Therapies for Thoracic Aortic Aneurysms and Acute Aortic Dissections: Old Controversies and New Opportunities

DIanna M. Milewicz, Francesco Ramirez

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

Abstract

Thoracic aortic aneurysms that progress to acute aortic dissections are often fatal. Thoracic aneurysms have been managed with treatment with β-adrenergic blocking agents (β-blockers) and routine surveillance imaging, followed by surgical repair of the aneurysm when the risk of dissection exceeds the risk for repair. Thus, there is a window to initiate therapies to slow aortic enlargement and delay or ideally negate the need for surgical repair of the aneurysm to prevent a dissection. Mouse models of Marfan syndrome - a monogenic disorder predisposing to thoracic aortic disease - have been used extensively to identify such therapies. The initial finding that TGFβ (transformation growth factor-β) signaling was increased in the aortic media of a Marfan syndrome mouse model and that its inhibition via TGFβ neutralization or At1r (Ang II [angiotensin II] type I receptor) antagonism prevented aneurysm development was generally viewed as a groundbreaking discovery that could be translated into the first cure of thoracic aortic disease. However, several large randomized trials of pediatric and adult patients with Marfan syndrome have subsequently yielded no evidence that At1r antagonism by losartan slows aortic enlargement more effectively than conventional treatment with β-blockers. Subsequent studies in mouse models have begun to resolve the complex molecular pathophysiology underlying onset and progression of aortic disease and have emphasized the need to preserve TGFβ signaling to prevent aneurysm formation. This review describes critical experiments that have influenced the evolution of our understanding of thoracic aortic disease, in addition to discussing old controversies and identifying new therapeutic opportunities.

Original languageEnglish
Pages (from-to)126-136
Number of pages11
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume39
Issue number2
DOIs
StatePublished - 1 Feb 2019

Keywords

  • Marfan syndrome
  • aneurysm
  • aneurysm, dissecting
  • aorta
  • therapeutics

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