Targeting transforming growth factor-β signaling in aortopathies in Marfan syndrome.

topathy, with initial experiments showing prevention of aortic root expansion in a mouse model of MFS using RAS blockade,3 which was followed by studies in human patients that showed similar results.4,5 These findings were welcomed with enthusiasm as a pharmacological solution for MFS, and have prompted several human clinical trials, which are presently ongoing to determine the possible benefit of RAS blockade in aortopathy in MFS patients.6 TGFβ signaling has also received attention as a key factor in the aortopathy of MFS patients, as not only the canonical regulatory pathway involving downstream Smad proteins but also a non-canonical pathway involving ERK and JNK kinases has been recently described as implicated in MFS pathology upon activation of the TGFβ pathway.7,8 Moreover, circulating levels of TGFβ have received attention because they are not only elevated in patients with MFS aortopathy but are also responsive to pharmacological treatment, thus suggesting their possible use as a surarfan syndrome (MFS) is characterized by mutations in the fibrillin-1 gene and dysregulation of transforming growth factor-β (TGFβ) signaling, which is phenotypically associated with gradual weakening of connective tissue throughout the body, including the lungs, bones and cardiovascular system.1 A primary cause of mortality in MFS patients reaching adolescence or adulthood is aortic rupture or dissection. Surgery is generally performed to remove the affected portion of the aorta, but more than half of patients who have had their aortas repaired require additional surgery or manifest aortic rupture because of expansion of the unrepaired regions of the aorta over time.2 At present, measures to identify patients exhibiting progressive expansion or re-expansion of the aorta after surgery is a topic of importance. On medical therapy, β-blockers have been historically used as the anchoring agent. The renin-angiotensin system (RAS) has also recently been implicated in the pathogenesis of Marfan aorM