What is the clinical utility of serum biomarkers in the diagnosis of acute and chronic aortic diseases?

Biomarkers in Aortic Dissection

The excessive mortality associated with acute aortic dissection (AAD) makes the need for timely, accurate diagnosis critical. Variability in presentation, however, may delay definitive imaging. A serum biomarker – if widely available, cost-effective, and adequately sensitive and specific – could facilitate the diagnosis, counter some of the clinical uncertainty associated with presentation, and avoid delays in imaging and treatment.¹ D-dimer is the most promising biomarker for risk stratification in suspected AAD and is available for use at the point-of-care. A cutoff level of 500 ng/mL has been confirmed in multiple studies to rule out acute aortic dissection. The largest study on the use of D-dimer in AAD demonstrated a sensitivity and specificity of 96% (95% confidence interval [CI], 78.1 to 99.9) and 61% (95% CI, 42.2 to 78.2) respectively, at a cutoff level of 500 ng/mL, within the first 6 hours of presentation of acute aortic dissection.² This study also demonstrated that AAD could be ruled in using a cutoff of 1600 ng/mL in the initial six hours.

Other classes of biomarkers for AAD include smooth muscle biomarkers, aortic proteins, inflammatory markers, and fibrolytic markers. Circulating smooth muscle myosin heavy chain, a smooth muscle biomarker, shows marked elevations limited to the initial three to six hours after onset of symptoms and may be especially useful for proximal lesions; its clinical use has been limited by technical issues and the narrow time window in which it is elevated.³ The BB isozyme of creatinine kinase, another smooth muscle biomarker but with peak in levels at approximately six hours after onset, may extend the diagnostic time window beyond that offered by smooth muscle myosin.⁴ Calponin, the troponin counterpart of smooth muscle, offers an even wider time window of up to 24 hours, and may be more beneficial in the timely, accurate diagnosis of AAD.⁵ The use of soluble elastin fragments may be limited clinically, as the dynamic range of this protein is limited to less than two-fold increases over healthy controls.⁶ Peak levels of C-reactive protein (CRP) have been shown to predict adverse long-term events in patients with type B dissection; elevated CRP levels may indicate the degree of inflammatory response in the dissected wall.⁷ Matrix metalloproteinases may have a role not only in the rapid diagnosis of AAD, but also in long-term follow-up to monitor aortic remodeling.⁸ Circulating transforming growth factor β may have value in monitoring aortic size and response to therapy with losartan and/or beta-blockade in Marfan's syndrome.⁹

Biomarkers in Thoracic and Abdominal Aortic Aneurysms

In an aging population, aortic aneurysms of the abdomen (AAA) will become increasingly relevant. While no single biomarker has emerged as clinically relevant by itself, multiple biomarkers, in combination with clinical data, may predict aneurysmal growth. A multivariate formula using initial AAA dimensions, serum elastin peptide levels, and procollagen-IIIN-terminal propeptide has been shown to predict cases reaching 5 cm in diameter within five years, with a sensitivity of 91% and specificity of 87% (i.e. nine out of ten AAAs that will be operated on within five years).¹⁰ Because thoracic aortic aneurysm has a strong genetic basis, the use of conventional inflammatory biomarkers may be less informative. However, the ratio of matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1, a relative index of proteolysis, has been shown to be increased in both patients with thoracic aortic aneurysm and dissection compared with control patients.¹¹

Biomarkers in Takayasu Arteritis

Traditionally, the erythrocyte sedimentation rate and CRP level have been used as markers of disease activity in Takayasu arteritis.¹² More recently, pentraxin-3 (PTX-3), a "vascular selective CRP," has shown promise as a potential biomarker for Takayasu arteritis.¹³ PTX-3 is selectively produced by vascular endothelial cells, macrophages, and neutrophils; it may be more specific for arterial inflammation than CRP; and may reflect pathogenic activity of Takayasu aortitis regardless of the use of corticosteroids.¹³

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References

1. Suzuki T, Bossone E, Sawaki D, et al. Biomarkers of aortic diseases. Am Heart J 2013; 165:15-25.
2. Suzuki T, Distante A, Zizza A, et al. Diagnosis of acute aortic dissection by D-dimer: the International Registry of Acute Aortic Dissection Substudy on Biomarkers (IRAD-Bio) experience. Circulation 2009; 119:2702-7.
3. Suzuki T, Katoh H, Tsuchio Y, et al. Diagnostic implications of elevated levels of smooth-muscle myosin heavy-chain protein in acute aortic dissection. Ann Intern Med 2000; 133:537-41.
4. Suzuki T, Katoh H, Kurabayashi M, et al. Biochemical diagnosis of aortic dissection by raised concentrations of creatinine kinase BB-isozyme. Lancet 1997; 350:784-5.
5. Suzuki T, Distante A, Zizza A, et al. Preliminary experience with the smooth muscle troponin-like protein, calponin, as a novel biomarker for diagnosing acute aortic dissection. Eur Heart J 2008; 29:1439-45.
6. Shinohara T, Suzuki K, Okada M, et al. Soluble elastin fragments in serum are elevated in acute aortic dissection. Arterioscler Thromb Vasc Biol 2003; 23:1839-44.
7. Sakakura K, Kubo N, Ako J, et al. Peak C-reactive protein level predicts long-term outcomes in type B acute aortic dissection. Hypertension 2010; 55:422-9.
8. Sangiorgi G, Trimarchi S, Mauriello A, et al. Plasma levels of metalloproteinases-9 and -2 in the acute and subacute phases of type A and type B aortic dissection. J Cardiovasc Med (Hagerstown) 2006; 7:307-15.
9. Matt P, Schoenhoff F, Habashi J, et al. Circulating transforming growth factor-beta in Marfan syndrome. Circulation 2009; 120:526-32.
10. Lindholt JS, Heickendorff L, Vammen S, et al. Five year results of elastin and collagen markers as predictive tools in the management of small abdominal aortic aneurysms. Eur J Vasc Endovasc Surg 2001; 21:235-40.
11. Koullias GJ, Ravichandran P, Korkolis DP, et al. Increased tissue microarray matrix metalloproteinase expression favors proteolysis in thoracic aortic aneurysms and dissections. Ann Thorac Surg 2004; 78:2106-11.
12. Kerr GS, Hallahan CW, Giordano J, et al. Takayasu arteritis. Ann Intern Med 1994; 120:919-24.
13. Ishihara T, Haraguchi G, Kamiishi T, et al. Sensitive assessment of activity of Takayasu's arteritis by pentraxin3, a new biomarker. J Am Coll Cardiol 2011; 57:1712-3.

Keywords: Aneurysm, Dissecting, Aortic Aneurysm, Biomarkers, Confidence Intervals, Sensitivity and Specificity, Uncertainty, Fibrin Fibrinogen Degradation Products

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