Often known as a "silent killer," ascending thoracic aortic aneurysms (ATAAs) may grow asymptomatically until they rupture, at which point, mortality is over 90%.
But ATAAs may also carry a potential flip side: Apparent protection against the development of atherosclerotic plaque and by extension, for those who have one, a significantly reduced risk for coronary artery disease and myocardial infarction (MI).
"We noticed in the operating room that many patients we worked on who had an ATAA had pristine arteries, like a teenager's," John Elefteriades, MD, William W.L. Glenn Professor of Cardiothoracic Surgery and former chief of cardiothoracic surgery at Yale University and Yale New Haven Hospital, New Haven, Connecticut, told theheart.org | Medscape Cardiology. "The same was true of the femoral artery, which we use to hook up to the heart-lung machine."
Elefteriades and colleagues have been investigating the implications of this association for more than two decades. Many of their studies are highlighted in a recent review of the evidence supporting the protective relationship between ATAAs and the development of atherosclerosis and the possible mechanisms driving the relationship.
"We see four different layers of protection," Sandip Mukherjee, MD, medical director of the Aortic Institute at Yale New Haven Hospital and a senior editor of the journal AORTA, told theheart.org | Medscape Cardiology. Mukherjee collaborated with Elefteriades on many of the studies.
The first layer of protection is lower intima-media thickness, specifically, 0.131 mm lower than in individuals without an ATAA. "It may not seem like very much, but one point can actually translate into a 13%-15% decline in the rate of myocardial infarction or stroke," Mukherjee said.
The second layer is lower levels of low-density lipoprotein (LDL) cholesterol. Lower LDL cholesterol levels (75 mg/dL) were associated with increased odds of ATAAs (odds ratio [OR], 1.21), whereas elevated levels (150 mg/dL and 200 mg/dL) were associated with decreased odds of ATAAs (OR, 0.62 and 0.29, respectively).
Lower calcification scores for the coronary arteries are the third layer of protection (6.73 vs 9.36 in one study).
The fourth protective layer is a significantly reduced prevalence of coronary artery disease. A study of individuals with ATAA compared to controls found 61 of those with ATAA had coronary artery disease vs 140 of controls, and 11 vs 83 had experienced an MI. Of note, patients with ATAAs were protected despite having higher body mass indices than controls.
Other MI risk factors such as age increased the risk even among those with an ATAA but, again, much less so than among controls; a multivariable binary logistic regression of data in the team's review showed that patients with ATAAs were 298, 250, and 232 times less likely to have an MI than if they had a family history of MI, dyslipidemia, or hypertension, respectively.
Why the Protection?
The ligamentum arteriosum separates the ascending from the descending (thoracoabdominal) aorta. ATAAs, located above the ligamentum, tend to be pro-aneurysmal but anti-atherosclerotic. In the descending aorta, below the ligamentum, atherosclerotic aneurysms develop.
The differences between the two sections of the aorta originate in the germ layer in the embryo, Elefteriades said. "The fundamental difference in tissue of origin translates into marked differences in the character of aneurysms in the different aortic segments."
What specifically underlies the reduced cardiovascular risk? "We don't really know, but we think that there may be two possible etiologies," Mukherjee said. One hypothesis involves transforming growth factor–beta (TGF-beta), which is overexpressed in patients with ATAA and seems to increase their vulnerability to aneurysms while also conferring protection from coronary disease risk.
Some studies have shown differences in cellular responses to TGF-beta between the thoracic and abdominal aorta, including collagen production and contractility. Others have shown that some patients who have had an MI have polymorphisms that decrease their levels of TGF-beta.
Furthermore, TGF-beta plays a key role in the development of the intimal layer, which could underpin the lack of intimal thickening in patients with ATAA.
But overall, studies have been mixed and challenging to interpret, Elefteriades and Mukherjee agreed. TGF-beta has multiple remodeling roles in the body, and it is difficult at this point to isolate its exact role in aortic disease.
Another hypothesis involves matrix metalloproteinases (MMPs), which are dysregulated in patients with ATAA and may confer some protection, Mukherjee said. Several studies have shown higher plasma levels of certain MMPs in patients with ATAAs. MMPs also were found to be elevated in the thoracic aortic walls of patients with ATAA who had an aortic dissection, as well as in the aortic smooth muscle cells in the intima and media.
In addition, some studies have shown increased levels of MMP-2 in the aortas of patients with ATAAs compared with patients with coronary artery disease.
Adding to the mix of possibilities, "We recently found a gene that's dysregulated in our aneurysm patients that is very intimately related to atherosclerosis," Elefteriades said. "But the work is too preliminary to say anything more at this point."
"It would be fabulous to prove what it is causing this protection," Mukherjee added. "But the truth is we don't know. These are hypotheses."
"The most important message from our work is that most clinicians need to dissociate an ATAA from the concept of atherosclerosis." Elefteriades said. "The ascending aorta is not an atherosclerotic phenomenon."
How to Manage Patients With ATAA
What does the distinct character of ATAAs mean for patient management? "Finding a drug to treat ATAAs — to prevent growth, rupture, or dissection — has been like a search for the Holy Grail," Elefteriades said. "Statins are not necessary, as this is a non-atherosclerotic process. Although sporadic studies have reported beneficial effects from beta-blockers or angiotensin II receptor blockers (ARBs), this has often been based on 'soft' evidence, requiring a combination of outcome measures to achieve significance."
That said, he noted, "The mainstay, common sense treatment is to keep blood pressure controlled. This is usually achieved by a beta-blocker and an ARB, even if the benefit is not via a direct biologic effect on the aneurysmal degenerative process, but via simple hemodynamics — discouraging rupture by keeping pressure in the aorta low."
Mukherjee suggested that these patients should be referred to a specialty aneurysm center where their genes will be evaluated, and then the aneurysm will be followed very closely.
"If the aneurysm is larger than 4.5 cm, we screen the patient every single year, and if they have chest pain, we treat them the same way as we treat other aneurysms," he said. "As a rule of thumb, if the aneurysm reaches 5 cm, it should come out, although the size at which this should happen may differ between 4.5 cm and 5.5 cm, depending on the patient's body size."
As for lifestyle management, Elefteriades said, "Protection from atherosclerosis and MI won't go away after the aneurysm is removed. We think it's in the body's chemistry. But even though it's very hard for those patients to have a heart attack, we don't recommend they eat roast beef every night — although I do think they'd be protected from such lifestyle aberrations."
For now, he added, "Our team is on a hunt to find a drug to treat ascending disease directly and effectively. We have ongoing laboratory experiments with two drugs undergoing investigation at some level. We hope to embark soon on clinical trials."
'A Milestone'
James Hamilton Black III, MD, vice chair of the writing committee for the 2022 American College of Cardiology/American Heart Association Aortic Disease Guideline and chief of Division of Vascular Surgery and Endovascular Therapy at Johns Hopkins Medicine, Baltimore, commented on the review and the concept of ATAA's atherosclerotic protection for theheart.org | Medscape Cardiology.
"The association of ascending aortic aneurysms with a lower risk for MI is an interesting one, but it's probably influenced, at least in part, by the patient population." That population is at least partially curated since people are coming to an academic center. In addition, Black noted, "the patients with ATAAs are younger, and so age may be a confounding factor in the analyses. We wouldn't expect them to have the same burden of atherosclerosis" as older patients.
Nevertheless, he said, "the findings speak to an emerging body of literature suggesting that although the aorta is a single organ, there are certainly different areas, and these would respond quite differently to environmental or genetic or heritable stressors. This isn't surprising, and there probably are a lot of factors involved."
Overall, he said, the findings underscore "the precision medicine approaches we need to take with patients with aortic diseases."
In a commentary on the team's review article, published in 2022, John G.T. Augoustides, MD, professor of anesthesiology and critical care at the Perelman School of Medicine in Philadelphia, Pennsylvania, suggested that ATAA's "silver lining" could advance the understanding of thoracic aortic aneurysm (TAA) management, be integrated with the expanding horizons in hereditary thoracic aortic disease, and might be explored in the context of bicuspid aortic valve disease.
Highlighting the "relative absence" of atherosclerosis in ascending aortic aneurysms and its importance is a "milestone in our understanding," he concluded. "It is likely that future advances in TAAs will be significantly influenced by this observation."
Elefteriades, Mukherjee, and Black have no relevant conflicts of interest.
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