Heritable Thoracic Aortic Disease Overview
Summary
Purpose.
The goals of this overview on heritable thoracic aortic aneurysms and dissections (shortened in this GeneReview to heritable thoracic aortic disease) are the following.
Goal 1.
To describe the clinical characteristics of thoracic aortic disease
Goal 2.
To review the causes of heritable thoracic aortic disease and risk assessment for thoracic aortic aneurysm and dissection by gene
Goal 3.
To provide an evaluation strategy to identify the genetic cause of thoracic aortic disease in a proband (when possible)
Goal 4.
To inform genetic risk assessment in family members of a proband
Goal 5.
To inform (when possible) management regarding, surveillance for thoracic aortic aneurysm, and medical/surgical intervention based on the genetic cause
Diagnosis
Clinical Characteristics
Differential Diagnosis
Management
This section provides information regarding risk assessment for thoracic aortic aneurysm and dissection, surveillance for thoracic aortic disease, and recommendations for medical and surgical management based (when possible) on the genetic cause.
Risk Assessment for Thoracic Aortic Aneurysm and Dissection
At the time of diagnosis of HTAD appropriate imaging studies should be performed to obtain measurements of the aortic diameter at standard anatomic locations [Hiratzka et al 2010] in order to assess for associated risks (see Table 2). Nomograms have been established to predict normal aortic diameter for body surface area (BSA) and gender [Devereux et al 2012, Kälsch et al 2013]. Aortic diameters that exceed the upper limit in these nomograms are considered enlarged or dilated.
- Echocardiography is used to detect aortic root dilation. Measurements should be taken at reproducible anatomic locations: (1) aortic valve annulus, (2) mid-sinuses of Valsalva, (3) sinotubular junction, and (4) ascending aorta [Hiratzka et al 2010].
- CT or MRI can be used to detect dilation above the aortic root if echocardiography cannot properly evaluate these locations. Measurements should be taken at the: aortic sinuses of Valsalva, sinotubular junction, mid-ascending aorta, proximal aortic arch, mid-aortic arch, proximal descending thoracic aorta (approximately 2 cm distal to the left subclavian artery), mid-descending thoracic aorta, aorta at diaphragm, and abdominal aorta at the origin of the celiac axis.
Surveillance for Thoracic Aortic Disease
Proband. After diagnosis of aortic dilatation, aortic imaging should be repeated at standard anatomic locations in six months to assess the rate of aortic growth.
- When the aortic diameter remains stable, repeat the examination yearly.
- When the rate of change in the aortic diameter exceeds 0.5 cm per year, more frequent imaging should be considered
- When the diameter of the ascending aorta and/or the aortic root exceeds about 4.0 cm in an adult, repeat the examination more frequently.
Family members who have tested positive for the HTAD-gene pathogenic variant identified in an affected relative. Surveillance is the same as for thoracic aortic disease in a proband.
First-degree relatives (i.e., parents, sibs, offspring) of an affected individual in whom the specific genetic cause of HTAD has not been identified. Perform surveillance for thoracic aortic disease using the imaging modality (echocardiography vs CT or MRI) that will best detect the type of thoracic aortic disease in the proband. For example, at-risk relatives of a proband who had an aortic root aneurysm can be screened by echocardiography; in contrast, at-risk relatives of a proband who had an ascending aortic aneurysm may need to be screened by CT or MRI (if echocardiography cannot visualize the aortic root adequately).
Recommendations for Medical and Surgical Management of Thoracic Aortic Disease
Guidelines for management of thoracic aortic disease have been published [Hiratzka et al 2010].
Management of thoracic aortic aneurysm and/or dissection requires coordinated input from a multidisciplinary team of specialists familiar with HTAD, including a clinical geneticist, cardiologist, and cardiothoracic and vascular surgeons.
Proper clinical management, including early detection through thoracic aortic imaging, surveillance for enlargement of the aortic diameter or aneurysms, medical therapy, and timely prophylactic repair of an aneurysm reduces the high morbidity and mortality associated with thoracic aortic dissections.
Accumulating data indicate that identification of the specific genetic cause of hereditary thoracic aortic disease (Table 1), and in some cases the specific pathogenic variant, can inform the risk of developing a thoracic aortic aneurysm and dissection (Table 2), the optimal range of aortic diameters for prophylactic surgical repair (Table 2), and the risk for additional vascular disease and need for vascular surveillance (see Table 1).
Medical Treatment
To reduce hemodynamic stress on the ascending aorta, beta adrenergic-blocking agents (e.g., atenolol) are routinely advised for individuals with HTAD [Shores et al 1994, Hiratzka et al 2010]. Losartan was added as an alternative to beta adrenergic-blocking agents in 2014 after studies showed its efficacy in children and young adults with Marfan syndrome who were randomly assigned to losartan or atenolol [Lacro et al 2014].
Treatment guidelines for thoracic aortic disease recommend starting medical therapies once the aorta is dilated. Initiation of these therapies in individuals with a known pathogenic variant in an HTAD-related gene and no enlargement of the aorta should also be considered, particularly when mutation of that gene is associated with aortic dissection with little to no enlargement of the aorta (see Table 2).
Hypertension should be aggressively treated and controlled in individuals with HTAD, including at-risk family members even when the specific genetic cause of HTAD has not been identified.
Other cardiovascular risk factors, including smoking and hyperlipidemia, should be addressed.
Avoidance of isometric exercises and contact sports is recommended for individuals who have aortic dilatation or a pathogenic variant in an HTAD-related gene.
Prophylactic Surgical Repair of the Aorta
Although β-blockers can slow the rate of enlargement of a thoracic aortic aneurysm, the mainstay of prevention of premature deaths from dissection of a type A thoracic aortic aneurysm is surgical repair.
Surgery is typically recommended when the diameter of the aorta is approximately twice normal. This recommendation is based on the observation that at aortic diameters greater than 5.5 to 6.0 cm the risk of an adverse event (dissection, rupture, death) exceeded the risk associated with elective repair. However, other studies showed that in up to 60% of patients with an acute type A dissection the aortic diameter was less than 5.5 cm and that some had had little to no aortic enlargement [Pape et al 2007].
When the specific cause of HTAD has been identified. The current treatment guidelines for thoracic aortic disease have made gene-specific recommendations regarding the diameter at which an aorta warrants surgical repair.
Current data for gene-specific HTAD is summarized in Table 2. It is important to note that the data in Table 2 are primarily based on measurements of aortas that have dissected. Studies have indicated that, although the aortic root is minimally distorted at the time of dissection, the ascending aorta may have further enlarged as a result of the acute dissection [Rylski et al 2014]. These observations strongly suggest that better data for gene-specific surgical management are needed.
Gene-specific recommendations exist for the four following genes; data are limited on other genes.
- ACTA2. Elective surgical repair should be considered when the aortic root or ascending aorta reaches a maximum diameter of 4.5 cm. [Regalado et al 2015].
- FBN1. The aortic root can be monitored to 5 cm unless there is a family history of dissection at smaller diameters, rapid enlargement (i.e., greater than 0.5 cm/year), or significant aortic regurgitation [Hiratzka et al 2010].
- TGFBR1 or TGFBR2 or Loeys-Dietz syndrome. Surgical management is more aggressive with aortic root repair at 4.0 cm [Williams et al 2007, MacCarrick et al 2014]. More recent data indicate that such aggressive management may not be required for all patients with TGFBR1 and TGFBR2 [Tran-Fadulu et al 2009, Jondeau et al 2016].
Other considerations in the timing of prophylactic surgical repair of the aorta. Consider repair at aortic diameters <5.0 cm in the presence of any of the following [Hiratzka et al 2010]:
- Rapid enlargement (>0.5 cm per year)
- A family history of aortic dissections at diameters <5.0 cm
- Significant aortic regurgitation
When the specific cause of HTAD has not been identified, surgical repair is based on the aortic diameter at the time of type an aortic dissection in affected relatives (as determined either by imaging immediately at or prior to dissection or by postmortem findings).