Thoracic aortic disease has long presented diagnostic and therapeutic challenges. Thoracic aortic aneurysms are typically difficult to diagnosis, because they usually have no associated symptoms or findings on physical examination. Moreover, once discovered, the optimal medical management of aneurysms remains uncertain, as do the thresholds for aortic repair. Fortunately, over the past several decades advanced imaging techniques have enhanced our ability to diagnosis thoracic aortic disease accurately and rapidly, and the techniques for aortic repair—be they open or endovascular—have become significantly safer and more effective. Yet our ability to predict just when such intervention is required remains limited.

There is much about the underlying pathophysiology of thoracic aortic aneurysms that we have yet to understand. The challenge of investigating the pathophysiology is made greater by the fact that thoracic aortic aneurysms have diverse etiologies, can involve various and even multiple aortic segments (i.e., the aortic root, the ascending thoracic aorta, the aortic arch, the descending thoracic aorta, or the thoracoabdominal aorta), and can present in a variety of ways (from a mildly dilated aorta to an acute aortic syndrome). Consequently, to optimally manage thoracic aortic aneurysms in general, we must better understand how different segments of the aorta behave in different disease states.

Historically, most decision-making about thoracic aortic aneurysms has been based upon what meets the eye. For example, studies have shown that in patients with an acute aortic dissection (AoD), those with an underlying bicuspid aortic valve (BAV) experience the sentinel AoD at significantly younger ages than their counterparts with tricuspid aortic valves. Consequently, experts postulated that BAV-associated aneurysms were likely virulent and akin to the aortic root aneurysms seen in Marfan syndrome (MFS), which prompted the authors of the 2010 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for the Diagnosis and Management of Patients With Thoracic Aortic Disease to lower the threshold for aortic repair in those with a BAV to 5.0 cm (down from the traditional 5.5 cm), with consideration of surgery even at diameters as low as 4.0 cm in certain clinical settings (1). However, a large community cohort study of 416 patients with a BAV subsequently revealed that in those with a BAV and a baseline aortic aneurysm, the annualized rate of AoD was a relatively low 0.4% (2). Another report examined the maximal aortic diameter at the time of acute AoD and found that the mean aortic diameter among those with an underlying BAV was actually significantly larger than among those with normal tricuspid aortic valves (66 ± 15 mm vs. 56 ± 11 mm, respectively; p = 0.0001) (3), which refuted the hypothesis that BAV-associated aneurysms are especially vulnerable, and therefore, at higher risk. In response to such evidence, the ACC/AHA Guideline Committee appropriately revised the recommended threshold for repair of BAV-related aneurysms, raising it back to 5.5 cm, the same as the threshold for those with a tricuspid aortic valve (4).

In this issue of the Journal, Weinsaft et al. (5) present outcome results from patients enrolled in the GenTAC (National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) registry, a multicenter prospective registry of patients with genetically mediated thoracic aortic aneurysms. Of the study's 1,991 patients, most had either a bicuspid aortic valve (39%) or MFS (22%). Although, by design, none of the patients had an AoD before enrollment, almost one-third of patients had undergone antecedent aortic root and ascending and/or arch aortic repair; presumably such operations had been done prophylactically in those with large aortas to reduce the risk of future AoD. Consequently, only the remaining two-thirds of GenTAC patients had a native proximal aorta that would be fully vulnerable to AoD, and thus, type A AoD rates would be expected to be at least proportionally lower in this cohort. This likely explains the fact that over the course of the study, there were 9 type A AoD and 22 type B AoD, whereas in clinical practice approximately two-thirds of AoD are typically type A and one-third are type B.

Because this was a population with genetically mediated aneurysms, the overall incidence of AoD was fairly low (0.7% per year). Importantly, the cumulative annual incidence of AoD among those with MFS was considerably high at 4.5%, whereas, conversely, the annual incidence among those with BAV was quite low at 0.3%. Therefore, the data strongly suggest that although proximal aortic aneurysms in both MFS and BAV may all be genetically mediated, the underlying pathophysiology is likely different, and consequently, management strategies ought not to be equivalent. Remarkably, although both MFS and BAV are associated with aneurysms of the proximal aorta, the distal aorta is quite vulnerable in MFS (even at a normal size), whereas it is spared in BAV. In the current study, 15 of 22 type B AoD occurred in patients with MFS and none in those with BAV.

Because it has been well established that patients with MFS and aortic root aneurysms are at high risk for AoD at young ages, the primary therapeutic strategy has been the timely repair of aneurysms of ≥5.0 cm. Timely prophylactic surgery with durable aortic repair procedures has dramatically improved the prognosis of patients with MFS. However, with fewer patients with MFS experiencing acute type A AoD, we are now increasingly confronted with later distal aortic complications in this population, and management paradigms for the distal aorta are much less well established. In the current GenTAC study, patients were followed in centers with expertise in thoracic aortic disease, with almost one-third having undergone prophylactic aortic repair and most receiving beta-blocker therapy, yet among those with MFS, the rate of AoD remained high and the distal aorta was most often affected. Den Hartog et al. (6) recently reported that in patients with MFS, a previous proximal aortic repair was, in and of itself, a risk factor for late type B AoD.

Predicting the risk of AoD for any given patient with a thoracic aortic aneurysm remains a challenge. In the IRAD (International Registry of Acute Aortic Dissection) study, 59% of those presenting with a type A AoD also had a proximal aortic diameter of <5.5 cm (7), which is below the recommend threshold for aortic repair; even more remarkably, 40% had an aortic diameter of <5.0 cm, which is below the more aggressive surgical threshold used for those with MFS. The track record for the distal aorta is even worse. In IRAD, 82% of patients with a type B AoD presented with descending aortic diameters less than the 5.5 cm threshold for aortic repair (8), and 21% presented with diameters <3.5 cm (9). More remarkably, in the current GenTAC study, among those with a type B AoD, the average descending aortic diameter was only approximately 3.3 cm.

Clearly, there must be more to the risk of AoD than just aneurysm diameter and etiology. Specific gene mutations affect risk, as does a family history of AoD (10). The mechanical properties of the aortic wall (e.g., wall thickness, stiffness, distensibility) and the flow profile of luminal blood (e.g., shear stress) are certainly important, and with modern computed tomography and magnetic resonance imaging techniques, we can now investigate systematically why and when certain regions of the aorta become vulnerable. Biomarkers also hold promise, and several studies have shown that an elevated plasma tumor growth factor-beta level in MFS correlates with adverse aortic event rates (11). Hopefully, by broadening our clinical perspective, we will be able to better define a patient's risk and then, in turn, individualize our treatment strategies.

Footnotes

↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.

Dr. Isselbacher has reported that he has no relationships relevant to the contents of this paper to disclose.

2016 American College of Cardiology Foundation

References

(2010) 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients With Thoracic Aortic Disease: Executive Summary. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. J Am Coll Cardiol55:e27–e129.

(2016) Surgery for Aortic dilatation in patients with bicuspid aortic valves: a statement of clarification from the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol67:724–731.

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