AT1 receptor antagonism to reduce aortic expansion in Marfan syndrome: lost in translation or in need of different interpretation?

Abstract

Marfan syndrome is an inherited autosomal dominant disorder of the connective tissue caused by mutations in the gene encoding fibrillin-1 ( FBN1 ).1,2 This disease has affected the ATVB community with the loss of 1 of our highly respected members, David Williams.3 The most devastating health issues of patients with Marfan syndrome are dissection and rupture of the proximal aorta. Aortic dimensions are routinely monitored in patients with Marfan syndrome, and surgical graft imposition is performed to sustain life. However, surgical intervention is a formidable process. To abrogate surgical repair, there is a desperate need for a medical approach for attenuating aortic expansion. Presently, patients with Marfan syndrome are routinely provided with β-adrenoceptor blockade. This standard of care is derived from the study of Shores et al.4 However, the benefit derived from administration of β-adrenoceptor blockade is far from established. Although FBN1 is a component of extracellular matrix, mutations in this protein do not directly promote the structural fragility that characterizes the specific aortic regions of patients with Marfan syndrome. Instead, a concept has developed that Fbn1 mutations lead to enhanced transforming growth factor β (TGF-β) activation that is the mechanistic basis of Marfan pathology. This concept originated from the demonstration that Fbn1 deficiency led to excessive activation of TGF-β signaling because of reduced binding, sequestration, and inactivation of TGF-β.5 Activation of TGF-β in Fbn1 -deficient mice was associated with a lung pathology similar to that observed in some patients with Marfan syndrome. This paradigm of FBN1 regulation of TGF-β activation was extended to aortic disease by generating heterozygous mice that express a C1039G mutation.6 These mice develop pronounced dilation of the ascending aorta associated with thickened media containing disrupted elastin fibers. In this model, the major proof of concept for the role of …