The revised role of TGF-β in aortic aneurysms in Marfan syndrome

Abstract

Background: Recently, we demonstrated that losartan reduced the aortic root dilatation rate (AoDR) in adults with Marfan syndrome (MFS); however, responsiveness was diverse. The aim was to determine the role of transforming growth factor-β (TGF-β) as therapeutic biomarker for effectiveness of losartan on AoDR.

Methods: Baseline plasma TGF-β levels of 22 healthy controls and 99 MFS patients, and TGF-β levels after 1 month of losartan treatment in 42 MFS patients were measured. AoDR was assessed by magnetic resonance imaging at baseline and after 3 years of follow-up.

Results: Patients with MFS had higher TGF-β levels compared with healthy controls (121 pg/ml versus 54 pg/mL, p = 0.006). After 1 month of therapy, losartan normalised the TGF-β level in 15 patients (36%); the other 27 patients (64%) showed a significant increase of TGF-β. After 3 years of losartan therapy, patients with a decrease in TGF-β had significantly higher AoDR compared with patients with increased TGF-β (1.5 mm/3 years versus 0.5 mm/3 years, p = 0.04). Patients showing a decrease in TGF-β after losartan therapy had significantly elevated baseline TGF-β levels compared with patients with increased TGF-β (189 pg/ml versus 94 pg/ml, p = 0.05).

Conclusion: Patients responding to losartan therapy with a reduction of the plasma TGF-β level had higher baseline TGF-β levels and a higher AoDR. Most likely, TGF-β levels may be considered to be a readout of the disease state of the aorta. We propose that increased angiotensin II is the initiator of aorta dilatation and is responsible for increased TGF-β levels in MFS. The concept of TGF-β as initiator of aortic dilatation in MFS patients should be nuanced.

Fig. 1

a Flowchart shows an overview of Marfan syndrome patients and controls. Plasma TGF-β was analysed by ELISA (R&D Systems). b In 15 of the 42 MFS patients losartan normalised plasma TGF-β levels to that of controls. In 27 of MFS patients no reduction of plasma TGF-β was observed. c Decrease in TGF-β level is associated with an increase in AoDR in patients using losartan therapy (r = 0.47, p = 0.02). Linear regression analysis was used. AoDR = Aortic root dilatation rate; TGF-β = transforming growth factor β

Fig. 2

Schematic overview of proposed mechanism involving AngII- and TGF-β-mediated signalling in aortic dilatation in MFS. AngII induces a number of detrimental processes via AT1 when (chronically) elevated. AngII directly activates Smad2 (pSmad2) and increases TGF-β production, which can be secreted and subsequently binds to its cell surface receptor and thereby increases Smad2 activation further. Losartan blocks AT1 and thus inhibits AngII-mediated signalling including Smad2 activation, TGF-β production, blood pressure increase, pro-inflammatory responses, myofibroblast differentiation and ROS generation. AngII = angiotensin II; AT1 = angiotensin II receptor type 1; pSmad2 = phosphorylated Smad2; ROS = reactive oxygen species; TGF-β = transforming growth factor β