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 fi 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.

Systems pharmacology–based integration of human and mouse data for drug repurposing to treat thoracic aneurysms

“…Based on the relatively high expression of their respective targets in the aorta of MFS mice, this shorter list of top-ranked drugs was narrowed down to the steroid fludrocortisone and the muscle relaxant baclofen ( Figure 2B). However, fludrocortisone was excluded from further analyses because of its potential to induce iatrogenic arterial hypertension, the major risk factor for thoracic aortic disease (14).…”

“…Earlier studies of MFS mice with nondissecting TAA (Fbn1 C1039G/+ mice) have correlated aneurysm onset and progression with increased TGF-β signaling in the media stimulated by improper angiotensin II (AngII) type I receptor (AT1r) activity (6,7). More recent findings indicate a more complex disease mechanism involving the gradual stratification of stress-stimulated interactions among different cell types and multiple regulatory pathways, of which the AT1r and TGF-β signaling pathways are a critical subset (8)(9)(10)(11)(12)(13)(14).…”

Pathogenesis of Abdominal Aortic Aneurysm

“…It was originally demonstrated more than 70 years ago when turkeys eating sweet pea seed, Lathyrus odoratus, which contains the lysis oxidase inhibitor, B-aminopropionitrile, die of acute aortic dissections. The beta blocker propranolol was found to decrease deaths from dissection in B-aminopropionitrile fed turkeys [40][41][42][43]. Beta-blockers such as propranolol benefit the aortic wall through negative inotropic and chronotropic effects.…”

Association of Lactate Dehydrogenase with In-Hospital Mortality in Patients with Acute Aortic Dissection: A Retrospective Observational Study

“…AAD patients with a time interval of ≤14 days from the onset of symptoms to hospital admission were included in the present study. Exclusion criteria included (1) uncompleted LDH tests, (2) prior history of a malignant tumor or liver cirrhosis, (3) diagnosis with pregnancy, and (4) presence of AAD for more than 14 days.…”

“…Acute aortic dissection (AAD) is a catastrophic aortic disease with high mortality and morbidity that requires immediate diagnosis and treatment [1,2]. From 1% to 2% of patients with AAD die per hour for the first 24∼48 hours [3]. Previous studies have found that many noninvasive markers, such as CRP and D-dimer, are considered to be associated with AAD severity [4,5].…”