For> 10 years ago, an unexpected role for the transforming growth factor-β cytokine pathway has been put forward in driving thoracic aortic aneurysms and dissections. Here, we reassess the evidence for a detrimental transforming growth factor-β overdrive in thoracic aortic aneurysms and dissections. In our view, most of the available mechanistic data argue against this theory.

Syndromic thoracic aortic aneurysms and dissections (TAADs) develop in patients with connective tissue disorders because of genetic mutations that affect structural components of the extracellular matrix and the cell contractile machinery. Early pathogenic hypotheses attributed the aortopathy to structural failure of the aortic tissue. Over 14 years ago, Neptune et al, 1 Habashi et al, 2 and Lindsay and Dietz 3 proposed a novel hypothesis to explain how fibrillin-1 (FBN1) mutations in Marfan syndrome (MFS) lead to pulmonary emphysema and aortic aneurysm and pointed to increased transforming growth factor-β (TGFβ) activation as the culprit mechanism. This constituted a major paradigm shift, and a new hope emerged that the life-threatening manifestations of MFS might be prevented by a simple medical treatment, losartan, shown to prevent the disease in mice through its TGFβ-antagonizing properties. 2