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Abdominal Aortic Aneurysm Growth's Prediction
Abdominal aortic aneurysm represents a distinct group of vascular lesions, in terms of surveillance and treatment. Amongst clinically applicable biomarkers, D-dimers, LDL-C, HDL-C, TC, ApoB, and HbA1c were found to bear the most significant association with AAA growth rates. In terms of the experimental biomarkers, PIIINP, osteopontin, tPA, osteopontin, haptoglobin polymorphisms, insulin-like growth factor I, thioredoxin, neutrophil extracellular traps (NETs), and genetic factors, as polymorphisms and microRNAs were positively correlated with increased AAA expansion rates.
Despite abdominal aortic aneurysm (AAA) being an asymptomatic entity, rupture complicates this silent pathology with a high mortality risk. Aneurysm identification on incidental imaging or screening programs at an early stage and small diameter allows for a close surveillance and repair . However, not all aneurysms expand with the same rate and are not associated with the same risk of rupture, while diameter cannot always predict the physical evolution of an AAA . A plethora of studies using imaging modalities and AAA anatomical characteristics tended to define models that could describe the expansion model of small or larger AAAs . From ultrasonography to modern mathematical flow models, different methods have been used to identify these markers that could eliminate this group of patients needing closer re-evaluation and earlier management .
As different anatomical characteristics recorded on imaging modalities have been associated with aneurysm expansion, an analogous interest exists regarding the application of biomarkers that could identify AAA growth . However, important discrepancies exist among the available studies . A large spectrum of biomarkers is recorded in the current literature, from the commonly applied clinical circulating biomarkers to more specific sophisticated genetic models that could be used to evaluate AAA expansion rate . The need to predict aneurysm evolution and if possible, to hamper sac expansion, is of high interest, as this approach would permit a closer surveillance screening and a more individualized therapeutic approach.
Along this line, a systematic review was conducted to present the existing evidence of different circulating biomarkers that may have a potential role on AAA growth prediction.
2. Development and Findings
AAA represent a category of vascular lesions with high morbidity and mortality, especially in the case of aneurysm rupture. Current guidelines suggest elective repair based mainly on aneurysmal diameter and/or other characteristics of the AAA . Proposed screening strategies vastly stand on imaging techniques, including mainly DUS, adhering to the phenomenon of increased rupture risk in patients of specific demographic attributes and AAA diameter . Studies have shown that patients with particular aneurysmal attributes would be acceptable surgical candidates, especially for endovascular interventions, even if AAA diameter has not achieved the diameter’s threshold . While AAA growth is observed through typical, time-set imaging follow-up, stratification of high-risk patients with expeditious AAA growth, through serum biomarkers, could be a valid approach for individualized imaging surveillance. These patients could benefit from a rather targeted surveillance approach as well as an early endovascular or open surgical repair.
The pathogenesis of AAAs advocates for an extensive list of serum circulating or histologically detected biomarker candidates. Each category bears an important role in the different phases of the natural history of AAA . Biomarkers detected through histological evaluation of an AAA open surgical repair specimen do not conform with the concept of preoperative surveillance and disease progression and therefore cannot be used in clinical practice. However, serum circulating biomarkers appertaining to recognized pathophysiologic processes of AAA pathogenesis, including thrombosis, inflammation, extracellular matrix (ECM) degradation, lipid metabolism, as well as genetic predisposition, could potentially form the basis of a stratification screening or surveillance strategy for patients in need of more frequent follow-up.
As proposed by many studies, certain mediators or by-products of thrombosis and lipid metabolism have been linked to AAA growth. These biomarkers can be easily and cost-effectively implemented in everyday clinical practice . D-dimers, a known fibrin degradation by-product, has been shown to be associated with AAA expansion, as higher levels have been correlated with increased growth rate. Correlation of other thrombosis-related biomarkers, including PAP complex , homocysteine , and TAT , has also been reported. Higher levels of HDL-C, a biomarker related to lipid metabolism, have been correlated with decreased AAA growth rates in a screening population . Furthermore, increased levels of total cholesterol and apolipoprotein B, both markers easily quantified and major constituents of lipid metabolism, have been associated with increased growth rates of AAA . On the other hand, given the potentially protective nature of diabetes mellitus in AAA, glycated hemoglobin (HbA1c) has been studied as a possible biomarker of inverse association with AAA expansion . A lower growth rate was observed in patients with higher HbA1c levels; 1.8 mm/year decrease of rate in HbA1c 44–77 compared to 28–39 mmol/mol . The recognized correlations of the abovementioned biomarkers, in addition to their cost-effectiveness and their wide-spread use in everyday clinical practice, renders them attractive candidates for future studies aiming to provide robust data on their relation to AAA expansion rates.
Concurrently, a plethora of less utilized biomarkers correlating to various stages of AAA progression have been studied, posturing as alluring secondary candidates. Firstly, extracellular matrix components and degradation enzymes have been associated with AAA growth rate. The well-defined role of elastin, biglycan, and type III collagen in the structural integrity of the aortic wall provided the basis for studies reporting data on the by-products of these proteins associated with ΑΑΑ progress and increased sac expansion . Inadvertently, extracellular matrix proteinases (MMP-2, MMP-9 , cathepsins B, D, L, and S ) responsible for ECM cleavage, and proteinases inhibitors (a1-antithrypsin , cystatin-B , cystatin-C ) play a significant role in the aortic wall remodeling occurring in AAA pathogenesis with several studies revealing either positive or inverse correlations with AAA growth rates. An abundance of modulators and mediators expressing the inflammatory and oxidative processes have also been studied with conflicting outcomes . Synchronously, studies on promising novel biomarkers requiring genome sequencing analysis have been conducted, with propitious results. Specifically, genomic DNA analysis of genetic polymorphisms showed increased risk of aggressive-growth over slow-growth AAA . Current data on these aforementioned biomarkers are promising, despite the fact that firm conclusions cannot be provided. Interestingly, calprotectin, a protein commonly associated with inflammatory cells (neutrophil granulocytes, monocytes, macrophages), has been related to AAA pathogenesis. These results provide further solid ground for future trials, aiming to assess the relation between the antimicrobial protein and AAA growth rate . As the knowledge on AAA pathogenesis increases, novel studies may offer validated markers that could be used for the detection of this high-risk group of patients while pharmaceutical factors may provide a conservative management on AAA presence and expansion.
The strength of the current review is limited by a series of factors. Firstly, the retrospective nature of the included studies confines its ability to reach pertinent results. Secondly, vast incoherencies among studies in terms of the types of biomarker assessed, studied population and cohorts, lack of control groups, follow-up intervals, and standardized methodological evaluations (imaging techniques, biomarkers quantification methods) impede the production of robust results, as well as the ability of quantitative analysis of the said results. Finally, most studies were judged as having “Moderate” risk of bias, mainly due to selection bias and inadequate confounder control.
Blood circulating biomarkers may offer a valid approach in the future for the detection of AAA expansion. The current literature provides a plethora of data with conflicting results and firm conclusions cannot be provided. In the presence of future robust data, specific serum biomarkers could potentially form the basis of an individualized surveillance strategy of patients presenting with increased AAA growth rates.
The entry is from 10.3390/jcm10081718
- Golledge, J. Abdominal aortic aneurysm: Update on pathogenesis and medical treatments. Nat. Rev. Cardiol. 2018, 16, 225–242.
- Kurvers, H.; Veith, F.; Lipsitz, E.; Ohki, T.; Gargiulo, N.; Cayne, N.; Suggs, W.; Timaran, C.; Kwon, G.; Rhee, S. Discontinuous, staccato growth of abdominal aortic aneurysms. J. Am. Coll. Surg. 2004, 199, 709–715.
- Olson, S.L.; Wijesinha, M.A.; Panthofer, A.M.; Blackwelder, W.C.; Upchurch, G.R.; Terrin, M.L.; Curci, J.A.; Baxter, B.T.; Matsumura, J.S. Evaluating Growth Patterns of Abdominal Aortic Aneurysm Diameter With Serial Computed Tomography Surveillance. JAMA Surg. 2021.
- Spanos, K.; Eckstein, H.-H.; Giannoukas, A.D. Small Abdominal Aortic Aneurysms Are Not All the Same. Angiology 2019, 71, 205–207.
- Forsythe, R.O.; Newby, D.E.; Robson, J.M.J. Monitoring the biological activity of abdominal aortic aneurysms beyond Ultrasound. Heart 2016, 102, 817–824.
- Jalalzadeh, H.; Indrakusuma, R.; Planken, R.N.; Legemate, D.A.; Koelemay, M.J.W.; Balm, R. Inflammation as a Predictor of Abdominal Aortic Aneurysm Growth and Rupture: A Systematic Review of Imaging Biomarkers. Eur. J. Vasc. Endovasc. Surg. 2016, 56, 333–342.
- Spanos, K.; Nana, P.; Kouvelos, G.; Mpatzalexis, K.; Matsagkas, M.; Giannoukas, A.D. Anatomical Differences Between Intact and Ruptured Large Abdominal Aortic Aneurysms. J. Endovasc. Ther. 2020, 27, 117–123.
- Wanhainen, A.; Verzini, F.; Van Herzeele, I.; Allaire, E.; Bown, M.; Cohnert, T.; Dick, F.; Van Herwaarden, J.; Karkos, C.; Koelemay, M.; et al. Editor’s Choice—European Society for Vascular Surgery (ESVS) 2019 Clinical Practice Guidelines on the Management of Abdominal Aorto-iliac Artery Aneurysms. Eur. J. Vasc. Endovasc. Surg. 2019, 57, 8–93.
- Forsythe, R.O.; Newby, D.E. Imaging Biomarkers for Abdominal Aortic Aneurysms: Finding the Breakthrough. Vol. 12, Circulation: Cardiovascular Imaging. Lippincott Williams and Wilkins; 2019. Available online: (accessed on 9 March 2021).
- Torres-Fonseca, M.; Galan, M.; Martinez-Lopez, D.; Cañes, L.; Roldan-Montero, R.; Alonso, J.; Rodríguez, C.; Sirvent, M.; Miguel, L.; Martínez, R.; et al. Pathophisiology of abdominal aortic aneurysm: Biomarkers and novel therapeutic targets. Clin. Investig. Arterioscler. 2019, 31, 166–177.
- Wanhainen, A.; Mani, K.; Golledge, J. Surrogate Markers of Abdominal Aortic Aneurysm Progression. Arter. Thromb. Vasc. Biol. 2016, 36, 236–244.
- Ahmed, R.; Ghoorah, K.; Kunadian, V. Abdominal aortic aneurysms and risk factors for adverse events. Cardiol. Rev. 2016, 24, 88–93.
- Chaikof, E.L.; Dalman, R.L.; Eskandari, M.K.; Jackson, B.M.; Lee, W.A.; Mansour, M.A.; Mastracci, T.M.; Mell, M.; Murad, M.H.; Nguyen, L.L.; et al. The Society for Vascular Surgery practice guidelines on the care of patients with an abdominal aortic aneurysm. J. Vasc. Surg. 2018, 67, 2–77.
- Lederle, F.A.; Kane, R.L.; MacDonald, R.; Wilt, T.J. Systematic review: Repair of unruptured abdominal aortic aneurysm. Ann. Intern. Med. 2007, 146, 735–741.
- Cao, P.; De Rango, P.; Verzini, F.; Parlani, G.; Romano, L.; Cieri, E. Comparison of Surveillance Versus Aortic Endografting for Small Aneurysm Repair (CAESAR): Results from a Randomised Trial. Eur. J. Vasc. Endovasc. Surg. 2011, 41, 13–25.
- Ouriel, K. The PIVOTAL study: A randomized comparison of endovascular repair versus surveillance in patients with smaller abdominal aortic aneurysms. J. Vasc. Surg. 2009, 49, 266–269.
- Golledge, J.; Tsao, P.S.; Dalman, R.L.; Norman, P.E. Circulating Markers of Abdominal Aortic Aneurysm Presence and Progression. Circulation 2008, 118, 2382–2392.
- Yagi, H.; Nishigori, M.; Murakami, Y.; Osaki, T.; Muto, S.; Iba, Y.; Minatoya, K.; Ikeda, Y.; Ishibashi-Ueda, H.; Morisaki, T.; et al. Discovery of novel biomarkers for atherosclerotic aortic aneurysm through proteomics-based assessment of disease progression. Sci. Rep. 2020, 10, 1–12.
- Hellenthal, F.A.M.V.I.; Buurman, W.A.; Wodzig, W.K.W.H.; Schurink, G.W.H. Biomarkers of abdominal aortic aneurysm progression. Part 2: Inflammation. Nat. Rev. Cardiol. 2009, 6, 543–552.
- Deeg, M.A.; Meijer, C.A.; Chan, L.S.; Shen, L.; Lindeman, J.H.N. Prognostic and predictive biomarkers of abdominal aortic aneurysm growth rate. Curr. Med. Res. Opin. 2016, 32, 509–517.
- Vega de Céniga, M.; Esteban, M.; Quintana, J.M.; Barba, A.; Estallo, L.; de la Fuente, N.; Martin-Ventura, J.L. Search for Serum Biomarkers Associated with Abdominal Aortic Aneurysm Growth—A Pilot Study. Eur. J. Vasc. Endovasc. Surg. 2009, 37, 297–299.
- Golledge, J.; Muller, R.; Clancy, P.; McCann, M.; Norman, P.E. Evaluation of the diagnostic and prognostic value of plasma D-dimer for abdominal aortic aneurysm. Eur. Hear. J. 2010, 32, 354–364.
- Burillo, E.; Lindholt, J.S.; Molina-Sánchez, P.; Jorge, I.; Martinez-Pinna, R.; Blanco-Colio, L.M. ApoA-I/HDL-C levels are inversely associated with abdominal aortic aneurysm progression. Thromb. Haemost. 2015, 113, 1335–1346.
- Sundermann, A.C.; Saum, K.; Conrad, K.A.; Russell, H.M.; Edwards, T.L.; Mani, K.; Björck, M.; Wanhainen, A.; Owens, A.P. Prognostic value of D-dimer and markers of coagulation for stratification of abdominal aortic aneurysm growth. Blood Adv. 2018, 2, 3088–3096.
- de Ceniga, M.V.; Esteban, M.; Barba, A.; Estallo, L.; Blanco-Colio, L.M.; Martin-Ventura, J.L. Assessment of Biomarkers and Predictive Model for Short-term Prospective Abdominal Aortic Aneurysm Growth—A Pilot Study. Ann. Vasc. Surg. 2014, 28, 1642–1648.
- Lindholt, J.S.; Jørgensen, B.; Fasting, H.; Henneberg, E.W. Plasma levels of plasmin-antiplasmin-complexes are predictive for small abdominal aortic aneurysms expanding to operation-recommendable sizes. J. Vasc. Surg. 2001, 34, 611–615.
- Halazun, K.J.; Bofkin, K.A.; Asthana, S.; Evans, C.; Henderson, M.; Spark, J.I. Hyperhomocysteinaemia is Associated with the Rate of Abdominal Aortic Aneurysm Expansion. Eur. J. Vasc. Endovasc. Surg. 2007, 33, 391–394.
- De Rango, P.; Farchioni, L.; Fiorucci, B.; Lenti, M. Diabetes and abdominal aortic aneurysms. Eur. J. Vasc. Endovasc. Surg. 2014, 47, 243–261.
- Theivacumar, N.S.; Stephenson, M.A.; Mistry, H.; Valenti, D. Diabetes mellitus and aortic aneurysm rupture: A favorable association? Vasc. Endovasc. Surg. 2014, 48, 45–50.
- Dattani, N.; Sayers, R.D.; Bown, M.J. Diabetes mellitus and abdominal aortic aneurysms: A review of the mechanisms underlying the negative relationship. Diabetes Vasc. Dis. Res. 2018, 15, 367–374.
- Lederle, F.A.; Johnson, G.R.; Wilson, S.E.; Chute, E.P.; Littooy, F.N.; Bandyk, D.F.; Krupski, W.C.; Barone, G.W.; Acher, C.W.; Ballard, D.J. Prevalence and Associations of Abdominal Aortic Aneurysm Detected through Screening. Ann. Intern. Med. 1997, 126, 441–449.
- Kristensen, K.L.; Dahl, M.; Rasmussen, L.M.; Lindholt, J.S. Glycated hemoglobin is associated with the growth rate of abdominal aortic aneurysms a substudy from the VIVA (Viborg vascular) randomized screening trial. Arter. Thromb. Vasc. Biol. 2017, 37, 730–736.
- Satta, J.; Haukipuro, K.; Kairaluoma, M.I.; Juvonen, T. Aminoterminal propeptide of type III procollagen in the follow-up of patients with abdominal aortic aneurysms. J. Vasc. Surg. 1997, 25, 909–915.
- Flondell-Sité, D.; Lindblad, B.; Kölbel, T.; Gottsäter, A. Markers of Proteolysis, Fibrinolysis, and Coagulation in Relation to Size and Growth Rate of Abdominal Aortic Aneurysms. Vasc. Endovasc. Surg. 2010, 44, 262–268.
- Dobrin, P.B. Elastin, collagen, and some mechanical aspects of arterial aneurysms. J. Vasc. Surg. 1989, 9, 396–398.
- Theocharis, A.D.; Karamanos, N.K. Decreased biglycan expression and differential decorin localization in human abdominal aortic aneurysms. Atherosclerosis 2002, 165, 221–230.
- Lu, H.; Aikawa, M. Many faces of matrix metalloproteinases in aortic aneurysms. Arterioscler. Thromb. Vasc. Biol. 2015, 35, 752–754.
- Klaus, V.; Schmies, F.; Reeps, C.; Trenner, M.; Geisbüsch, S.; Lohoefer, F.; Eckstein, H.-H.; Pelisek, J. Cathepsin S is associated with degradation of collagen I in abdominal aortic aneurysm. Vasa 2018, 47, 285–293.
- Wang, Y.; Liu, C.L.; Lindholt, J.S.; Shi, G.P.; Zhang, J. Plasma Cystatin B Association With Abdominal Aortic Aneurysms and Need for Later Surgical Repair: A Sub-study of the VIVA Trial. Eur. J. Vasc. Endovasc. Surg. 2018, 56, 826–832.
- Lindholt, J.S.; Erlandsen, E.J.; Henneberg, E.W. Cystatin C deficiency is associated with the progression of small abdominal aortic aneurysms. BJS 2001, 88, 1472–1475.
- Martinez-Pinna, R.; Lindholt, J.; Blanco-Colio, L.; Dejouvencel, T.; Madrigal-Matute, J.; Ramos-Mozo, P.; de Ceniga, M.V.; Michel, J.; Egido, J.; Meilhac, O.; et al. Increased levels of thioredoxin in patients with abdominal aortic aneurysms (AAAs). A potential link of oxidative stress with AAA evolution. Atherosclerosis 2010, 212, 333–338.
- Martín-Ventura, J.; Lindholt, J.; Moreno, J.; de Céniga, M.V.; Meilhac, O.; Michel, J.; Egido, J.; Blanco-Colio, L. Soluble TWEAK plasma levels predict expansion of human abdominal aortic aneurysms. Atherosclerosis 2011, 214, 486–489.
- Ahmad, M.; Kuravi, S.; Hodson, J.; Rainger, G.E.; Nash, G.B.; Vohra, R.K.; Bradbury, A.W. The Relationship Between Serum Interleukin-1α and Asymptomatic Infrarenal Abdominal Aortic Aneurysm Size, Morphology, and Growth Rates. Eur. J. Vasc. Endovasc. Surg. 2018, 56, 130–135.
- Jana, S.; Hu, M.; Shen, M.; Kassiri, Z. Extracellular matrix, regional heterogeneity of the aorta, and aortic aneurysm. Exp. Mol. Med. 2019, 51, 1–15.
- Paige, E.; Clément, M.; Lareyre, F.; Sweeting, M.; Raffort, J.; Grenier, C.; Finigan, A.; Harrison, J.; Peters, J.E.; Sun, B.B.; et al. Interleukin-6 Receptor Signaling and Abdominal Aortic Aneurysm Growth Rates. Circ. Genom. Precis. Med. 2019, 12, e002413.
- Wanhainen, A.; Mani, K.; Vorkapic, E.; De Basso, R.; Björck, M.; Länne, T.; Wågsäter, D. Screening of circulating microRNA biomarkers for prevalence of abdominal aortic aneurysm and aneurysm growth. Atherosclerosis 2017, 256, 82–88.
- Eilenberg, W.; Zagrapan, B.; Bleichert, S.; Ibrahim, N.; Knöbl, V.; Brandau, A.; Martelanz, L.; Grasl, M.-T.; Hayden, H.; Nawrozi, P.; et al. Histone citrullination as a novel biomarker and target to inhibit progression of abdominal aortic aneurysms. Transl. Res. 2021.
- Duellman, T.; Warren, C.L.; Matsumura, J.; Yang, J. Analysis of multiple genetic polymorphisms in aggressive-growing and slow-growing abdominal aortic aneurysms. J. Vasc. Surg. 2014, 60, 613–621.
- Zhang, W.; Shang, T.; Huang, C.; Yu, T.; Liu, C.; Qiao, T.; Huang, D.; Liu, Z.; Liu, C. Plasma microRNAs serve as potential biomarkers for abdominal aortic aneurysm. Clin. Biochem. 2015, 48, 988–992.
- Kin, K.; Miyagawa, S.; Fukushima, S.; Shirakawa, Y.; Torikai, K.; Shimamura, K.; Sawa, Y. Tissue- and plasma-specific MicroRNA signatures for atherosclerotic abdominal aortic aneurysm. J. Am. Heart Assoc. 2012, 1, e000745.
- Hauzer, W.; Witkiewicz, W.; Gnus, J. Calprotectin and Receptor for Advanced Glycation End Products as a Potential Biomarker in Abdominal Aortic Aneurysm. J. Clin. Med. 2020, 9, 927.
- Hauzer, W.; Ferenc, S.; Rosińczuk, J.; Gnus, J. The Role of Serum Calprotectin as a New Marker in Abdominal Aortic Aneurysms—A Preliminary Report. Curr. Pharm. Biotechnol. 2020, 21.