Table 1.

Summary of discussed study characteristics on potential neutrophil-derived biomarkers in AAA.

Neutrophil-Derived Factor	Diagnosis	Prognosis	Surgical Outcome	Rupture
Neutrophil-to-lymphocyte ratio	↑ NLR associated with AAA disease, increased rupture risk, elevated cardiovascular risk, and mortality as well as higher postoperative reintervention rates [89]	NLR failed to predict AAA and ILT growth over the next 6 months (unpublished data, n.s.)	NLR > 5 showed higher 30-day mortality after OSR [86] ↑ NLR within 1 week after OSR or EVAR associated with postoperative complications [87] preoperative ↑ NLR increased 5-year mortality and 30-day, 1-year, 5-year reintervention rates after EVAR [88]	↑ NLR (9.3 vs. 3.39) in patients with ruptured compared to intact AAA [86] NLR > 5 indicated a 5-fold increased risk of AAA rupture [86]
Neutrophil gelatinase-associated lipocalin	highest concentrations of NGAL/MMP-9 complexes were found in the luminal part of the ILT (compared to abluminal and central ILT layers, aneurysm wall and interface fluid) [91,92] surrogate marker for ILT biological activity [94]	reflects rather than predicts AAA growth [94]	serum and urine NGAL as renal predictors of acute kidney injury in AAA patients undergoing OSR [99]	↑ NGAL blood concentrations in ruptured AAA patients (compared to non-ruptured controls) [98] ↑ NGAL expression in tissue of ruptured AAA compared to nondilated aortas [98]
Neutrophil elastase	↑ NE blood levels in AAA patients compared to non-AAA controls [108,110] elastin-derived peptides induced NE release in AAA patients > aortic occlusive disease > healthy controls [108,109,110] ↑ circulating NE-derived fibrin degradation products in AAA patients correlated with AAA and ILT volume and ILT mechanical stress [115,116]		↑ NE/α1-antitrypsin complexes after OSR and EVAR; ↓ free elastase levels after OSR, but ↑ after EVAR [117] ↑ NE/α1-antitrypsin complexes only after OSR compared to EVAR, especially on the first day after surgery; EVAR was linked to a reduced postoperative systemic inflammatory response [118]
Myeloperoxidase	AAA patients: two times higher plasma MPO levels compared to healthy controls and more than eleven times higher MPO concentrations in aortic tissue [54] plasma and tissue-released MPO levels correlated with the maximal AAA diameter [54] MPO combined with D-dimer reached in a diagnostic score a sensitivity of 73% and specificity of 80% [54]	↑ baseline MPO concentration was significantly associated with faster AAA progression, independent of aortic baseline diameter [123] MPO combined with D-dimer in a prognostic score outperformed D-dimer alone by identifying patients with rapid AAA growth (≥2 mm over the next 6 months) with 72% sensitivity and 67% specificity [54]
Neutrophil extracellular traps	↑ citrullinated histones and cell-free DNA in the plasma and tissue of AAA patients [96,126,128] ↑ citH3 plasma levels in AAA patients compared to healthy controls [130] highest concentration of NET components in the adventitia, depositions of citrullinated histones in the ILT [126,128,130]	baseline citH3 levels exceeding 194 ng/mL indicated fast aneurysm expansion (≥2 mm diameter increase over 6 months in CTA) as prognostic marker value, with 77% sensitivity and 64% specificity [130]	normalization of plasma citH3 levels after OSR and EVAR [130]
Neutrophils and associated cytokines	↑ plasma concentrations of IL-1, IL-2, IL-6, IL-8 and TNF-α in AAA patients compared to healthy individuals [132,133,134,135] pro-inflammatory (IL-1α, IL-1β, IL-6, IL-8, TNF-α, TNF-β, oncostatin M) and anti-inflammatory (IL-10) cytokines were upregulated in AAA tissue compared to non-aneurysmal controls [131] ↑ IL-1β levels in tissue-conditioned medium of AAA patients (but not of ILT) compared to aortas from transplant donors [130] ILT displayed a negative IL-8 gradient from the luminal to the abluminal layer, IL-8 was associated with neutrophil presence at the luminal pole of the ILT, released IL-8 concentrations by ILT were fourfold higher compared to the aortic wall (media and adventitia) [40]	plasma IL-6 levels increased with AAA size [136] serum concentration of IL-6 predicts AAA growth in a mathematical model, but clinical relevance remains to be elucidated [137] plasma IL-10 positively correlated with the annual AAA expansion rate [138]	seventeen studies identified a significantly ↑ systemic inflammatory response after OSR with ↑ cytokine levels, especially of IL-6 and IL-8; some studies yielded contradictory results or showed no differences between OSR and EVA regarding levels of IL-1β, IL-10, and TNF-α [145] post-interventional normalization of the inflammatory state, preoperative serum levels (50–100 pg/mL) of IL-1α and IL-8 significantly dropped six months post-EVAR [146] preoperative IL-1α serum concentrations correlated with AAA size, serum IL-1α levels and neutrophil recruitment decrease post-EVAR [146]	↑ TNF-α levels in asymptomatic AAA patients compared to patients with either symptomatic AAA or aneurysm rupture [132,133,135] ↑ pro-inflammatory IL-6, IL-8, and TNF-α levels in plasma and aortic tissue extracts of ruptured AAA patients [139,140,141] ↓ anti-inflammatory IL-10 levels in AAA patient plasma or explanted AAA lesion culture [140,142,143] Conflicting results report ↑ IL-10 plasma levels in ruptured compared to non-ruptured AAA patients, may be a compensatory anti-inflammatory response [141]
Matrix metallo-proteinases and their inhibitors	MMP-1, MMP-2, MMP-3, MMP-9, MMP-12, MMP-13 are most common in AAA tissue [2,151,152,153] MMP-2 as a candidate gene for AAA formation [165] ↑ MMP-2 levels in AAA tissue, but systemic MMP-2 levels cannot predict the expansion of small AAA [166] ↑ aortic tissue MMP-7 expression and associated smooth muscle cell apoptosis [168] most abundant MMP-9 mRNA levels 20 and 2 times higher expressed than MMP-1 and MMP-2 transcripts, respectively [156] circulating MMP-9 levels were linked to AAA presence and ↑ MMP-9 concentrations in AAA patients compared to controls [157] ↑ MMP-9 and IL-6 levels were associated with future risk of developing AAA [158] MMP-9 expression correlated with AAA diameter (>50 mm diameter) and ILT thickness [159,161] ↑ MMP-1 levels in AAA tissue compared to organ transplant donors [164] 1.8-fold ↑ aortic tissue MMP-13 concentration in AAA compared to atherosclerotic aortas, but no expression in tissue of organ transplant donors [169] ↑ plasma TIMP-1 concentrations in AAA patients compared to healthy controls, but ↓ TIMP-1 levels in AAA wall compared to healthy aortic tissue [177,178]	plasma MMP-9 concentrations were associated with increased AAA growth rates, larger ILT and high aortic wall stress [160]	↑ preoperative plasma MMP-9 levels were associated with non-survival at 30 days from rupture surgery, MMP-9 as survival indicator [163]	↑ plasma MMP-1 levels were associated with increased rates of AAA rupture and reduced survival [163] ↑ MMP-8 and MMP-9 levels at the aneurysmal rupture site compared to anterior wall biopsies of the same AAA patients [162] A threefold ↑ of MMP-8 activity, a fivefold ↑ in the cysteine proteases K and L and a 30-fold ↑ in cathepsin S activation in developing and ruptured AAA compared to organ transplant donors [170] immunohistochemical MMP-8 abundance in growing and ruptured AAA [170] ↓ preoperative TIMP-1 plasma concentrations in (fatal) ruptured AAA patients compared to survivors or non-ruptured AAA patients (n.s.) [163] ↑ plasma TIMP-1 levels in AAA patients served as predictor of fatal AAA rupture [179]
Human neutrophil peptides	↑ plasma levels in AAA patients detectable within the ILT: luminal > abluminal, correlated with maximal ILT thickness [40,185]
Endothelin	↑ levels identified large (≥50 mm) vs. small (<50 mm) AAA [189]	↑ levels predict AAA growth above median (2.5 mm per year) [190]	↓ levels in ruptured, but successfully operated (OSR) and surviving AAA patients compared to patients with fatal postoperative organ failure [191]

Abbreviations: NLR, neutrophil-to-lymphocyte ratio; AAA, abdominal aortic aneurysm; ILT, intraluminal thrombus; n.s., not significant; OSR, open surgical repair; EVAR, endovascular aneurysm repair; NGAL, neutrophil gelatinase-associated lipocalin; MMP, matrix metalloproteinase; NE, neutrophil elastase; MPO, myeloperoxidase; citH3, citrullinated histone H3; CTA, computed tomography angiography; IL, interleukin; TNF, tumor necrosis factor; TIMP, tissue inhibitor of metalloproteinase; ↑, increased; ↓, decreased.