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

Abstract

BackgroundRecently, 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.MethodsBaseline 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.ResultsPatients 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).ConclusionPatients 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.

Increased aortic tortuosity indicates a more severe aortic phenotype in adults with Marfan syndrome

“…In line with these data, only the two patients with a mutation in the TGFBR2 gene in our cohort, showed an excessive ATI. In our earlier work, we demonstrated increased plasma TGFβ levels and correlations between TGFβ levels and aortic disease severity in MFS, which may be related to aortic tortuosity [17,18]. In line with our current and previous results, Hillebrand and colleagues also demonstrated Table 3 Univariate and multivariate analyses for combined clinical endpoint and aortic dissection.…”

Beneficial Outcome of Losartan Therapy Depends on Type of FBN1 Mutation in Marfan Syndrome

“…It seems that one of the other pathways has a detrimental effect on the vessel wall upon chronic angiotensin II receptor type 1 activation. [17][18][19][20] A possible explanation for the more enhanced beneficial effect of losartan in haploinsufficient patients may be that their aortic wall suffers from hyperextension because of a thinner fibrillin-1 network. The fibrillin-1 network is connected to the elastin and collagen network to limit excessive stretch, which may be hampered in these patients.…”

Marfan Syndrome, A Review

“…So increased psmad2 is not evidence of increased TGF-β activity, as has been suggested 46 . A more logical candidate for the increased p-smad2 and for the effect of losartan is angiotensin II, through the effect of the drug on angiotensin II receptor type 1 42,47,48 . The aggravating effect that has been found for inflammation in Marfan syndrome may be a result of local production of activin-A by mast cells and macrophages 49 .…”