Marfan syndrome (MFS) is a genetic disorder transmitted by an autosomal dominant trait which affects the connective tissue leading to the well known cardiovascular, musculoskeletal, ocular and pulmonary manifestations of the disease. The pioneer work of Dietz H et al (1) revealed that the disease is caused by mutations in the FBNI gene which encodes fibrillin-1, an important component of the extracellular matrix. The original thought was that the pathogenetic mechanism of MFS can be explained solely by the structural abnormality of fibrillin-1.
This belief was challenged by the same group of researchers who found initially in the mouse model of MFS (2) that fibrilin-1 has not only a structural role but interacts and regulates the transforming growth factor beta (TGFβ) signaling which has recognized effects on cellular differentiation and proliferation. In the mouse model of MFS, the blunting of excessive TGFβ by administration of neutralizing antibodies significantly reduced TGFβ activity and either abolished or improved the pulmonary, valvular, aortic and other systemic manifestations of the disease (3-5). Moreover, administration in pediatric patients with MFS of angiotensin II type 1 receptor blockers known to decrease TGFβ signaling, decreased aortic root dilatation (6).
In their recent publication, Matt P et al (7) probed a new frontier of the association of TGFβ with MFS by evaluating both in the mouse model and in patients the hypothesis that the upregulation of TGFβ in MFS might be reflected in elevated circulating TGFβ concentrations. They also correlated the levels of circulating TGFβ with the aortic root size and measured TGFβ levels following the administration of Losartan, ACE inhibitors and beta blockers.
In the mouse model there was a significant age related increase in the circulating TGFβ levels in the affected compared with the wild type mice. Administration of Losartan to the affected mice decreased significantly circulating TGFβ, to control levels. In addition, a good correlation was found between the circulating TGFβ levels and the size of the aortic root in treated and untreated animals. In humans, compared with 74 controls without MFS, the level of circulating TGFβ level was significantly higher in the 53 untreated and also in the 144 treated patients with MFS. Patients with MFS who received therapy with Losartan, beta blockers or their combination had significantly lower circulating TGFβ levels than untreated patients. In contrast with findings in the mouse model however, circulating TGFβ levels remained elevated beyond control levels following therapy, and TGFβ levels did not correlate with aortic root diameter. This lack of correlation can be perhaps explained by the fact that most patients with MFS in the study had relatively mild disease, by possible variability in circulating TGFβ levels which can be influenced by unknown factors and by limitations of a snapshot examination as compared with serial follow up evaluations.
In this regard, Akimastos A et al (8) just reported a moderately strong correlation between plasma TGFβ as well as matrix metalloproteinase (MMP) levels and changes in aortic root diameters during 24 weeks follow up of 17 patients with MFS on standard beta blocker therapy randomized to receive either the ACE inhibitor Perindopril or placebo. Compared to placebo, Perindopril significantly reduced TGFβ and MMP levels (8).
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