Abstract
Marfan syndrome is caused by mutations of the fibrillin-1 gene, which weakens the connective tissue integrity. Since 2003, bioavailability regulations of TGF-ß through fibrillin alterations have been presumed of being the culprit mechanisms for aortic aneurysm development. We present the analysis of our single-center Marfan children and adolescents cohort to assess the influence of age, sex, degree of cardiovascular involvement and dosage on losartan effectivity. This prospective longitudinal registered echocardiographical investigation (EudraCT 2009-016139-36) of 49 patients with an average follow-up of 72 months focused on aortic root z-scores, elasticity, and yearly progression rates. The 33 patients under medication with losartan showed an aortic root z-score reduction during the first 36 months compared to 22 patients without medication presenting constant mild progression. Yet, results diminished under losartan thereafter, adding up to similar progressions over 72 months in both groups (0.07 ± 0.10/year versus 0.04 ± 0.11/year). Although male patients exhibited higher root z-scores, progression with and without medication was comparable to females and not age-dependent. In conclusion, losartan evoked a significant aortic root z-score regression in young Marfan patients over the first 3 years, but this effect mitigated thereafter. The initial improvement concurred with ameliorated elasticity; lower stiffness levels predicted better clinical outcome, but likewise only up to 36 months. Sex differences in dilatation severity were observed but neither age nor sex had significant influence on progression rates. Losartan dosages were gradually increased in more severely affected patients and provided an equal rate of root progression over 72 months in comparison to patients under losartan treatment with lesser baseline dilatation severity.
Highlights
Marfan syndrome (MFS), a monogenetic disorder, is caused by pathogenic variants of the fibrillin-1 gene FBN1 [1]
The groundbreaking study of Habashi et al in 2006 showed the normalization of aneurysms after administration of TGF-ß neutralizing antibodies as well as losartan, an Angiotensin-II-type-1-receptor-blocker (ARB): The TGF-ß hyperactivity was attenuated in F bn1C1039G/+-mice, harboring a typical aortic disease-causing mutation [7]
During the first 36 follow-up months, patients on losartan treatment exhibited a regression of aortic root (AoR) z-scores, but presented with a significant progression thereafter over the following 3 years, with no similar changes noticeable in the patients without medication presenting with constant mild progression throughout the time period (Table 1)
Summary
Marfan syndrome (MFS), a monogenetic disorder, is caused by pathogenic variants of the fibrillin-1 gene FBN1 [1]. In 2003, Neptune proposed a second role for fibrillin-1 regarding the bioavailability of TGF-ß, showing that FBN1 alterations increase TGF-ß [3]. This was presumed the culprit mechanism for aortic aneurysms in thoracic aneurysm disorders like MFS [4]. The groundbreaking study of Habashi et al in 2006 showed the normalization of aneurysms after administration of TGF-ß neutralizing antibodies as well as losartan, an Angiotensin-II-type-1-receptor-blocker (ARB): The TGF-ß hyperactivity was attenuated in F bn1C1039G/+-mice, harboring a typical aortic disease-causing mutation [7]. Clinical trials in MFS children are sobering: While the first open-label administration of losartan add-on to ß-blocker in highly affected children
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