Table 1.
Inflammatory biomarkers in lower limb PAD diagnosis and prognosis.
| Assessed Biomarkers | Type of Biomarker | Studied Groups (n) | Outcome | Refs. |
|---|---|---|---|---|
| CRP, D-dimer, fibrinogen, NT-proBNP and cTnT | Prognosis | Systematic review and meta-analysis with 47 studies, 1990–2015. PAD patients (21,473). Minimum follow up 1 year. | Increased CRP (RR: 3.49, 95% CI: 2.35–5.19), D-dimer (RR: 2.22, 1.24–3.98), fibrinogen (RR: 2.08, 95% CI: 1.46–2.97), NT-proBNP (RR: 4.50, 95% CI: 2.98–6.81) and cTnT (RR: 3.33, 95% CI: 2.70–4.10) predicted risk of mortality in PAD patients. Association of CRP with MACE (RR: 1.86, 95% CI: 1.48–2.33). |
[10] |
| CRP | Prognosis | Systematic review and meta-analysis with 16 studies, 2002–2017. Participants (5041). Minimum follow up 1 year. | Higher CRP levels predict MACE in PAD patients (HR: 1.38, 95% CI: 1.16–1.63, per unit increase in logeCRP). | [11] |
| CRP | Diagnosis Prognosis |
PAD patients (317) and healthy controls (100). Mean follow up 3.6 years. | Increased CRP levels in PAD patients. Predictor of amputation (SHR: 1.76, 95% CI: 1.48–2.09) and MACE (amputation and CV mortality) (SHR: 1.53, 95% CI: 1.35–1.75). | [14] |
| CRP | Diagnosis | Prospective cohort (14916); symptomatic PAD (140) and healthy controls (140). Mean follow up 9 years. | Associated to incident PAD (RR: 2.8, 95% CI: 1.3–5.9). | [19] |
| CRP | Diagnosis | ARIC Study 1996–1998. Participants (9851), cases of PAD (316). Median follow up 17.4 years. | Associated to incident PAD and CLI (HR per 1 SD increase: 1.34, 95% CI: 1.18–1.52 and 1.34, 95% CI: 1.09–1.65, respectively). | [20] |
| CRP, IL-6 & TNF-α | Diagnosis | PAD patients (55) and healthy controls (34). | Increased CRP, IL-6 and TNF-α levels in PAD patients. IL-6 associated to PAD severity (ABI ≤ 0.90). | [21] |
| CRP, IL-6, TNF-α & ICAM-1 | Diagnosis | PAD patients with intermittent claudication (75) and healthy subject (43). | Increased CRP, IL-6, TNF-α and ICAM-1 levels in PAD patients and inversely associated with maximal walking distance. | [22] |
| CRP, IL-6, TNF-α & VCAM-1 | Diagnosis Prognosis |
PAD patients (60) and healthy controls (50). Mean follow up of 2.24 years. | Increased CRP, IL-6 and TNF-α levels in PAD patients. CRP, IL-6, TNF-α and ICAM-1 associated with ABI. PAD patients with CRP > 1 mg/L had 4-fold higher risk of ischemic event or death. | [23] |
| CRP, IL-6, ICAM-1 & D-dimer | Diagnosis | PAD patients (62) and healthy controls (18). | Increased CRP, IL-6, ICAM-1 and D-dimer levels in PAD patients. | [24] |
| CRP, IL-6, TNF-α, ICAM-1 & fibrinogen | Diagnosis Prognosis |
Framingham Offspring Study 1998–2001. Participants (2800), ABI < 0.9 (111). | CRP, IL-6, TNF-α and fibrinogen inversely associated to ABI. IL-6 related to ABI (OR: 1.21, 95% CI: 1.06–1.38) and intermittent claudication or lower extremity revascularization (OR: 1.36, 95% CI: 1.06–1.74). | [26] |
| CRP, IL-6, ICAM-1 & VCAM-1 | Diagnosis | Edinburgh Artery Study 1988. Participants (2800). Follow up 5 and 12 years. | CRP, IL-6, ICAM-1 and VCAM-1 associated to PAD severity. IL-6 predicted ABI at 5 and 12 years. | [27] |
| CRP | Prognosis | PAD patients with (29) or without (38) adverse CV events. Follow up 5 years. | CRP levels were higher in PAD subjects with adverse CV events. | [28] |
| CRP | Prognosis | PAD patients (397). Average follow up 6.6 years. | CRP predicts total mortality at 2-years follow-up (HR = 1.56 per SD). | [29] |
| CRP & D-dimer | Prognosis | PAD patients (377). Follow up 4 years. | CRP and D-dimer predicts all-cause mortality within 1 and 2 years of follow-up (HR: 1.15, 95% CI: 1.06–1.24 and 1.14, 95% CI: 1.02–1.27, respectively). | [30] |
| CRP, D-dimer & fibrinogen | Diagnosis | PAD patients (45) and healthy controls (44). | CRP, D-dimer and fibrinogen were higher in PAD and associated to ABI. | [31] |
| CRP | Diagnosis | PAD patients (463). Mean follow up 6.1 years. | Higher CRP levels in patients with CLI compared to IC. | [25] |
| CRP | Prognosis | PAD patients (68). Follow up 6 months. | Pre- and post-operative (24 h) IL-6 levels and post-operative (24 h) CRP levels associated with six-month in-stent restenosis (OR: 1.11, 95% CI: 1.00–1.23, 1.04, 95% CI: 1.02–1.06 and 1.15, 95% CI: 1.04–1.26, respectively). | [32] |
| IL-6, TNF-α, ICAM-1 & VCAM-1 | Diagnosis | PAD patients (20) and healthy controls (20). | Circulating IL-6, TNF-α, ICAM-1 and VCAM-1 levels were higher in PAD patients. | [33] |
| IL-6, TNF-α, ICAM-1 & VCAM-1 | Diagnosis | PAD patients (80) and healthy controls (72). | All inflammatory and adhesion markers were higher in PAD patients. | [34] |
| CRP, IL-6, ICAM-1, VCAM-1 and D-dimer | Diagnosis | PAD patients (423). | CRP, IL-6, ICAM-1, VCAM-1 and D-dimer related to impaired lower limb functionality. | [35] |
| IL-6 | Diagnosis | PAD patients (38). 1 year follow up. | Higher IL-6 levels were related to impaired walking distance. | [36] |
| VCAM-1 | Diagnosis | PAD patients (51) and healthy controls (75). | VCAM-1 is increased in PAD patients. | [37] |
| ICAM-1, VCAM-1 & D-dimer | Diagnosis | PAD patients (60) and healthy controls (20). | ICAM-1, VCAM-1 and D-dimer increased in CLI patients. | [38] |
| Fibrinogen | Prognosis | FRENA registry. PAD patients (1363). Mean follow up 18 months. | High fibrinogen associated with ischemic events (HR: 1.61, 95% CI: 1.11–2.32) or major bleeding (HR: 3.42, 95% CI: 1.22–9.61). | [39] |
| Fibrinogen | Prognosis | LEADER trial 1992-2001. PAD patients (785). Follow up 3 years. | Fibrinogen predictor of death at 6 months (OR: 1.65, 95% CI: 0.96–2.73) and 3 years (OR: 1.44, 95% CI: 1.02–1.94). | [40] |
| Fibrinogen | Prognosis | PAD patients (486). Median follow up 7 years. | Fibrinogen levels predict risk of all-cause mortality (HR: 1.90, 95% CI: 1.11–3.41 for fibrinogen >12.2μmol/L) and CV death (HR: 2.68, 95% CI: 1.39–5.16 for fibrinogen >12.2 μmol/L). | [41] |
| D-dimer | Prognosis | BRAVO study 2009. PAD patients (595). Follow up 3 years. | D-dimer levels were increased in PAD patients 2 months before an ischemic heart event. | [42] |
| NLR | Diagnosis | PAD patients (733). Median follow-up 10.4 months. | Elevated NLR associated with severe PAD (OR: 1.07, 95% CI: 1.00–1.15). | [43] |
| NLR | Diagnosis | PAD patients (300). | NLR inversely associated with ABI. | [44] |
| NLR | Diagnosis | PAD patients (153) and controls (128). | NLR correlated to PAD severity. | [45] |
| NLR | Prognosis | CLI patients (172). Mean follow up 34.7 months. | NLR predicted amputation risk (HR: 1.14, 95% CI: 1.08–1.19). | [46] |
| NLR | Prognosis | PAD patients (593). Median follow-up 20 months. | High NLR (>3.0) was an independent predictor of long-term cardiovascular mortality (HR: 2.04, 95% CI: 1.26–3.30). | [47] |
| NLR | Prognosis | PAD patients (95). Follow up 2 years. | Postoperative high NLR (≥2.75) predicts target vessel revascularization (HR: 3.1, 95% CI: 1.3–7.7) in PAD subjects after angioplasty with stent implantation. | [48] |
| NLR | Prognosis | CLI patients (561). Median follow up 31 months. | Preoperative high NLR (>5) correlated with 5-year amputation-free survival (HR: 2.32, 95% CI 1.73–3.12) in PAD patients subjected to infrainguinal revascularization. | [49] |
| NLR | Prognosis | PAD patients (1228). Minimum follow up 1 year. | Preoperative NLR associated with MALE (HR: 1.09, 95% CI: 1.07–1.11) and 10-year mortality (HR: 1.09, 95% CI: 1.07–1.12) after revascularization (stenting/bypass graft). | [50] |
| NLR | Prognosis | PAD patients (83). Follow-up period 12 months. | PAD patients with high NLR (≥5.25) had increased risk of death (HR: 1.97, 95% CI: 1.08–3.62) compared with low NLR subjects (<5.25). | [51] |
CRP, C reactive protein; IL-6, interleukin-6; TNF-α, tumor necrosis factor α; ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion molecule 1; NLR, neutrophil-to-lymphocyte ratio; ABI, Ankle brachial index; MACE, major adverse cardiovascular events; MALE, major adverse limb events; PAD, peripheral arterial disease; IC, intermittent claudication; CLI, Critic limb ischemia; HR, Hazard ratio; SHR, Sub-Hazard ratio; RR, Relative risk; SD, standard deviation.