Therapies for Thoracic Aortic Aneurysms and Acute Aortic Dissections

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.

Keywords: Marfan syndrome; aneurysm; aneurysm, dissecting; aorta; therapeutics.

Figure 1.

Pathology and progression of thoracic aortic aneurysms and dissections. A, Schematic illustration of the cellular and ECM (extracellular matrix) components in the 3 layers of the thoracic aorta. B, Cellular and ECM changes associated with aneurysm progression are illustrated, including endothelial dysfunction, elastin fiber fragmentation and loss, increased proteoglycan accumulation (blue), and smooth muscle cell loss (gray cell). C, Illustration of an acute aortic dissection because of a tear in intimal layer, progressing through the medial layer to form a false lumen and rupturing from the false lumen through the adventitial layer.

Figure 2.

TGFβ (transformation growth factor-β) and angiotensin signaling pathways. Depicted on the (left) and (right) are the TGFβ- and Ang II (angiotensin II)-signaling pathways, respectively, and their effects on aortic homeostasis. The interaction of the latent TGFβ complex with the extracellular fibrillin-containing microfibrils is shown outside the cell, whereas the interaction between TGFβ canonical (Smad) and noncanonical (MAPKs [mitogen-activated protein kinases]) signaling pathways is shown within the cell. Some of the regulatory interactions between the TGFβ and Ang II pathways are indicated in red. Ang I indicates angiotensin I; Arrb2, beta-arrestin-2; AT1R, angiotensin II type I receptor; AT2R, angiotensin II type II receptor; ECM, extracellular matrix; Erk1/2, extracellular signal–regulated kinase; Jnk, Jun N-terminal kinase; LTBP, latent TGFβ-binding protein; Shc, Src homology and collagen family of docking proteins; SMC, smooth muscle cell TAK1, TGFβ-activated kinase; TGFβRI, TGFβ receptor type I; and TGFβRII, TGFβ receptor type II. Modified from Yu and Jeremy with permission. Copyright ©2018, the Authors.