Thoracic Aortic Dissection

In the past, the aortic extracellular matrix (ECM) was viewed primarily as a passive structural framework, and aortic disease was equated solely with a mechanical failure of this framework. Because of our increasing understanding of aortic cellular and molecular biology, we now know that aortic disease is a manifestation of cellular dysfunction, irregular signaling, and excessive proteolysis. Mutations and variants involving several genes that encode crucial components of aortic smooth muscle cells (SMCs) and the surrounding ECM have been identified as causes of thoracic aortic aneurysm and dissection (TAAD). Vascular SMCs and the surrounding ECM communicate with each other and respond to mechanical signals via the mechanotransduction complex. Mutations of the many proteins associated with mechanotransduction can lead to decreased SMC contractility and the development of TAAD.¹

Marfan syndrome (MFS), the major cardiovascular complication of which is TAAD, is caused by mutations in the fibrillin-1 gene (FBN1). This gene encodes an ECM glycoprotein that is a component of the elastic fibers in the aorta.¹ Although FBN1 mutations have been traditionally linked to the development of MFS, recent evidence suggests an association between common FBN1 variants and sporadic TAAD.²

Transforming growth factor beta (TGF-β), a protein involved in cell proliferation, differentiation, and apoptosis, is also linked to the development of aortic disease. The bioavailability of TGF-β is tightly controlled; its inactive form is associated with fibrillin-1-containing ECM.³ Studies of fibrillin-1-deficient mice have found an increased bioavailability of active TGF-β due to a decreased amount of fibrillin-1-containing microfibrils.⁴ In addition, mutations in the genes that encode the TGF-β receptors (TGFBR1 and TGFBR2) are known to cause Loeys-Dietz syndrome and familial TAAD, and mutations in the gene encoding TGF-β2 (TGFB2) have recently been identified as a cause of familial TAAD associated with mild systemic manifestations of MFS.^3,5 This dysregulation of TGF-β signaling results in altered transcription of genes associated with ECM homeostasis, ultimately leading to the development of TAAD.³ Antagonizing TGF-β with the angiotensin II receptor type 1 blocker losartan has been shown to prevent elastin fragmentation and aortic aneurysm formation in mice with an FBN1 mutation.⁶ On the basis of these findings, as well as intriguing observations in children with MFS, clinical trials are now under way to determine whether losartan prevents TAAD in patients with MFS.⁷

Another protein associated with TAAD is SMAD3, a transcription factor for TGF-β. Mutations in SMAD3 cause aneurysms-osteoarthritis syndrome (AOS), an autosomal dominant disorder characterized by aortic and arterial aneurysms, arterial tortuosity, aortic dissection, mild craniofacial abnormalities, and early-onset osteoarthritis. Of significance is the fact that patients with AOS have a high incidence of early sudden death due to aortic dissection, which often occurs in a mildly dilated aorta (4–4.5 cm).⁸

Other components of the ECM–mechanotransduction complex–SMC network that have been implicated in aortic disease are collagen, components of the SMC contractile complex, and filamin A. Collagen is a major structural protein in the aortic wall that confers tensile strength and serves as a platform for SMC binding to the ECM. Mutations in the type III procollagen gene (COL3A1) cause vascular-type Ehlers-Danlos syndrome, an autosomal dominant connective-tissue disorder. The manifestations include aneurysms, dissection, and rupture of peripheral arteries and the thoracic and abdominal aorta.⁹ Mutations in genes encoding α-actin (ACTA2) and β-myosin (MYH11 and MYLK), both key components of the SMC contractile complex, also cause familial TAAD. In fact, ACTA2 mutations are present in 1 of every 7 families with familial TAAD.¹⁰ Mutations in MYH11 and MYLK have been found in families with familial TAAD, and MYH11 duplications have been implicated in cases of sporadic TAAD.^11,12 Filamin A is an actin-binding protein that links the SMC contractile unit to the cell surface, and an Ehlers-Danlos variant of periventricular heterotopia associated with joint and skin hyperextensibility and aortic dilation is caused by mutations in the gene encoding filamin A (FLNA).¹³

Regardless of whether the disease is genetically triggered or sporadic, the underlying process that leads to TAAD is characterized by ECM destruction and loss of SMCs, which result in aortic-wall degeneration. This process results from an imbalance between destructive factors—including proteases such as the matrix metalloproteinases¹⁴—and mechanisms for vascular protection and repair. The nature of and relationships among these destructive and protective factors are important topics for investigation.

From a clinical perspective, it is clear that a better understanding of the genetic, cellular, and molecular mechanisms of TAAD will improve our ability to prevent deaths caused by this disease. Knowledge of the underlying gene defect already provides clinical guidance with regard to treatment approaches and the timing of surgery¹⁵; this individualized approach to treatment will be increasingly fine-tuned as new genes are identified and their phenotypes are characterized. Furthermore, understanding the pathobiology of aortic-wall degeneration will help us develop new ways to prevent dilation and improve the durability of aortic repairs. Effective suppressive therapy could make surgical intervention unnecessary in many patients with small, sporadic aortic aneurysms by slowing their aortic dilation.¹⁶

Acknowledgment

The authors thank Stephen N. Palmer, PhD, ELS, for editorial support.