Screening for the vulnerable aorta: targeting high-risk groups in the population

Thoracic aortic aneurysms are often asymptomatic until patients present with a life-threatening acute aortic syndrome. The vulnerability of an aorta to an acute aortic syndrome is determined by cross-sectional diameter and underlying aetiological factors, such as genotype or acquired disease. Screening the general population for thoracic aneurysms presents multiple resource issues including the availability of imaging modalities. Targeted screening of high-risk groups provides the only currently pragmatic solution. Opportunistic imaging through lung cancer screening programmes could pick up a proportion. Until we have a comprehensive screening programme it is incumbent on all healthcare professionals to have a low threshold for considering acute aortic pathologies when reviewing patients presenting with chest pain.

Introduction

The diseases of the aorta are an important cause of worldwide cardiovascular mortality and morbidity.¹ Hospital admissions within the UK at the end of 2010 were identified as 8.8 for thoracic aortic dissections and 9.0 for thoracic aortic aneurysms, per 100,000 inhabitants.² More recently, significant regional variation has been documented in access to treatment and mortality outcomes in the UK.³ These authors speculated that one of the barriers to treatment underlying this unwarranted variation was a lack of clear guidelines on population screening for this disease. Aneurysms of the thoracic aorta commonly have a genetic basis or are acquired as a chronic degenerative process (sporadic). A smaller group of patients have aortic aneurysms, the long-term sequelae of an acute aortic syndrome. Less frequently, aneurysms are the result of processes, such as post-traumatic disruption, infection, inflammation or developmental anomalies. The clinical challenge remains identification, as thoracic aortic aneurysms are most frequently asymptomatic, sitting within the cavernous chest, only revealing themselves when associated with concurrent disease, an incidental clinical finding or an acute aortic syndrome. It is largely the size of the aneurysm, as well as the aetiology, that determines a patient’s vulnerability to a life-threatening acute aortic syndrome, such as aortic dissection. Screening for the ‘vulnerable aorta’ in the population is key to surveillance and timely intervention to avoid an aortic catastrophe. Given computed tomography (CT) or magnetic resonance imaging (MRI) are the only current modalities to detect thoracic aortic aneurysms, screening the entire population is precluded by challenges in capacity, cost and patient safety. Targeting screening to high-risk groups is the only pragmatic way to identify patients with a vulnerable aorta.

Defining the vulnerable aorta

The single most important feature that defines the vulnerability of an aorta to an acute aortic syndrome is cross-sectional diameter.⁴ Size forms the basis of international guidelines as the indication for prophylactic intervention.⁵ However, increasingly, non-size dependent factors are used to define the vulnerable aorta, with disease aetiology influencing cross-dimensional indications for surgery (table 1).

There is increasing recognition that many thoracic aortic aneurysms have a genetic basis (~30%), both syndromic and non-syndromic. The pathogenicity and penetrance of variants are important factors determining vulnerability. Syndromic disease is relatively well-defined with clear indications of when to intervene surgically, but with some variation in expression. Non-syndromic, familial and non-familial disease are less well-defined, but the high penetrance of many variants seen in specific genes (ACTA2, MYH11, MYLK, SMAD3, COL3A1) is increasingly well understood. Variants of unknown significance (VUS) represent an ongoing challenge to interpret and apply to clinical management. A large proportion of aneurysms are acquired, so-called sporadic (~70%), through multi-morbidity (e.g. hypertension), socio-behavioural factors (e.g. smoking and diet) and senescence, as well as long-term sequelae to acute aortic syndromes. Sporadic aneurysms have relatively predictable risk profiles, largely dependent on size. An even smaller group of patients at risk are those that have congenital variants in anatomy that predispose them to acute aortic syndromes. The hierarchy of importance of each of these processes to determining the vulnerability of the aorta, is yet to be understood. The summative effects of multiple univariate risk factors are, additionally, poorly understood. They do, however, point us towards choosing which high-risk groups to target for screening, and additionally, screening methodologies.

What do the guidelines suggest?

There are no recommendations for population-level screening, however, guidelines do exist for aortic imaging and genetic testing of certain individuals, families and high-risk groups. The American Heart Association (AHA) guidelines,⁵ under ‘recommendations for familial thoracic aortic aneurysms and dissections’, recommend image screening for all first-degree relatives of patients with thoracic aneurysm and/or dissection (Class I recommendation, level of evidence B) (table 2). There are then additional weaker recommendations for imaging and genetic analysis for particular groups, but with less evidence base. The AHA guidelines have, however, been superseded by new technologies, and even national health service guidelines. Several groups have published their own preferences for screening of a given proband and relatives based around genetic testing and imaging.⁶ These recommendations pose significant challenges for healthcare systems and resources as thoracic imaging becomes more prevalent and incidental aortic aneurysms are identified. The imaging follow-up burden of this cohort in surveillance programmes, is, and will be, immense. Within the UK, current NHS guidelines recommend proband diagnostic genetic testing at the relatively low threshold of 3.8 cm, further increasing the number of patients requiring imaging and investigations. The NHS National Genomic Test Directory⁷ for diagnostic genetic testing of a proband includes:

1. Thoracic aortic aneurysm (3.8 cm) or dissection with onset before age 50 years.
2. Thoracic aortic aneurysm or dissection with onset before age 60 years with a first-degree relative with thoracic aortic aneurysm or dissection.
3. Thoracic aortic aneurysm or dissection before age 60 years with no classical cardiovascular risk factors.
4. Thoracic aortic aneurysm or dissection before age 60 years with features suggestive of aortopathy, e.g. arterial tortuosity.
5. Clinical features suggestive of Loeys-Dietz syndrome.
6. Features of Marfan syndrome giving a systemic Ghent score of ≥7, following assessment by a clinical geneticist or specialist with expertise in aortopathy.
7. High clinical suspicion of a condition predisposing to aortic/arterial disease and diagnostic testing for other conditions such as Ehlers-Danlos syndrome (where indicated) has not identified a causative mutation.
8. Any deceased individual with a thoracic aortic aneurysm (3.8 cm) or dissection detected at autopsy meeting one of the above criteria and who have relatives who will benefit from cascade testing using a genetic diagnosis will be suitable for post-mortem genetic testing.

In Liverpool there is a specialist aortic nurse-led clinic for review of isolated proximal small aneurysms (<5.0 cm) in which patients are entered into a surveillance programme after a consultation and, additionally, undergo diagnostic genetic testing as indicated (above 3.8 cm). All patients with a clear pathogenic variant are referred on to genetics counsellors to initiate familial predictive genetic testing, while those with VUS are discussed with, or clinically assessed by, a clinical geneticist.

What additional features identify the vulnerable aorta?

Elefteriades et al.⁸ in 2015 published a novel paradigm for detection of silent aortic disease with a ‘guilt by association’ approach. These features include:

• Intracranial aneurysm
• Aortic arch anomalies
• Abdominal aortic aneurysms
• Simple renal cysts
• Bicuspid aortic valves
• Temporal arteritis (and other autoimmune conditions)
• Positive family history of aneurysm disease
• Positive thumb-palm sign.

We believe composite risk associated with age, hypertension and socio-behavioral factors, such as smoking, diet and exercise, will prove important groups. Currently, there is a lack of data around the efficacy of such approaches to population screening.

Piggy backing on lung cancer screening programmes

Internationally, there are many lung cancer screening trials, which are based on a low-dose, non-contrast CT scan in certain high-risk groups. For the Liverpool Lung Health Check Programme, the criteria are any smoker between the ages of 55 and 74 years. The degree of co-prevalence of lung cancer and abdominal aortic aneurysms has been explored, but the relationship between individuals undergoing lung cancer screening by CT and incidental findings of thoracic aortic aneurysms remains largely undefined, but potentially important and an opportunity.

Other modalities for screening the population

A promising opportunity in genetics is offered by mRNA signatures in blood, which may be used as biomarkers and screening tools. Recently, a preliminary study from the Yale group showed that mRNA has a sensitivity (72%) and specificity (90%) with a thoracic aortic aneurysm compared with control.⁹ This approach awaits validation. In addition, there is the potential for whole genome sequencing for aneurysms in the future.

Future perspective on screening

The UK Abdominal Aortic Aneurysm (AAA) screening programme is well established and offered to men aged 65 years using targeted ultrasound. Any thoracic aortic aneurysm screening programme faces the challenge of requiring CT scans, being less prevalent, and a requirement for additional genetic testing (proband and relatives) given the incidence of a gene-based aetiology. While a number of groups have published their local policies and procedures for targeted imaging and genetic screening of individuals and families,^6,10 national healthcare providers in the UK are yet to recommend comprehensive, funded pathways. Drafting behind a national lung cancer screening programme may well be an opportunity to pick up the majority of asymptomatic thoracic aortic aneurysms, although this has yet to be understood as limited to smokers. In addition, this approach will miss many younger syndromic patients.

Equity in access

Differences in the prevalence of thoracic aortic aneurysm in different population groups (age, gender, ethnicity, socioeconomics and other demographics) suggest it is important to be mindful in ensuring inclusivity to diagnosis and treatment.

Conclusion

Thoracic aortic aneurysms are often asymptomatic until patients present with a life-threatening acute aortic syndrome. The vulnerability of an aorta to an acute aortic syndrome is determined by cross-section diameter and underlying aetiological factors, such as genotype acquired disease. Screening the population for thoracic aneurysms through imaging and genetics presents challenges in the requirement for CT scanning, and the pathogenic uncertainty of many genetic variants. Targeted screening of high-risk groups provides the only currently pragmatic solution. Opportunistic imaging through lung cancer screening programmes will pick up a proportion, however, at the present time international guidelines are restricted to investigating probands, no matter how they are incidentally picked up, and their relatives. Until we have a comprehensive screening programme it is incumbent on all healthcare professionals to have a low threshold for considering acute aortic pathologies when reviewing patients presenting with chest pain. Early diagnosis is key to a successful outcome.

Key messages

• Thoracic aortic aneurysms are often asymptomatic until patients present with life-threatening acute aortic syndromes
• Generalised screening of populations for thoracic aortic aneurysm is currently not feasible due to limitations on availability of imaging services
• The only pragmatic solution to screening the population for this disease is a focus on high-risk groups
• High-risk patients with a vulnerable aorta are identifiable based on genomics and risk factors for acquired disease

Conflicts of interest

None declared.

Funding

None.

Editors’ note

This is the fourth article in our aortic dissection series. See Fowler editorial introducing the series (https://doi.org/10.5837/bjc.2023.008), Booth article on epidemiology, pathophysiology and natural history (https://doi.org/10.5837/bjc.2023.009) and Mariscalco article on diagnosis and acute management (https://doi.org/10.5837/bjc.2023.012).

References

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7. NHS England. National genomic test directory: testing criteria for rare and inherited disease. London: NHS England, 2021. Available from: https://www.england.nhs.uk/wp-content/uploads/2018/08/rare-and-inherited-disease-eligibility-criteria-v2.pdf

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