Marfan syndrome (MFS) is a pleiotropic inheritable connective tissue disorder with its main manifestations in the ocular, skeletal, and cardiovascular organ systems. 1 Life expectancy—largely determined by aortic complications—has significantly increased over the last decades, mainly thanks to improved diagnostics, increased awareness, and prophylactic aortic root surgery. Strategies for medical treatment aimed at reducing the risk for aortic dissection and delaying the time to elective surgery have been developed and were initially mainly based on interfering with haemodynamics. The majority of MFS patients harbour mutations in the fibrillin-1 gene (FBN1), encoding the extracellular matrix protein fibrillin-1, a major constituent of the microfibrils, which provide structural support in many tissues, including the aorta. Studying the role of fibrillin-1 has led to a better understanding of the underlying pathophysiology and has provided new prospects for targeted treatment.

Based on the demonstration of increased transforming growth factor-b (TGFb) signalling in mouse and human tissues of MFS, it was hypothesized that mutations in fibrillin-1 could lead to perturbed sequestration of the inactive TGFb complex. 2 TGFb was considered as the major culprit—the ‘bad guy’to tackle. Strategies to pursue this goal were set up with great enthusiasm, which was further enhanced by the initial results in a MFS mouse model and in a small human trial. 3, 4 The exciting news was that TGFb could be adequately inhibited not only by using specific neutralizing antibodies in mice, but also using the tried and tested human drug losartan, an angiotensin II type 1 receptor blocker. In the Fbn1C1039G/+ mouse model for MFS, treatment with TGFb neutralizing antibodies and losartan showed spectacular results, not only reducing aortic root growth to normal levels but also inhibiting elastic fibre fragmentation in the aortic wall. 3 The effect on aortic growth reduction seemed recapitulated in a small non-randomized human study in 18 paediatric MFS patients with a severe phenotype, showing a significant reduction in aortic root growth after adding losartan to conventional treatment. 4 Expectations were very high following these