Scott Damrauer, MD, and colleagues have made groundbreaking discoveries in the genetics of thoracic aortic aneurysm and dissection (TAAD).
Scott Damrauer, MD
Surgeon-scientist Scott Damrauer, MD, and team are revealing genetic factors in the general population that put people at risk for potentially fatal aortic conditions. Their research focuses on thoracic aortic aneurysm and dissection (TAAD), a condition that can be life-threatening if left undetected.
Mechanics and Background of TAAD
This article concerns the thoracic aorta, which originates at the heart's left ventricle and ascends from the aortic root to the aortic arch. Immediately above the aortic root, the aorta feeds the left and right coronary arteries. The branches of the brachiocephalic trunk, the left common carotid artery, and the left subclavian artery originate at the aortic arch, which then joins the descending artery behind the heart.
The walls of the aorta comprise three musculoelastic layers: the intima, or inner layer, the media, and the outer adventitia. These layers expand and contract with each heartbeat and may, with time and the burdens of hypertension, atherosclerosis, or disease, stiffen or dilate. Dilation of the aorta is associated with aneurysm of the thoracic ascending aorta and its effects, dissection and rupture.
Generally, a thoracic aortic aneurysm is defined as the dilation of the aorta beyond a diameter of 4.5 cm. For individuals who lack genetic risk factors, surgical repair is often recommended at 5.0-5.5 cm However, these guidelines are not perfect. Researchers have shown in acute dissection of the ascending aorta (type A aortic dissection, a life-threatening event) that as many as 60% of dissections occur at diameters <5.5 cm.
The issue of diameter in TAAD is complicated by the absence of imaging screening guidelines for the general population. Even were such guidelines available, however, the existing limited guidelines for abdominal aortic aneurysms (AAA) suggest challenges for general TAAD screening. Dr. Grace Wang of Penn Vascular Surgery notes in a recent JAMA editorial that the current screening guidelines for AAA are plagued by low adherence, with only an estimated 15% of eligible patients receiving appropriate screening. This means, Dr. Wang notes, that 25-40% of patients will have their abdominal aneurysms diagnosed incidentally, and a substantial proportion will remain undetected.
Of those who develop TAAD, roughly 20% will have a syndromic cause. For the remaining 80% of individuals affected by TAAD, the cause is unknown, though risk factors are relatively well-defined. These include male gender, uncontrolled hypertension, smoking, atherosclerosis, and hypercholesterolemia.
Aneurysms, dissection, and rupture
Thoracic aneurysms are thought to occur in ~ 5 persons per 100,000 individuals/year, but considering the random nature of discovery, the incidence may be much higher. Although thoracic aneurysms can rupture, the greater risk is that of aortic dissection, which manifests as a tear in the intima of the aorta lumen thats permits blood to enter between and separate the layers of the vessel wall. Together, rupture and dissection are a cause of death for approximately 30,000 people per year in the United States. The out-of-hospital death rate for rupture can exceed 50%. Dissection kills about half of patients within 30 days, whether or not they reach a hospital.
Unanswered questions
Recent evidence suggests that TAAs diagnosed and managed surgically before dissection can confer survival rates nearly matching population controls. However, as previously noted, early identification of TAAD is complicated (outside of the syndromic population) by a dearth of diagnostic screening standards and the absence of useful prognostic or predictive tools. Finding ways to predict who among the non-syndromic population is at risk for TAAD is thus of acute interest to researchers, particularly those seeking a genetic identity for TAAD.
Hereditary TAAD
TAAD genetics have traditionally focused on hereditary contributors to the disease that follow autosomal dominant inheritance patterns, many times within the spectrum of the heritable connective tissue syndromes (e.g. the Marfan, Loeys-Dietz, and Ehlers-Danlos syndromes). At the same time, there are other nonsyndromic forms of hereditary TAAD that affect only the aorta. Overall, the genes responsible for these hereditary forms of disease tend to play a role in the structural integrity of cardiovascular connective tissues, thus predisposing affected individuals to TAAD. Given the recognized heritability of syndromic TAAD and the understanding that rare variants have large effects in causing familial disease, clinician-researcher Scott Damrauer, MD, and colleagues at Penn Medicine have proposed a role for genetic mechanisms in non-hereditary forms of TAAD.
MVP GWAS TAAD study
Dr. Damrauer and Michael Levin, MD, recently lead a multicenter genome-wide association study (GWAS) initiated in the Veterans Affairs Million Veteran Program (MVP). A national research program, the MVP examines the ways in which genes, lifestyle, military experiences, and exposures affect the health and wellness of Veterans.
The MVP GWAS tested approximately 25 million DNA sequence variants derived from large cohorts with and without TAAD from the MVP matched with similarly defined independent cohorts. At its conclusion, the GWAS identified 21 TAAD risk loci (17 of which had not been previously reported), suggesting that common DNA variants increase the risk of TAAD in the non-syndromic population and offer new potential targets for therapeutic intervention.
Among other study findings:
- Human genetic evidence that TAAD is not solely inherited through protein-altering variants of large effect size but that the combination of small effects across many genes may also increase an individuals risk TAAD;
- Confirmation of a number of previously suspected causal epidemiological risk factors for TAAD, including smoking, elevated blood pressure, and taller standing height;
- Identification of causal tissues and cell types for TAAD;
- Construction of a genome-wide polygenic risk score (PRS) for TAAD that identifies a subset of the population at substantially greater risk for the condition.
Recent advances in the identification of thoracic aortic dilation risk
Beyond genetics, much progress has been made in clarifying the contributory factors for thoracic aorta dilation risk. The Aorta Optimized Regression for Thoracic Aneurysm (AORTA) Score, for example, is a recently reported model to predict the likelihood of an ascending aortic aneurysm in asymptomatic individuals using records from available electronic demographic and clinical sources. These included age, BMI, blood pressure indices, and the presence or absence of diabetes, hypertension, and hyperlipidemia. The model was validated against imaging modalities, including MRI, CT scans, and transthoracic echocardiography from three large data sources: the UK Biobank, the Framingham Heart Study, and Mass General Brigham.
A chief motivation for producing the AORTA score was to permit the identification of individuals likely to have non-syndromic ascending aortic enlargement. As such, the AORTA score did well, explaining 28.2%, 30.8%, and 32.6% of the variance in ascending aortic diameter in the 3 cohorts studied. In so doing, the model provided substantial proof that incorporating clinical risk factors and genetic information can help identify individuals who are likely to have a dilated ascending aorta on imaging.
Dr. Wang, of Penn Vascular Surgery, noted in her JAMA editorial that the AORTA score was timely and will likely serve as an example for future screening efforts. She observed, as well, that the need to better identify individuals who can undergo elective repair is of utmost importance, as is the challenge of screening for aortic aneurysms in certain subgroups.
Improving aortic diameter prediction in a diverse cohort
Complementing the efforts of the AORTA study, Dr. Damrauer and colleagues at Penn Medicine conducted a study to ascertain whether adding polygenic scores (PGS) to clinical prediction algorithms improves aortic diameter prediction when applied to a diverse cohort from the Penn Medicine Biobank.
Cohort participants had a median age of 61 years and a mean ascending aortic diameter of 3.4 cm. The study employed statistical models to integrate PGS weights derived from a genome-wide association study of thoracic aortic diameter performed in the UK Biobank. These were compared with the performance of the previously published AORTA score. Importantly, a third of the cohort was genetically similar to an African reference population.
When stratified by population, the UK Biobank-derived PGS consistently improved upon the clinical AORTA score among individuals genetically similar to a European reference population but conferred minimal improvement among individuals genetically similar to the African reference population. Comparable performance disparities were observed in models developed to discriminate cases/non-cases of thoracic aortic dilation (≥4.0 cm).
Conclusions - This study demonstrated that the inclusion of a PGS in the AORTA Score results in a small but clinically meaningful performance enhancement. As genetic data becomes increasingly available due to the rapid speed and availability of whole genome sequencing, integration of a model accounting for both local health characteristics and genetic data may become more universally applicable with the potential to more accurately identify individuals who warrant screening. Moreover, with the expansion of GWAS sizes and improvements in understanding the genetic underpinnings of ascending aortic diameter and aneurysmal degeneration, the AORTA Score enhancement attributable to PGS inclusion will likely continue to grow.