„Often referred to as the ’silent killer,‘ ascending thoracic aortic aneurysms (ATAAs) can grow asymptomatically until they rupture, at which point mortality is over 90%. However, ATAA’s may also have a potential upside: obvious protection against the development of atherosclerotic plaque and thus a significantly reduced risk of coronary heart disease and myocardial infarction (MI) for those who have them.
„We noticed in the operating room that many patients we worked on, who had an ATAA, had flawless arteries, like those of a teenager,“ said John Elefteriades, William WL Glenn Professor of Heart-Thorax Surgery and former chief of Heart-Thorax Surgery at Yale University and Yale New Haven Hospital, New Haven, Connecticut, as reported by theheart.org | Medscape Cardiology. „The same held true for the femoral artery, through which we connect the heart-lung machine.“
„From more than two decades, Elefteriades and colleagues have been studying the effects of this connection. Many of their studies are highlighted in a current review of evidence that demonstrates the protective relationship between ATAA’s and the development of atherosclerosis, as well as the potential driving mechanisms of this relationship.
„We see four different protective layers,“ said Sandip Mukherjee, MD, medical director of the Aortic Institute at Yale New Haven Hospital and chief editor of the Journal AORTA, as reported by theheart.org | Medscape Cardiology. Mukherjee collaborated on many studies with Elefteriades.
The first protective layer exhibits a lower intima-media thickness, specifically 0.131 mm lower than those without ATAA’s. „It may not seem like much, but a point can actually lead to a 13% to 15% decrease in the rate of heart attack or stroke,“ said Mukherjee.
The second layer consists of lower levels of Low-Density Lipoprotein (LDL). Lower LDL levels (75 mg/dl) were associated with an increased likelihood of ATAAs (Odds Ratio) 1.21, while elevated levels (150 mg/dl and 200 mg/dl) were associated with a decreased likelihood of ATAAs (OR: 0.62 and 0.29, respectively).
Lower calcification levels in the coronary arteries make up the third protective layer (6.73 vs. 9.36 in one study).
The fourth protective layer represents a significantly decreased prevalence of coronary heart diseases. A study comparing individuals with ATAAs to control individuals found that 61 of those with ATAAs had coronary heart disease, compared to 140 of the control individuals, and 11 versus 83 had experienced a heart attack. Remarkably, patients with ATAAs were protected, even though they had higher body mass indexes than the control individuals.
Other MI risk factors such as age increased the risk even in patients with ATAA’s, however, markedly less than in the control individuals; a multivariable binary logistic regression of the data in the team’s study showed that in patients with ATAA’s, the likelihood of experiencing a myocardial infarction was 298-, 250-, or 232-fold lower than if they had a family history of myocardial infarction, dyslipidemia, or hypertension.
Why the protection?
The ligamentum arteriosum separates the ascending from the descending (thoracoabdominal) aorta. ATAAs that reside above the ligamentum tend to act as proaneurysmal but antiatherosclerotic. In the descending aorta, below the ligamentum, atherosclerotic aneurysms develop.
The differences between the two sections of the aorta originate from the embryo’s germ layer, Elefteriades said. „The fundamental difference in the origin tissue leads to distinct differences in the character of aneurysms in the different aortic segments.“
What exactly underlies the reduced cardiovascular risk? „We don’t really know, but we believe there could be two possible causes,“ Mukherjee said. One hypothesis concerns the Transforming Growth Factor Beta (TGF-beta), which is overexpressed in patients with ATAA’s and seems to increase their susceptibility to aneurysms while also providing protection against the risk of coronary disease.
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 had a heart attack have polymorphisms that lower their TGF-beta levels.
Furthermore, TGF-beta plays a key role in the development of the intima layer, which could explain the lack of intima thickening in patients with ATAA’s.
However, overall, Elefteriades and Mukherjee agreed that the studies are mixed and difficult to interpret. TGF-beta has several remodeling functions in the body, and it is currently difficult to isolate its exact role in aortic diseases.
Another hypothesis concerns Matrix Metalloproteinases (MMPs), which are dysregulated in patients with ATAA’s and could provide some protection, Mukherjee said. Several studies have shown higher plasma levels of certain MMPs in patients with ATAA’s. It has also been found that MMPs were increased in the thoracic aortic walls of patients with ATAA, who had an aortic dissection, as well as in the smooth muscle cells of the aorta in the intima and media.
Moreover, some studies have shown higher levels of MMP-2 in the aorta of patients with ATAA’s compared to patients with coronary heart disease.
„We recently found a gene that is dysregulated in our aneurysm patients and is closely related to atherosclerosis,“ Elefteriades said. „But the work is too preliminary to say more at this point.“
„It would be fantastic to prove what this protection does,“ Mukherjee added. „But the truth is, we don’t know. These are hypotheses.“
„The most important message of our work is that most clinicians need to distance an ATAA from the concept of atherosclerosis,“ Elefteriades said. „The ascending aorta is not an atherosclerotic phenomenon.“
How to treat patients with ATAA
What does the special nature of ATAAs mean for patient management? „Finding a drug to treat ATAAs – to prevent growth, rupture, or dissection – has been like looking for the Holy Grail,“ Elefteriades said. „Statins are not necessary, as this is a non-atherosclerotic process. Although sporadic studies have reported positive effects of beta-blockers or angiotensin II receptor blockers (ARBs), this often relied on ’soft‘ evidence requiring a combination of these factors outcome measures to achieve significance.“
However, he noted, „The most important treatment method using common sense is to keep blood pressure under control. This is usually achieved through a beta-blocker and an ARB, even though the benefit is not in a direct biological effect on the degenerative process of the aneurysm, but through simple hemodynamics – by keeping the pressure in the aorta low to prevent a rupture.“
Mukherjee suggested referring these patients to a specialized aneurysm center, where their genes would be evaluated, and then the aneurysm would be carefully monitored.
„If the aneurysm is larger than 4.5 cm, we monitor the patient every year, and if they have chest pain, we treat them the same way as other aneurysms,“ he said. „As a rule of thumb, when the aneurysm reaches a size of 5 cm, it should come out, with the size at which it should happen varying between 4.5 cm and 5.5 cm, depending on the patient’s body size.“
As for lifestyle management, Elefteriades said, „The protection against atherosclerosis and myocardial infarction does not disappear after the aneurysm is removed. We believe it lies in the body’s chemistry. But even though it is very difficult for these patients to suffer a heart attack, we don’t recommend them to eat roast beef every night – although I think they would be protected from such lifestyle disparities.“
He added, „Our team is looking for a drug that can directly and effectively treat ascending diseases. We are currently conducting laboratory experiments with two drugs that are in development, and we hope to start clinical trials soon.“
James Hamilton Black III, MD, deputy chair of the writing committee for the Aortic Disease Guideline of the American College of Cardiology/American Heart Association 2022 and head of the Division of Vascular Surgery and endovascular Therapy at Johns Hopkins Medicine, Baltimore, commented on the review and the concept of the atherosclerotic protection of ATAA for theheart.org | Medscape Cardiology.
„The association of ascending aortic aneurysms with a lower MI risk is interesting, but is likely at least partially influenced by the patient population. This population is at least partially curated, as people come to an academic center. Additionally, Black noted, „The patients with ATAAs are younger, so age could be a confounding factor in the analyses. We wouldn’t expect them to have the same burden of atherosclerosis as older patients.“
However, he said, „The results speak to a new literature that indicates that while the aorta is a single organ, it certainly has different areas that would react quite differently to environmental, genetic, or hereditary stressors. That’s not surprising, and there are probably many factors at play.“
Overall, he said, the results „underscore the precise medical approaches we must take with patients with aortic diseases.“
In a commentary on the team’s review article, published in 2022, John GT Augoustides, MD, professor of Anesthesiology and Critical Care Medicine at the Perelman School of Medicine in Philadelphia, Pennsylvania, suggested that the „silver lining“ of ATAA is the understanding of the thoracic aorta…