Inherited Thoracic Aortic Disease: New Insights and Translational Targets

Abstract

Inherited thoracic aortopathies denote a group of congenital conditions that predispose to disease of the thoracic aorta. Aortic wall weakness and abnormal aortic hemodynamic profiles predispose these patients to dilatation of the thoracic aorta, which is generally silent but can precipitate aortic dissection or rupture with devastating and often fatal consequences. Current strategies to assess the future risk of aortic dissection or rupture are based primarily on monitoring aortic diameter. However, diameter alone is a poor predictor of risk, with many patients experiencing dissection or rupture below current intervention thresholds. Developing tools that improve the risk assessment of those with aortopathy is internationally regarded as a research priority. A robust understanding of the molecular pathways that lead to aortic wall weakness is required to identify biomarkers and therapeutic targets that could improve patient management. Here, we summarize the current understanding of the genetically determined mechanisms underlying inherited aortopathies and critically appraise the available blood biomarkers, imaging techniques, and therapeutic targets that have shown promise for improving the management of patients with these important and potentially fatal conditions.

Keywords: Marfan syndrome; aneurysm, dissecting; aortic aneurysm; bicuspid aortic valve; biomarkers.

Figure 1.

Anatomy and histology of the thoracic aorta. Schematic representation of the thoracic aorta three-dimensional (3D) rendering from a contrast-enhanced magnetic resonance imaging (MRI) angiogram and both and tricuspid aortic valve from taken from MRI cine imaging (images captured on 3T Biograph mMR, Siemens, Erlangen, Germany; 3D rendering performed in Horos GNU Lesser General Public License, version 3) and a histological sample of the aortic wall stained with hematoxylin and eosin. The 3 layers of the aortic wall are demonstrated, and a basic representation of the composition for each layer is demonstrated.

Figure 2.

Summary of the processes thought to be involved in thoracic aortopathy development. The pathway affected as part of abnormal underlying processes in individual inherited thoracic aortopathies is highlighted. ECM indicates extracellular matrix; MMP, matrix metalloproteinase; nsHTAD, nonsyndromic heritable thoracic aneurysm and dissection; TGFβ, transforming growth factor-β; TIMP, tissue inhibitor of metalloproteinase; and VSMC, vascular smooth muscle cell.

Figure 3.

Summary of the management for imaging, family screening, and counseling management for inherited thoracic aortopathies. First-line genetic testing targets are in bold. BAV indicates bicuspid aortic valve; and nsHTAD, nonsyndromic heritable thoracic aortic disease.

Figure 4.

Emerging molecular imaging methods for identifying high-risk aortopathy. Histological sections from a patient with Marfan syndrome who underwent elective aortic root replacement for dilated aorta highlighting known pathological end points in thoracic aortic disease (A and C) and corresponding examples of molecular imaging for each disease process (B and D). A, Elastin van Gieson staining demonstrating elastic fiber breaks (green arrows). B, Uptake of elastin-specific contrast agent was performed in control (wild-type [WT]) and FBN1^C1039G/+ mice at the level of the ascending aorta with reduced uptake in the ascending aorta of FBN1^c1039G/+ mice, suggesting lower elastin content and more elastin breaks. Adapted from Okamura et al. Copyright © 2014, American Heart Association, Inc. C, Picrosirius red staining for type I and III collagen with areas of reduced uptake in the media and adventitia (green and orange arrows). Collagen-rich (left, yellow arrow) and collagen-poor (right, yellow arrows) abdominal aortic aneurysms in an angiotensin II infusion/transforming growth factor-β neutralization mouse model. ESMA indicates elastin-specific magnetic resonance imaging contrast agent. Reprinted from Klink et al with permission. Copyright © 2011, Elsevier.