Using Genetics for Personalized Management of Heritable Thoracic Aortic Disease: How Do We Get There?

Abstract

The major diseases affecting the thoracic aorta are aortic aneurysms and acute aortic dissections (TAAD). Medical treatments can slow the enlargement of aneurysms, but the mainstay of treatment to prevent premature deaths due to dissections is surgical repair of the TAA, typically recommended when the aortic diameter reaches 5.0 – 5.5 cm. Studies on patients with acute aortic dissections indicate that up to 60% occur at aortic diameters less than 5.5 cm. Clinical predictors are thus needed to identify those at risk for dissection at aortic diameter less than 5.0 cm, and to determine the aortic diameter that justifies the risk of surgical repair to prevent an acute aortic dissection. Data from genetic studies over the past decade have established that mutations in specific genes can identify patients at risk for the disease and predict the risk of early dissection at diameters less than 5.0 cm. This information has the potential to optimize the timing of aortic surgery to prevent acute dissections.

The major diseases affecting the thoracic aorta are aortic aneurysms and acute aortic dissections (TAAD). The natural history of ascending thoracic aortic aneurysms (TAA) is asymptomatic enlargement over time until occurrence of an ascending aortic dissection (Stanford type A). Less deadly dissections originate in the descending thoracic aorta distal to the left subclavian artery (Stanford type B). Although medical treatments can slow aneurysm enlargement, the mainstay of treatment to prevent premature deaths due to dissections is surgical repair of the TAA. This is typically recommended when aortic diameter reaches 5.0 – 5.5 cm (1). However, studies on patients with acute type A aortic dissections indicate that up to 60% occur at aortic diameters less than 5.5 cm (2). Clinical predictors are thus needed to identify those at risk for dissection at aortic diameter less than 5.0 cm, and to determine the aortic diameter that justifies the risk of surgical repair to prevent an acute dissection. Genetic studies over the past decade have established that mutations in specific genes can identify patients at risk for the disease and predict the risk of early dissection at diameters less than 5.0 cm. This information has the potential to optimize the timing of aortic surgery to prevent acute type A dissections.

It is established that patients with Marfan syndrome (MFS), an autosomal dominant syndrome with skeletal and ocular features, are highly predisposed to TAAD and typically present with aortic root aneurysms (3). MFS results from mutations in FBN1, which encodes fibrillin-1, a component of elastin-associated microfibrils. Loeys-Dietz syndrome (LDS) is a syndrome related to MFS that also predisposes patients to TAAD. LDS patients display arterial tortuosity, craniofacial abnormalities, and skeletal features of MFS, along with aneurysms and dissections of the aorta and other arteries and thin, translucent skin reminiscent of patients with vascular Ehlers Danlos syndrome (4). LDS results from mutations in the transforming growth factor-β receptor type I or II genes (TGFBR1 or TGFBR2). More recently, heterozygous mutations in SMAD3 and TGFB2 have been identified in families that share some clinical features with MFS and LDS (5–7).

Emerging clinical data on the phenotype associated with specific genes provide evidence that the underlying mutation could inform patient management, including the timing of surgical repair of TAAs and the risk for additional vascular disease. For example, MFS patients with FBN1 mutations have a low risk for acute aortic dissections at diameters less than 5.5 cm and for aneurysms of other arteries (8). Interestingly, common genetic variants in the FBN1 gene (termed single nucleotide polymorphisms or SNPs) increase the risk for TAAD in the general population (9), and ongoing studies are investigating whether these could inform which patients could be managed in a manner similar to MFS patients (10). In contrast, data suggest that aortic dissections occur in patients with TGFBR1 and TGFBR2 mutations at aortic diameters less than 5.0 cm and these patients have aneurysms and dissections of other arteries (4;11). These findings led to the recommendation in ACCF/AHA Treatment Guidelines for Thoracic Aortic Disease that the underlying genetic mutation dictate the timing of aortic repair. The current recommendation for LDS patients is repair of the aorta at 4.2 cm (1). However, many European countries treat LDS and MFS similarly and perform repair when the aorta reaches 5.0 cm, surprisingly without observing premature dissections in either MFS or LDS patients (12). Additionally, studies suggest that the risk of aortic dissection with minimal enlargement may be less for TGFBR1 compared with TGFBR2 mutation carriers (11).

Up to 20% of nonsyndromic TAAD patients have first degree relatives with TAAD, indicating a significant genetic contribution to the disease. Analysis of these familial TAAD (FTAAD) pedigrees showed that TAAD is primarily inherited as a single gene, autosomal dominant condition with reduced penetrance (13;14). These families demonstrate variable expression of TAAD, with variation in the age of disease onset, risk of ascending aortic dissections at diameters below 5.0 cm, prevalence of type B dissections, and involvement of the aortic root, the ascending aorta, or both (fusiform aneurysms involving the root and ascending aorta). Additionally, FTAAD families show variable co-segregation of other cardiovascular complications with TAAD. These can include bicuspid aortic valve, patent ductus arteriosus, abdominal aortic aneurysms, and other vascular diseases (e.g., intracranial aneurysms, other arterial aneurysms, and occlusive arterial disease) (13;15–18). Nine genes that predispose to autosomal dominant TAAD have been identified to date (6;7;11;15;17;19–21). FBN1, TGFBR1, TGFBR2, SMAD3, and TGFB2 mutations have been identified in ~6–8% of FTAAD families with no features of MFS or LDS, suggesting a similar pathogenesis for aneurysm formation between syndromic disease and FTAAD (6;7;11;20;22). Mutations in ACTA2, MYH11, MYLK, and PRKG1 have also been identified in FTAAD without MFS or LDS features. These genes are all involved in vascular smooth muscle cell (SMC) contraction and are termed SMC contractile genes. SMCs are arranged circumferentially in multiple layers in arteries. For contractile function, SMCs express smooth muscle-specific isoforms of α-actin and myosin (encoded by ACTA2 and MYH11), which polymerize to form thin and thick filaments, respectively. MYLK and PRKG1 encode kinases that control SMC contraction and relaxation, respectively. Loss-of-function mutations have been identified in MYLK and gain-of-function mutations in PRKG1 (19;21). Of these, ACTA2 is the most commonly altered gene in FTAAD, responsible for disease in 14% of patients (17). The other contractile genes contribute to 4% of FTAAD. In addition to FTAAD, ACTA2 mutations predispose to occlusive vascular diseases in smaller arteries, including early onset coronary artery disease, stroke, moyamoya-like cerebrovascular disease, and primary pulmonary hypertension (18;23;24).

We examined aortic disease, management, and outcome associated with the first aortic event (defined as dissection or TAA repair) in a cohort of patients with ACTA2 mutations (manuscript submitted). Aortic disease presentation associated with ACTA2 mutations differed from MFS. Patients with ACTA2 mutations had fusiform aneurysms involving the aortic root and ascending aorta and were more likely to present with acute dissections than MFS patients. For individuals undergoing surgical repair of fusiform TAAs without evidence of dissection, the maximum diameter was either in the aortic root or in the ascending aorta and ranged from 4.2–6.5 cm (median 5.2, IQR 5–5.5). In contrast, the maximum diameter ranged from 3.8– 9.5 cm (median 5.75, IQR 4.7–6.75) at presentation with an acute type A dissection. Thus, cardiovascular surgeons followed guidelines established for MFS patients, but one-third of the individuals with ACTA2 mutations dissected at aortic diameters less than 5 cm. These data suggest that surgical repair of TAAs in individuals with ACTA2 mutations should be considered when the aorta reaches a diameter of 4.5 cm.

The question remains as to whether aortic diameter at the time of dissection can be used to guide decisions about when to repair the aorta in individuals with genetically triggered thoracic aortic disease. A recent study sought to determine if thoracic aortic diameter or geometry was altered with acute type A aortic dissection by comparing CT images obtained within two years of a dissection with CT images obtained at presentation with dissection from patients who did not have MFS or a bicuspid aortic valve (25). The majority of the patients in the study had a type B dissection and experienced a retrograde dissection of the ascending aorta. The ascending aorta was found to significantly increase in diameter and volume after dissection, suggesting that diameters noted at presentation do not accurately reflect the size of the aorta at the time of dissection. Importantly, the aortic root diameter was not significantly altered after an acute aortic dissection.

Therefore, guidelines for surgical repair of the aorta that are based on aortic diameter at dissection cannot use the size of the dissected ascending aorta as a reliable gauge. However, the size of the aortic root may be used as a reliable gauge since it is not distorted by dissections. Since the majority of genetically triggered aneurysms involve the aortic root, which is typically monitored to determine timing of surgical repair, the size of the aortic root specifically should be collected to assemble the most reliable data for setting surgical guidelines for aortic repair in patients with specific gene mutations.

In summary, many patients with genetically triggered thoracic aortic disease exhibit an increased risk for aortic dissection with little to no enlargement of the aorta. The ideal way to determine the risk associated with each gene would be to obtain CT images proximately before dissection to determine the diameter of the aorta prior to the dissection. Since these images are rarely available, data should be obtained on post dissection images and measurements that include the aortic root and ascending aorta. As these patients typically demonstrate aortic root enlargement, and studies show that aortic root diameter is not significantly distorted after dissection, aortic root measurements may be used to guide decisions about surgical intervention based on aortic diameter. Ideally, better biomarkers than aortic diameter would be available to assess risk for acute aortic dissection, but until these are developed it is critical to ensure that the most accurate data is gathered to inform guidelines for surgical management of genetically triggered aortic disease.