European Journal of Vascular & Endovascular Surgery
Volume 36, Issue 3 , Pages 273-280, September 2008

Potential Circulating Biomarkers for Abdominal Aortic Aneurysm Expansion and Rupture - a Systematic Review

  • S. Urbonavicius

      Affiliations

    • Vascular Research Unit, Department of Vascular Surgery, Viborg Hospital, Denmark
    • Institute of Medical Biochemistry of Aarhus University, Denmark
    • Corresponding Author InformationCorresponding author. S. Urbonavicius MD, Vascular Research Unit, Department of Vascular Surgery, Viborg Hospital, Denmark. Tel.: +4560846760; fax: +45868804.
    • ,
  • G. Urbonaviciene

      Affiliations

    • Vascular Research Unit, Department of Vascular Surgery, Viborg Hospital, Denmark
    • ,
  • B. Honoré

      Affiliations

    • Institute of Medical Biochemistry of Aarhus University, Denmark
    • ,
  • E.W. Henneberg

      Affiliations

    • Vascular Research Unit, Department of Vascular Surgery, Viborg Hospital, Denmark
    • ,
  • H. Vorum

      Affiliations

    • Institute of Medical Biochemistry of Aarhus University, Denmark
    • ,
  • J.S. Lindholt

      Affiliations

    • Vascular Research Unit, Department of Vascular Surgery, Viborg Hospital, Denmark

Received 20 November 2007; accepted 14 May 2008. published online 18 July 2008.

Article Outline

Abstract 

Background

The maximal diameter of abdominal aortic aneurysms (AAAs) is the dominating indication for repair. However half of the AAAs repaired would never have ruptured if left unrepaired, although small AAAs occasionally rupture. Earlier surgery may be associated with a lower mortality. More precise indicators for surgery are warranted. This systematic review identifies potential systemic biomarkers for AAA rupture or expansion.

Methods

MEDLINE/PubMed and EMBASE (from 1985 trough May 2007) were searched with the medical subject heading abdominal aortic aneurysm and keywords “size”, “progression” or “growth” or “expansion rate” or “rupture” on the basis of MESH tree and as a text search restricted to English, German, French and Italian. In addition, reference lists were studied and manual searches performed. Observational studies investigating the association of circulating biomarkers with AAA rupture, expansion or size were selected.

Data extraction

Two reviewers (SU and GU) independently extracted the following data: year of publication, study characteristics, duration of follow-up, circulating biomarker, AAA expansion rate or size or rupture.

Results

699 papers were identified. After exclusion of thoracic aneurysms and cardiac studies (n=118), surgical or medical treatment studies (n=179), case reports and animal studies (n=87), as well as reviews or letters (n=66), 249 articles were selected. Also excluded were 230 papers that did not report AAA size, expansion rate or rupture. 39 papers were included. Several potential biomarkers were identified. The strongest association with AAA was obtained with serum elastin peptides (SEP) and plasmin-antiplasmin (PAP) complexes. Matrix-degrading metalloproteinase 9 (MMP9) and interferon-gamma (IFN-gamma) could have clinical potential while many putative biomarkers showed poor association.

Conclusions

Several circulating agents in peripheral blood may predict AAA size, expansion rate or rupture. Few of them have clinical potential for future use. Confirmative studies and development of multivariate models are needed, together with continuing search for new biomarkers using the discovery based sciences within proteomics and/or genomics.

Keywords: Abdominal aortics aneurysms, Expansion, Rupture, Circulating biomarkers

 

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Introduction 

Abdominal aortic aneurysm (AAA) is an important health problem. In cross-sectional population studies of older men the prevalence varies from 3% to 8%. AAA causes about 1% deaths in developed countries. In elderly men AAA may cause as many as 2% of all deaths.1 The incidence of asymptomatic and ruptured AAA has increased in several countries during the last few decades.

Efforts to limit the mortality rate from AAA rupture depend on early detection and elective AAA repair. The indication for elective repair is mainly based upon the maximal diameter of AAA above 5.5cm.1, 2 Consequently, the benefit of early diagnosis of AAAs by ultrasound screening is limited because most AAAs are too small for intervention at the time of diagnosis. Currently there is no established medical treatment for small AAAs, but small AAAs do rupture occasionally. If we could predict which small AAAs are most likely to require later intervention, intervention could perhaps be offered earlier with less morbidity and mortality because age is one of the major risk factors, and fatal ruptures during surveillance could be limited.3 However, two large randomized trials have shown a strategy of early AAA repair to be inefficient.1, 4 In addition, only half of those large AAA we operate upon would have ruptured if they were left untreated. Consequently, an improved risk model is desirable, to which circulating biomarkers may contribute information.

A biomarker can be defined as a measurable cell, protein, peptide, gene, or metabolic product that represents biologic processes in an organism at a given time.5 One or several biomarkers might be an indicator for the disease or the risk that the disease will progress. The diameter of the AAA is a surrogate marker of the growth rate, which reflects the magnitude of the degenerative process of the wall, and thus becomes a surrogate marker of rupture. The risk of rupture increases when growth exceeds the expected expansion rate.6 Active investigations continue to identify markers other than size that would predict a risk of rupture.7 Circulating biomarkers could also indicate optimal intervals between the surveillance intervals. Finally, the identification of biomarkers also may identify potential pathogeneic pathways, and thus may open possibilities for pharmacological inhibition of growth, and provide a tool for monitoring this inhibition.

Systematic literature search 

The MEDLINE/PubMed and EMBASE databases were searched for publications with the medical subject heading “abdominal aortic aneurysms” and keywords “size”, “progression” or “growth” or “expansion rate” or “rupture”. The search was conducted both on basis of the MESH tree and as a text search. We restricted our search to four languages (English, German, French and Italian) and to the period 1985 to May 2007. We excluded earlier studies, because ultrasound and CT technologies were not available before 1985. We focused only on human studies that reported aneurysm size, expansion rates (using linear regression modelling) and/or rupture.

Results 

A total of 699 abstracts available in English were identified. After exclusion of thoracic aneurysms and cardiac studies (n=118), surgical, endovascular or medical treatment studies (n=179), case reports and animal studies (n=87), as well as reviews or letters (n=66), 249 abstracts were selected. Of these we also excluded 169 papers that only investigated AAA wall material and 41 papers that analyzed AAA but did not analyze differences in size, expansion rate or rupture. 39 papers were included, using the biomarkers listed in Table 1.

Table 1. Summary of published studies reporting the role of circulating biomarkers in the growth and rupture of AAA
BiomarkerNumber of patients in the studyRelation between biomarkers and AAA expansionSummary of findingsAuthor, year
SEP83r=0.4Serum-elastin-peptides seem to predict expansion, but a larger, longer study is needed to establish clinical recommendations.Lindholt J. et al., 1997

PIIINP

SEP

99
r=0.24; (0.02–0.44)

r=0.31; (0.11–0.49)

A predictive model using EP, PIIINP, and initial AAA size seems capable of predicting nine out of 10 AAAs that will be operated on within 5 years.Lindholt J. et al., 2001
SEDP60
r=0.809, p<0.001

r=0.034, p=0.825

There was a significantly positive correlation between S-EDP and diameter in patients with rAAA,but not in patients with aAAA (r=0.034, p=0.825)Petersen et al., 2001
PIIINP139r=0.55; p=0.002Acceleration of AAA growth is reflected in serum PIIINP.Satta J. et al., 1997
PIIINP; PICP86no correlationBecause no correlation between plasma and tissue levels of PIIINP was found, the plasma level of PIIINP cannot be used as marker of this process.Treska V. et al., 2000

SEP

PIIINP

SEP

PIIINP

62
r=0.33; p=0.01

r=0.45; p=0.01

r=0.31; p=0.02

r=0.45; p=0.01

Increased elastolysis is associated with increased AAA wall distensibility; whereas increased collagen turn-over is associated with reduced distensibility.Wilson KA et al., 2001
MMP-936
r=0.33

r=0.51

Plasma MMP-9 may predict the natural history of AAA.Lindholt J. et al., 2000
MMP9MMP276no correlationBoth MMP-2 and -9 and NIIINP failed to show relevance as serum markers for aortic dilatation.Eugster T et al., 2005
P-Elastase79r=0.30; p<0.01P-elastase was positively correlated with the mean annual AAA expansion rate.Lindholt J et al., 2003
Cystatin C8r=−0.203; p<0.03Increased abdominal aortic diameter correlated inversely with serum cystatin C levels.Shi GP et al., 1999
Cystatin C142
r=−0.22

r=−0.24

Deficiency of cystatin C was associated with increased aneurysm size and expansion rate.Lindholt J. et al., 2001
tPA70r=0.37; p=0.002AAA progression may be partly caused by an activation of plasminogen by tPALindholt J. et al., 2003
PAP70r=0.39The progression of AAA is correlated with the PAP levelLindholt J. et al., 2001
IFN-gamma50r=0.37; p<0.02Elevated INF-gamma concentrations seem to predict an increased rate of expansion in AAA.Juvonen J. et al., 1997
TNF-alpha IL-890statistically significant correlation p<0.05IL-8 and TNF-alpha can be used as endogenous markers of the process of AAA development.Treska V. et al., 2000
IL-67r=0.28; p=0.002In multivariate analysis, the level of IL-6 was independently correlate-with indexed aortic diameter.Rodhe LE et al., 1999
MIF112r=0.28; p=0.005A significant association between serum MIF level and AAA initial size and AAA expansion rate was found.Pan JH et al., 2003
Osteopontin198r=0.24; p=0.001OPN may be a useful biomarker for AAA presence and growth.Golledge J et al., 2007
Osteoprogerin146r=0.20; p=0.04The findings support a role for OPG in the growth of human AAAMoran CS et al., 2005
CRP
sympt 52

ruptured 62

no correlationA significant elevation of CRP could be found in patients who presented symptoms or rupture of an AAA.Domanovits H et al., 2002
C-reactive Protein545significant bivariate interactionCRP levels are elevated in larger aneurysms but do not appear to be associated with rapid expansion. The most useful predictor of aneurysmal expansion in men is aortic diameter.Norman P. et al., 2004
Fibrinogen110r=0.323; p<0.01Fibrinogen may be a useful marker to monitor the progression of AAA.Al-Barjas HS et al., 2006
Serum highly sensitive CRP39r=0.477; p=0.002Serum hsCRP is associated with aneurysmal size.Vainas T. et al., 2003
CRP151no correlationCRP did not correlate with size or expansion rate of AAA.Lindholt J et al., 2001
S-CotinineHomocysteine122
r=0.24; p=0.038

no correlation

S-cotinine were positively correlated with the mean annual AAA expansion rate.Lindholt J. et al., 2003
D-dimer, fibrinogen/fibrin36
r=0.644; p=0.0001

r=0.561; p=0.0009

The largest diameter of AAA correlated with the preoperative levels of D-dimer and FDP. Activated state of both blood coagulation and fibrinolysis in AAA patients are associated with the morphological characteristics of aneurysms.Yamazumi K. et al., 1998
Homocysteine58
5.09±0.84

5.79±1.5, p<0.05

An association between the presence of AAA in patients selected for surgical treatment of AAA and elevated homocysteine plasma levels was found.Brunelli T et al., 2000
Homocysteine108r=0.28, p=0.003HyperHCY patients have faster expansion rates than patients with normal HCY.Halazun KJ et al., 2007
C. pneumoniae infection110
IgA r=0.28

IgG r=0.45

Aneurysm progression correlated with evidence of chronic C. pneumoniae infection.Lindholt J. et al., 2001
C. pneumoniae serology68IgA, p=0.046C. pneumoniae may contribute to aortic aneurysm disease progression- IgA titers positive for C. pneumoniaeFalkensammer B. et al., 2007
Chlamydophila pneumoniae serology119no correlationStudy fails to demonstrate a connection between C pneumoniae seropositivity and AAA ruptureNyberg A et al., 2007

SEP- serum elastin peptides, SEDP - serum elastin derived peptides, PIIINP- aminoterminal propeptide of type III procollagen, PICP- tissue carboxyterminal propeptide of type I procollagen, MMP-2,MMP-9- matrix-degrading metalloproteinases, tPA- tissue like plasminogen activator, PAP- plasmin- antiplasmin complexes, IFN-gamma- interferon-gamma, TNF-alpha- tumor necrosis factor-alpha, IL-6- interleukin 6, IL-8- interleukin 8, MIF- macrophage migration inhibitory factor, CRP - C Reactive Protein, hs - highly sensitive, C. pneumoniae - Chlamydophila pneumoniae, S – serum.

Matrix changes: elastin and collagen 

Elastin 

Elastin is one of the major components of the aorta, and experimental findings suggest that degradation products, elastin peptides, also stimulate leukocyte recruitment and cytokine production.8

Lindholt et al.9 invited 4404 men to screening in 1994 in order to detect AAA. 112 patients with small AAA were offered annual follow-up. Blood samples were obtained in 83 patients and serum elastin peptide (SEP) levels were determined using an Enzyme-Linked ImmunoSorbent Assay (ELISA)-technique with polyclonal antibodies against elastin peptides. A clear, but modest, correlation between SEP and the (expansion) growth rate within the first year of observation was identified in this prospective study (r=0.4). These findings suggested that SEP could be used as a biomarker predicting AAA expansion.

Alan Scott10 in Chichester (United Kingdom) followed 35 patients unfit for surgery, of whom 12 ruptured later. Together with Lindholt, they found that the SEP was significantly higher in those patients whose AAA ruptured later. ROC analysis showed that SEP could predict a later rupture with en optimal sensitivity and specificity of 67% and 60%, respectively. By combining SEP and last measured AAA-size in a linear model with rupture as the dependent variable, the ROC analysis showed an optimal sensitivity and specificity of 83% and 66%, respectively. The finding was statistically significant; however, the study was underpowered due to the small sample size.

Petersen et al. studied serum samples from 45 consecutive patients, having elective AAA repair and 15 patients with contained AAA rupture. Patients with contained rupture had significantly lower levels of SEP than patients undergoing elective AAA repair. SEP was measured by a competitive ELISA. There was a significantly positive correlation between SEP and diameter in patients with contained rupture (r=0.809, p<0.001), but not in patients undergoing elective AAA repair (r=0.034, p=0.825).11

Later Lindholt et al.12 developed antibodies for a new ELISA. This new ELISA showed a similar association with expansion rate but had poor correlation (r=0.31) with the earlier ELISA. The authors concluded that a standardized ELISA would be needed for clinical use.

Collagen metabolism: PIIINP 

Changes in the interstitial collagens may predispose the aneurysm to rupture. Measurement of blood procollagen peptides may serve as biomarkers of collagen turnover. In 1997, Satta et al.13 investigated the relationship between serum amino terminal propeptide of type III procollagen (PIIINP) and the rate of AAA expansion, and the possible predictive value of this biomarker with respect to AAA rupture. They measured serum PIIINP in 139 patients with asymptomatic small AAAs who were followed-up at intervals of 6 to 12 months. AAA growth was significantly and positively associated with the concentration of PIIINP in serum (r=0.55).

Treska and Topolcan14 used radioimmunoassay methods to evaluate the plasma and tissue carboxyterminal propeptide of type I procollagen (PICP) and PIIINP concentrations in relation to their size and symptoms. Eighty-six patients operated for both symptomatic AAA and asymptomatic patients with aneurysm diameter over 5cm were examined together with 25 patients scheduled for hernia repair or laparoscopic cholecystectomy as a control group. The only difference in plasma PIIINP levels was between patients with AAA and the control group. No significant associations between PICP, PIIINP plasma levels, AAA-diameter and symptomatology of AAA were observed.

Lindholt et al.12 showed a significant, but weak correlation between PIIINP and expansion rate (r=0.24). In addition, they showed an independently significant association between initial AAA size, SEP, and serum PIIINP and expansion rate. The multivariate formula could, by ROC analysis, predict cases reaching 5cm in diameter within 5 years with a sensitivity and specificity of 91% and 87%, respectively, increasing to 91% and 94%, respectively, by accepting a 2mm variation in those measurements. Within the first 5 years, 23 were lost for follow-up. If all 23 are included in the analysis, the sensitivity and specificity would have been 87% and 85%, respectively.

The relationship between AAA distensibility and circulating markers of elastin peptides and collagen metabolism was examined by Wilson et al. in a cross sectional study.15 SEP, plasma elastin-α1-antitrypsin complexes (E-AT), and PIIINP were measured in 62 male patients with asymptomatic small AAA with mean aorta diameter of 42 (37-45) mm. The investigator showed that elastolysis was associated with increased AAA wall distensibility; whereas increased collagen turn-over was associated with reduced distensibility.

In 2004, Claridge et al.16 performed case-control study within the Huntingdon Aneurysm Screening Programme. Blood samples were taken to measure PIIINP, lipid levels, iron metabolism and cotinine levels. The investigators did not find any significant differences in PIIINP levels between subjects with a small aneurysm and subjects with a normal aorta.

Matrix modulating proteases and their inhibitors 

Matrix-degrading metalloproteinases 

The relationship between aortic diameter, aneurysmal expansion rate, and the expression of matrix-degrading metalloproteinases (MMP) has been investigated. As mentioned earlier, Lindholt et al.17 obtained blood samples from a cohort of men after the diagnosis of a small AAA (3–5cm) at population screening. Annual control scans were performed to check for expansion rate of AAA. Circulating levels of MMP-2, MMP-9, and tissue-inhibitor-metalloproteinase (TIMP) 1 and 2 were measured in a random group of 36 men. Despite the small sample size, MMP9 correlated significantly (r=0.33) with expansion rate, while no other trend was noticed.

Hovsepian et al.18 used an ELISA to determine MMP-9 in 25 patients with AAA, 15 patients with aortic occlusive disease (AOD) and 5 controls. Blood plasma MMP-9 concentrations were significantly higher in patients with AAA as compared with patients with AOD or healthy subjects. However the investigators did not observe any significant correlation between blood plasma MMP-9 levels and aneurysm size, although there was a trend toward the highest levels in male patients with large AAAs.

In contrast, Eugster et al.19 compared serum MMP-9 and MMP-2 in 76 men with an aortic dilatation ≥25mm with randomly assigned patients having normal aortic diameters. They found no correlation between either serum MMP-2 or -9 with AAA diameter. However, the coagulation process during the creation of serum could easily influence the measured levels due to secretion from platelets or leukocytes.

Elastase 

Obviously, elastase was one of the first proteases to be associated with the breakdown of aortic elastin, and smoking, one of the strongest risk factors for AAA, is known to increase elastase secretion from leucocytes present in the wall of the aneurysm.

Lindholt et al.20 found a significant but poor to modest correlation with growth rate (r=0.30), but without any evidence that elastase could predictg cases requiring surgery latter.

Cystatin C 

Cathepsins are strong candidates as key participants in aneurysm development. These elastolytic enzymes are expressed strongly in the AAA wall, whereas there is reduced expression of their endogenous inhibitor cystatin C. The possibility that circulating levels of cystatin C may relate to the development of AAAs was explored by Shi et al.21 This Harvard group used ELISA to measure serum cystatin C level in 122 patients referred to an outpatient cardiology clinic for echocardiographic testing and underwent measurements of carotid artery intimal to medial thickness (IMT) ratios and aortic diameter. Among these subjects, 8 patients had an aortic diameter larger than 2.5cm. The authors reported a significant weak negative correlation between aortic size and cystatin C levels (r=−0.203). The association remained significant after adjustment for body surface area and serum creatinine (glomerular filtration is known to influence cystatin C levels).

In a further prospective study of 142 men with small AAA22 followed for a mean of 2.9 years, there was a weak negative correlation with AAA size (r=−0.22) and annual expansion rate (r=−0.24), but no mentionable potential for predicting cases requiring surgery later.

Plasmin, plasmin activators and the fibrinolytic system 

The cysteine, serine and metallo-proteinase systems all have been reported to be involved in the matrix degradation of the aortic wall, causing AAA. Plasmin is a common activator and could be involved in the pathogenesis of AAA by activating all three systems. Plasmin is formed from plasminogen and this process is regulated by the balance between plasminogen activators (tissue plasminogen activator (t-PA) and urokinase plasminogen activator (uPA)) and plasminogen activator inhibitor type 1 (PAI-1). However, when it reaches the circulation, plasmin immediately is inactivated by antiplasmin, forming plasmin-antiplasmin (PAP) complexes.

Lindholt et al. measured PAP in a cohort of 70 men with small AAA and found a significant, positive but modest correlation with growth rate (r=0.39) and a potential of predicting cases requiring surgery within the first five years, especially in combination with the initial AAA size, with an optimal sensitivity and specificity both at 83%.23 They later studied the activators of plasmin in the same cohort. Surprisingly, it was not uPA, which normally is involved in plasmin-related matrix remodeling, but tPA that trigger this association. A significant, positive and relatively modest correlation was found between tPA and expansion rate (r=0.37).24 In a later up date of the findings, they showed by ROC analysis that tPA was predictive of cases expanding to above 5cm within the first 5 years with an optimal sensitivity and specificity of 0.73 and 0.71, respectively.25

Relationships between blood coagulation, the fibrinolysis system, and the morphology of aneurysms in patients with AAA was investigated by Yamazumi et al.26 The authors reported that the size and tortuosity of AAA was associated with blood levels of fibrinolytic factors such as D-dimer, fibrinogen/fibrin degradation products, and plasmin inhibitor-plasmin complexes. Al-Barjas et al.27 obtained plasma samples from a group of 110 patients with AAA and also demonstrated positive correlation between the AAA size and fibrinogen concentration (r=0.323).

Inflammation 

Cytokines and chemokines 

Juvonen et al.28 measured circulating levels of interleukin 1 beta (IL-1β), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) in 50 patients with AAA, 42 patients with coronary artery disease (CAD) and healthy volunteers. IFN-γ correlated positively and significantly with aneurysmal expansion rate (r=0.37), while no other trend was noticed.

Treska et al.29 examined 90 patients with AAA classified according to symptoms and AAA diameter. The TNF-α and IL-8 levels were found to be significantly low in large AAA and in symptomatic AAAs. IL-6 levels were increased with increasing AAA diameter and symptoms. IL-8 levels showed a statistically significant correlation with the diameter and TNF-α with the symptoms of AAA. Later, they analyzed plasma endothelin 1 and 2 levels in AAA, above or below 5cm in diameter and with or without symptoms, but without any important associations being identified.30

Jones et al.31 calculated AAA growth rate from linear regression analysis in 466 patients with ≥3 diameter measurements and could not find any significant correlation with plasma IL-6 concentration.

Macrophage migration inhibitory factor (MIF) is a well known proinflammatory factor that influences the migration and proliferation of various cell types. Pan et al.32 followed a cohort of 112 men with small AAAs (defined as 3 to 5cm) annually for 1 to 5 years and MIF was measured by ELISA. The authors showed that serum-MIF levels correlated significantly but weakly with annual expansion rate (r=0.28), a correlation which persisted after adjustment for initial AAA size, smoking habits, diastolic blood pressure, ankle blood pressure index and age.

Golledge et al. used ELISA to measure serum osteopontin (OPN).33 The regulation of OPN expression seems to play a key role in macrophages and vascular smooth muscle cells (SMC) migration, linked to vascular remodelling and the development of atherosclerosis. In 198 patients with complete follow-up of aortic diameter at 3 years, initial serum OPN predicted AAA growth after adjustment for other risk factors, however, the correlation was poor (r=0.24). Osteoprotegrin (OPG) also has been evaluated by Moran et al.34 in a cohort of 146 men with small AAA followed up for 3 years. They observed a significant but poor correlation between serum level of OPG and aneurysm growth rate (r=0.20).

C-reactive protein 

C-reactive protein (CRP) is a non-specific acute phase reactant mainly produced in the liver stimulated by various cytokines believed to be involved in the pathogenesis of AAA. Thus it may be a potential biomarker. Four studies have been reported.

A prospective cohort study35 of 545 men with small aneurysms were followed for a median of 48 months by Norman et al. Baseline CRP levels were higher in larger aneurysms but CRP was not associated with expansion rate. However, the reported mean annual expansion rate was close to half of that observed in similar cohorts in Europe.

Lindholt et al.36 measured CRP in their cohort, but not with the hypersensitive assay, and could not find any association with size or expansion rate.

Serum highly sensitive CRP (hsCRP) and the size of aneurysm was measured in 39 patients with AAA by Vainas et al.,37 and showed a modest correlation with aneurysm size (r=0.477). Interestingly, they suggested that CRP produced in vascular tissue might contribute to aneurysm formation.

At the same time Domanovits et al.38 compared the level of hsCRP in 111 asymptomatic outpatients, 52 symptomatic patients without rupture and 62 patients with rupture of the aneurysm. Patients with symptomatic AAA and patients with ruptured AAA had significantly elevated CRP compared to asymptomatic patients.

Triggering factors 

Hyperhomocysteinaemia 

In 2000, Brunelli et al.39 reported that homocysteine (HCY) plasma levels correlated with AAA size. However, they did not adjust for renal function with which HCY is correlated and tends to be impaired in aneurysmal disease, especially among those with large AAAs. Lindholt et al. could not detect any association between HCY and the growth rate of AAA in a cohort of 70 men with small AAAs.24

However, in another recent study, Halazun et al.40 used fluorescence polarisation immunoassays to measure fasting total HCY levels in 108 patients undergoing surveillance for AAA. Patients with high HCY levels had faster AAA expansion rates than patients with normal HCY, but the correlation coefficient was weak (r=0.28).

Overall there are no consistent findings for HCY as a biomarker.

Chlamydia pneumoniae and antibodies 

Chlamydia pneumoniae (C. pneumoniae) has been suggested to be associated with atherosclerosis. The association between AAAs and infectious agents has also prompted exploration of the possibility that serum antibody titres might provide useful biomarkers of disease progression. Lindholt et al. showed that antibodies against C. pneumoniae correlated positively with expansion rate, not only in a Danish cohort but also in an English cohort. They measured immunoglobulin (Ig) G and IgA titres against C. pneumoniae by a microimmunofluorescence test. Multiple linear and logistic regression analyses showed that an IgA titre of ≥20 was a significant independent predictor of increased AAA expansion.41 The same results were found in the English cohort.42

However, antibiotic trials have been disappointing, and the presence and role of C. pneumoniae in the AAA-wall must be questioned. The possible link between Chlamydia serology and AAA was later also investigated by Falkensammer et al.43 in a case-control study. For 68 patients with AAA and age-matched controls, no differences were detected in the levels of IgA and IgG titres against C. pneumoniae. However, patients with IgA titres positive for C. pneumoniae showed faster progressing disease (defined as an annual increase of the aneurysm diameter of ≥0.5cm) compared to patients with negative IgA titres.

Nyberg A et al.44 examined the relationship between C pneumoniae seropositivity and AAA rupture; 119 patients with AAA and 36 matched controls were prospectively investigated with C pneumoniae serology. Patients with ruptured AAA had similar levels of IgG antibodies against C pneumoniae as patients with an electively operated AAA, a small AAA and controls. This study failed to demonstrate any association between C pneumoniae seropositivity and AAA rupture.

Overall there are no consistent findings relating C pneumoniae seropositivity to disease progression, however all 4 included studies were small.

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Conclusion 

Several potential biomarkers for the progression of AAA have been investigated. Most show either no correlation or a weak correlation with the clinical course of AAA. Few have any potential for clinical use (Table 1). SEP seems to be one of the better biomarkers to predict expansion and rupture, but a standardized ELISA and larger studies are needed. PAP complexes also may have clinical potential. MMP9 and IFN-γ may warrant further evaluation.

Many of the findings are from the Viborg cohort with substantial risk of chance findings. Another limitation relates to the fact that many biomarkers for AAA are not disease specific; most of them also are markers for atherosclerosis. AAA is a multifactorial disease; some aneurysms may have a stronger genetic component while environmental factors such as smoking play a greater role in others.

In the future, large longitudinal observational and intervention studies will be necessary to assess the true potential of matrix-turnover and other biomarkers. New methods, including proteomics and genome wide association studies, may identify new pathways and new potential biomarkers.

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Competing Interests 

None.

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PII: S1078-5884(08)00291-8

doi:10.1016/j.ejvs.2008.05.009

European Journal of Vascular & Endovascular Surgery
Volume 36, Issue 3 , Pages 273-280, September 2008

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