Thoracic aortic aneurysms (TAA) occur with an incidence of approximately 5 to 10 per 100,000 individuals per year.1-4 The incidence is similar in men and women, but the average age at diagnosis is a decade higher in women (70s) than in men (60s).5 The etiology and location of a given TAA dictates its natural history and the approach to management. Medical literature and guidelines define the aorta into five main anatomic segments: the root or sinus segment, which extends from the aortic valve annulus to the sinotubular junction; the ascending thoracic aorta, which extends from the sinotubular junction to the innominate artery; the aortic arch, which extends from the innominate to the left subclavian artery; the descending thoracic aorta, which extends from the left subclavian artery to the diaphragm; and the abdominal aorta, which extends from the diaphragm to the level of the aortic bifurcation.4,6 A true aneurysm is a segmental full-thickness dilation of the blood vessel that affects the three layers of the arterial wall (intima, media, adventitia).4 Acute aortic dissection (AAD) for the ascending aorta is defined according to the DeBakey (Type I, Type II) or Stanford classification scheme (Type A).4 Approximately 60% of TAAs are found at the aortic root or ascending aorta, 40% occur in the descending aorta, 10% are localized to the aortic arch, and 10% to the thoracoabdominal aorta.7 Notably, a TAA can involve more than one aortic segment.3,7 Most TAAs are asymptomatic and discovered incidentally when imaging studies, such as chest x-rays, CT scans, or echocardiograms are performed for seemingly unrelated indications.3 When symptomatic, TAAs can present with upper back or chest pain, as well as compression-related symptoms affecting the surrounding structures, leading to nerve dysfunction or arterial compression with ischemia or thromboembolism.3 Aneurysms of the aortic root or ascending aorta may result in secondary aortic regurgitation with an accompanying diastolic murmur.3 Nevertheless, the vast majority of TAAs are asymptomatic before an acute event and a high mortality rate is associated with aortic rupture or dissection, with an early mortality of 1% to 2% per hour after onset of symptoms following acute aortic dissection of the ascending aorta.4,8 TAAs account for approximately one third of hospitalizations related to aortic aneurysms, with the remaining two thirds occurring due to aneurysms of the abdominal aorta.4
The etiology and natural history of a TAA are the most important considerations in determination of diameter thresholds for the purpose of clinical management.4 Correlation of aortic diameter with body size and sex is also key in threshold determination.5 A community study by Paruchuri et al demonstrated an increased risk of type A aortic dissection between 4.0 cm and 4.4 cm when compared to a control diameter of ≤ 3.4 cm.9 This in turn formed the basis for the definition of a dilated ascending aorta as ≥ 4.0 cm by the American College of Cardiology (ACC) and American Heart Association (AHA) Guideline for the Diagnosis and Management of Aortic Disease4 (ACC/AHA Guidelines) and is congruent with the 2014 European Society of Cardiology guideline on the diagnosis and treatment of aortic diseases, in which aortic dilation was similarly defined as a diameter of the ascending aorta > 4.0 cm.4,10 Subsequently, the abrupt increase in risk at a diameter of ≥ 4.5 cm justifies definition of an aneurysm.9 These thresholds apply to individuals whose height, body surface area (BSA) or both are within 1-2 standard deviations of the population mean and may need to be adjusted downward or upward depending on the individual.4 Risk assessment can also be conducted using aortic z-scores and other diameter indexing methods.4
TAAs can be caused by congenital conditions, heritable disorders, multifactorial degenerative conditions, previous aortic dissection, infections, and inflammatory diseases.2,4,11 Heritable causes are more likely to be identified for aortic root aneurysms and aneurysms of the ascending thoracic aorta, which are more likely to present at a younger age (60 years) when compared with aneurysms of the descending aorta (72 years).4,12 Ascending TAAs also typically lack risk factors for atherosclerosis, such as diabetes, hypertension, and smoking and demonstrate low prevalence of aortic calcifications or atheromas, which are more prevalent in descending TAAs, wherein these “degenerative” injuries are considered preconditions.4,12 Aortic root and ascending thoracic aortic aneurysms are also often associated with bicuspid aortic valve (BAV). Finally, many aortic root and ascending thoracic aortic aneurysms are sporadic and idiopathic in nature.4
A variety of genetic or heritable conditions are thought to account for approximately 20% of TAAs; collectively, these are referred to as heritable thoracic aortic disease (HTAD). This encompasses syndromic HTAD, which is associated with multiorgan features, and nonsyndromic HTAD, wherein abnormalities are limited to the aorta with or without its branches.4,13 HTAD is most often is associated with aneurysms of the aortic root, ascending aorta, or both, but may present with distal aortic disease and aortic dissection and pathogenic variants in multiple genes can lead to TAA, cerebral aneurysms, and abdominal aortic aneurysms (AAA). For example, mutations in TGFBR2 predispose to TAA as well as intracranial aneurysms and aneurysms and dissections of other arteries.4 ACTA2 mutations lead to TAA and occlusive vascular disease, including early onset stroke and coronary artery disease.4
The ACC/AHA Guidelines provide diverging management pathways for medical and surgical therapy depending on family history and underlying etiology of TAA.4 Aortic dissection in patients with HTAD can occur at lower aortic diameters than the surgical thresholds recommended in guidelines for sporadic thoracic aortic disease and elective surgery before aortic dissection in these patients has been shown to yield better long-term survival with fewer aortic reinterventions than surgery after aortic dissection.4,14-17 This is reflected in current guidelines from the American College of Cardiology (ACC) and American Heart Association (AHA) for management of HTAD patients.4
Genetic information drives the approach to disease surveillance and management, including timing of surgical repair, and informs risk for additional vascular diseases and systemic complications. The 2022 ACC/AHA Guidelines recommend that patients with aortic root/ascending aortic aneurysms or aortic dissection undergo evaluation for hereditary etiology and advise obtaining a multigenerational family history of thoracic aortic disease (TAD), unexplained sudden deaths, and peripheral and intracranial aneurysms.4,18-20 Genetic testing is recommended for patients with aortic root/ascending aortic aneurysms and risk factors for HTAD, which include TAD and syndromic features of Marfan syndrome, Loeys-Dietz syndrome, or vascular Ehlers-Danlos syndrome, TAD presenting at age <60 years, a family history of either TAD or peripheral/intracranial aneurysms in a first- or second-degree relative, or a history of unexplained sudden death at a relatively young age in a first- or second-degree relative.4,14-16 Genetic counseling is recommended for patients with an established pathogenic or likely pathogenic variant in a gene predisposing to HTAD, and it is recommended that the patient’s clinical management is informed by the specific gene and variant in the gene.4,17,21,22 Cascade genetic testing and surveillance of family members is also recommended.4
Disease mechanisms responsible for the pathophysiology of TAA include dysregulated transforming growth factor-β (TGFβ) signaling, extracellular matrix homeostasis, and vascular smooth muscle cell contraction.23 Therefore, it follows that HTAD-associated genes identified to date can be broadly classified into three categories: (1) genes encoding components of the extracellular matrix (e.g. FBN1, MFAP5, LOX and COL3A1); (2) genes encoding components of the TGFβ pathway (e.g. TGFBR1/2, TGFB2/3, SMAD2/3); (3) genes encoding components of the smooth muscle cell contractile mechanism (e.g. ACTA2, MYH11, MYLK, PRKG1).23,24 Relevant associated syndromes include: Marfan syndrome (FBN1), Loeys-Dietz syndrome (TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3), Vascular Ehlers-Danlos syndrome (COL3A1), Arterial tortuosity syndrome (SLC2A10), Shprintzen-Goldberg syndrome (SKI), Ehlers-Danlos syndrome with periventricular nodular heterotopia (FLNA), Meester-Loeys syndrome (BGN), LOX-related TAA (LOX), and Smooth muscle dysfunction syndrome (ACTA2). The following genes have been tied to nonsyndromic HTAD: ACTA2, MYH11, MYLK, PRKG1, MAT2A, MFAP5, FOXE3, and THSD4. Genes associated with bicuspid aortic valve-associated ascending aneurysm include NOTCH1, TGFBR2, MAT2A, GATA5, SMAD6, LOX, ROBO4, and TBX20. Finally, Turner syndrome is also associated with TAA. It is important to note that it is possible for some individuals with pathogenic variants in a gene that can lead to syndromic HTAD to have very few or no syndromic features, and variants in some genes causing syndromic HTAD may also result in nonsyndromic HTAD.4
A multigene panel comprising all genes that are suspected to cause HTAD is recommended by ACC/AHA Guidelines as the most cost-effective and clinically useful approach to genetic testing.4 Clinical genetic testing is also indicated for patients who meet clinical diagnostic criteria for Marfan syndrome but do not have ectopia lentis, as genetic testing can exclude the alternative diagnosis of Loeys-Dietz syndrome.4 Genetic testing laboratories categorize variants as pathogenic, likely pathogenic, variant of uncertain/unknown significance, benign, and likely benign. Variants of unknown significance that have not been confirmed to have a causal relationship with TAD should not be used for clinical management. As of this drafting, 11 genes have sufficient data to confirm that mutations in these genes confer a highly penetrant risk for TAA and acute aortic dissections, with or without syndromic features, according to curation of genes by the ClinGen Aortopathy Working Group.13,14 These include the following genes: FBN1, LOX, MYH11, ACTA2, MYLK, PRKG1, COL3A1, TGFBR2, TGFBR1, TGFB2, and SMAD3.4,13,14 Mutations in these genes can be identified in the majority of HTAD families with systemic features of MFS or Loeys-Dietz syndrome (LDS), but only approximately 30% of HTAD families without these syndromic features have mutations in these genes, indicating there are more genes yet to be discovered13 and a significant number of patients/families with HTAD have no identifiable pathogenic variant.24 The 2022 ACC/AHA Guidelines note that it should be recognized that there is no upper limit to the age at which patients present with TAD that precludes an underlying genetic cause of the disease.4
