbr1 or Tgfbr2 and a transgenic mouse overexpressing mutant Tgfbr2. Knockin and transgenic mice, but not haploinsufficient animals, recapitulated the LDS phenotype. While heterozygous mutant cells had diminished signaling in response to exogenous TGF-β in vitro, they maintained normal levels of Smad2 phosphorylation under steady-state culture conditions, suggesting a chronic compensation. Analysis of TGF-β signaling in the aortic wall in vivo revealed progressive upregulation of Smad2 phosphorylation and TGF-β target gene output, which paralleled worsening of aneurysm pathology and coincided with upregulation of TGF-β1 ligand expression. Importantly, suppression of Smad2 phosphorylation and TGF-β1 expression correlated with the therapeutic efficacy of the angiotensin II type 1 receptor antagonist losartan. Together, these data suggest that increased TGF-β signaling contributes to postnatal aneurysm progression in LDS.

Background-Marfan syndrome (MFS) is caused by mutations in the fibrillin-1 gene and dysregulation of transforming growth factor-␤ (TGF-␤). Recent evidence suggests that losartan, an angiotensin II type 1 blocker that blunts TGF-␤ activation, may be an effective treatment for MFS. We hypothesized that dysregulation of TGF-␤ might be mirrored in circulating TGF-␤ concentrations. Methods and Results-Serum obtained from MFS mutant mice (Fbn1C1039G/ϩ ) treated with losartan was analyzed for circulating TGF-␤1 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-␤1 concentrations increased with age and were elevated in older untreated Fbn1 C1039G/ϩ mice compared with wild-type mice (Pϭ0.01; nϭ16; meanϮSEM, 115Ϯ8 ng/mL versus nϭ17; meanϮSEM, 92Ϯ4 ng/mL). Losartan-treated Fbn1 C1039G/ϩ mice had lower total TGF-␤1 concentrations compared with age-matched Fbn1

Conclusion:Physician judgment should be used in determining susceptibility to venous thromboembolism (VTE) and the need for VTE prophylaxis in patients undergoing major elective abdominal surgery.Summary: There were an estimated 900,000 VTE events in U.S. hospitalized patients in 2005 (Heit JA, et al. American Society of Hematology Annual Meeting Abstract 2005;106 abstract 910). However, pulmonary embolism (PE) after elective abdominal surgery seems very uncommon. Opponents of a "one size fits all" approach to VTE prophylaxis argue routine VTE prophylaxis for all patients increases cost and compromises resources to administer what is potentially a dangerous treatment for an infrequent event in certain categories of patients. They further argue that trials of VTE prophylaxis use some VTE events as end points for efficacy, such as calf vein thrombosis, that may not be clinically significant, at least in the short-term. In 2004 the Kentucky Surgical Care Improvement Project found a very low rate of PE in 5285 elective specialty surgery patients. There were 15 PEs detected in these patients, and none were fatal despite erratic and very limited use of VTE prophylaxis. The authors also queried the University Health System Consortium database from 2004 and also found a very low rate of VTE complication in patients undergoing elective operations (Surg 2008;144:654-660). It is possible, however, that American College of Chest Physicians (ACCP) recommendations may have altered practices of VTE prophylaxis in elective surgical patients, and rates of fatal and non-fatal PE could be influenced by changing indications for VTE prophylaxis. The authors' study was designed to assess and compare rates of VTE prophylaxis and PE from an 18-month consecutive period in 2003 to 2004 with an identical period of observation in 2007 to 2008. Their hope was to assess the effect of the ACCP recommendations advocating an increase in VTE prophylaxis.The authors queried the University Health System Consortium database comprising data from 123 academic teaching hospitals. They identified patients undergoing colorectal resections, total hip replacement, total knee replacement, and hysterectomies from two consecutive 18-month periods: 2003 to 2004 and 2007 to 2008. VTE rates ranged from 0.6% to 3.2%, and PE rates ranged from 0.28% to 1.09%. There was an increased use of VTE prophylaxis for all procedures between 2003 to 2004 and 2007 to 2008, except for hysterectomy. Comparing the two periods, the authors found VTE rates were not significantly affected among patients who received pharmacologic prophylaxis and actually decreased in patients who did not receive any pharmacologic prophylaxis, despite an absence of significant change of severity of illness in the patient populations.Comment: The author's arguments are a step backward from routine VTE prophylaxis to an approach where "the need for prophylaxis would be assessed on an individual basis, based on retrospective data, expert consensus, and clinical judgment." What the authors may have actu...