Molecular mechanisms of inherited thoracic aortic disease – from gene variant to surgical aneurysm

Elizabeth Robertson, Candice Dilworth, Yaxin Lu, Brett Hambly, Richmond Jeremy

Aortic dissection is a catastrophic event that has a high mortality rate. Thoracic aortic aneurysms are the clinically silent precursor that confers an increased risk of acute aortic dissection. There are several gene mutations that have been identified in key structural and regulatory proteins within the aortic wall that predispose to thoracic aneurysm formation. The most common and well characterised of these is the FBN1 gene mutation that is known to cause Marfan syndrome. Others less well-known mutations include TGF-β1 and TGF-β2 receptor mutations that cause Loeys-Dietz syndrome, Col3A1 mutations causing Ehlers-Danlos Type 4 syndrome and Smad3 and-4, ACTA2 and MYHII mutations that cause familial thoracic aortic aneurysm and dissection. Despite the variation in the proteins affected by these genetic mutations, there is a unifying pathological end point of medial degeneration within the wall of the aorta characterised by vascular smooth muscle cell loss, fragmentation and loss of elastic fibers, and accumulation of proteoglycans and glycosaminoglycans within vascular smooth muscle cell-depleted areas of the aortic media. Our understanding of these mutations and their post-translational effects has led to a greater understanding of the pathophysiology that underlies thoracic aortic aneurysm formation. Despite this, there are still many unanswered questions regarding the molecular mechanisms. Further elucidation of the signalling pathways will help us identify targets that may be suitable modifiers to enhance treatment of this often fatal condition.