Circulating transforming growth factor-beta in Marfan syndrome

Abstract

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

Methods and results: Serum obtained from MFS mutant mice (Fbn1(C1039G/+)) treated with losartan was analyzed for circulating TGF-beta1 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-beta1 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-beta1 concentrations compared with age-matched Fbn1(C1039G/+) mice treated with placebo (P=0.01; n=18; 90+/-5 ng/mL), and circulating total TGF-beta1 levels were indistinguishable from those of age-matched wild-type mice (P=0.8). Correlation was observed between circulating TGF-beta1 levels and aortic root diameters in Fbn1(C1039G/+) and wild-type mice (P=0.002). In humans, circulating total TGF-beta1 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 beta-blocker (n=80) showed significantly lower total TGF-beta1 concentrations compared with untreated MFS patients (P< or =0.05).

Conclusions: Circulating TGF-beta1 concentrations are elevated in MFS and decrease after administration of losartan, beta-blocker therapy, or both and therefore might serve as a prognostic and therapeutic marker in MFS.

Figure 1

Circulating TGFβ1 concentrations in Fbn1^C1039G/+ and wild-type mice and their correlation with the aortic root size. (A) Mean total TGFβ1 serum concentrations showing increased concentrations with age, and significantly higher circulating total TGFβ1 levels in 6 to 10 month old Fbn1^C1039G/+ mice compared to age-matched wild-types and losartan-treated Fbn1^C1039G/+ mice. (B) Mean free TGFβ1 serum concentrations changed in the same manner as seen with total TGFβ1. A subgroup of Fbn1^C1039G/+ mice was treated with a higher dose of losartan (1.2 g/l in drinking water instead of the 0.6 g/l standard dose) which resulted in a further reduction in circulating total and free TGFβ1 concentrations. (C) Correlation was observed between circulating total TGFβ1 concentrations and the sinus of Valsalva (SOV) diameters in untreated Fbn1^C1039G/+ and wild-type mice (regression prediction lines with mean value and CI 95%). (D) Correlation was observed between free TGFβ1 concentrations and SOV size in untreated Fbn1^C1039G/+ and wild-type mice (regression prediction lines with mean value and CI 95%).

Figure 2

Circulating total TGFβ1 concentrations in human samples, their correlation with z-scores in MFS patients, and the association with gender and age, respectively. (A) Mean total TGFβ1 plasma concentrations were elevated in MFS patients without cardiovascular drug therapy compared to healthy control individuals. MFS patients with losartan and/or β-blocker treatment showed a significant decrease in circulating total TGFβ1 levels compared to non-treated Marfans, and those with an ACEi therapy showed a tendency towards lower total TGFβ1 concentrations. *45 patients with combined losartan and β-blocker therapy; †10 patients with combined ACEi and β-blocker therapy (B) Correlation between circulating total TGFβ1 concentrations and z-scores in MFS patients without previous aortic root surgery was not significant (regression prediction lines with mean value and CI 95%). In addition, no significant correlation was observed in MFS patients without previous aortic surgery and no cardiovascular drug therapy (n=12, r=0.1, P=0.7). (C) Mean total TGFβ1 concentrations showed no significant difference between male and female in healthy control individuals and people with MFS. (D) No correlation was observed between total TGFβ1 concentrations and age in controls and those with MFS (r=0.3; r=0.07).