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Peripheral arterial disease (PAD) is an important manifestation of atherosclerosis, with increasing prevalence worldwide. A growing body of evidence shows that the systemic inflammatory response is closely related to the development, progression, and prognosis of atherosclerosis. In the last decade, several studies have suggested the role of measured inflammatory biomarkers as predictors of severity and prognosis in PAD in an effort to stratify the risk of these patients, to improve treatment selection, and to predict the results after interventions. A simple inflammatory marker, more available than any other, is the neutrophil–lymphocyte ratio (NLR), which can be easily obtained in clinical practice, based on the absolute count of neutrophils and lymphocytes from the differential leukocytes count. Many researchers evaluated vigorously the NLR as a potential prognostic biomarker predicting pathological and survival outcomes in patients with atherosclerosis. In this work, we aim to present the role of NLR as a prognostic marker in patients with PAD through a thorough review of the literature.
Peripheral arterial disease (PAD) is an important manifestation of atherosclerosis, which affects >202 million people worldwide,1 and is associated with cardiovascular events,2 with increased all-cause and cardiovascular mortality.3,4 PAD, despite the advances registered in its treatment, still has a worse prognosis compared with coronary artery disease (CAD)5 by various factors, including the high rate of in-stent restenosis, which occurs with an important contribution of the inflammatory response.6,7 These negative outcomes have brought in sight the need of biomarkers as predictors of outcomes to ensure better risk stratification, proper selection of treatment approaches, and, if necessary, additional multitarget approaches (such as the endovascular brachytherapy).8
In recent years, the literature has highlighted the value of systemic inflammation as an important element in the development, progression, and prognosis of atherosclerosis.9,10 It is worth to mention that PAD is the atherosclerotic manifestation that shows the greater relationship with systemic inflammation.11 Several inflammatory markers have been shown to be useful in clinical studies on risk stratification and prognosis of patients with PAD,12,13 as well as in those with disease in other vascular beds as cerebral and coronary.14–16
Among the inflammatory markers, neutrophil–lymphocyte ratio (NLR), defined as the ratio of absolute counts of neutrophils and lymphocytes, has gained space as an effective biomarker in the stratification and prognosis of atherosclerotic cardiovascular disease (CVD), and in particular PAD.17 The NLR is a derived marker, simple, relatively inexpensive, more available than any other, and has shown itself to be a good predictor for other multiple cardiovascular outcomes18–20 that reflect an imbalance in the inflammatory cells and the role of activated neutrophils in atherogenesis.21,22 In a representative sample from the National Health and Nutrition Examination Survey, including 9,427 subjects, the average NLR was 2.15 in the general population, being significantly higher in subjects who reported diabetes, CVD, and smoking than in those who did not.23
In this article, we reviewed the clinical studies that evaluated the role of inflammatory biomarkers as predictors of outcomes in patients with PAD, with particular emphasis on NLR.
Multiple inflammatory markers such as C-reactive protein (CRP) and interleukin-6 (IL-6) have been associated with cardiovascular events.15,24,25 CRP is associated with CAD, ischemic stroke, and mortality by vascular and nonvascular causes.15,26
On CAD, a high NLR is associated with severity of disease, as was evident in a cohort of 3,005 patients undergoing coronary angiography for several indications, in which those with NLR >3 had more advanced obstructive CAD (odds ratio [OR] 2.45, P<0.001) and worse prognosis, with higher rates of major cardiovascular events (hazard ratio [HR] 1.55, P=0.01) within 3 years of follow-up.27 NLR is a predictor of mortality in patients with ischemic heart disease both in stable CAD19 and in acute coronary syndrome.20,28,29 A high NLR at admission for acute coronary syndrome is associated with all-cause in-hospital (OR 2.04, P=0.013) and 6-month mortality (OR 3.88, P<0.001).18 In treated patients, a high pre-intervention NLR was an independent predictor of in-stent restenosis after percutaneous coronary intervention (OR 1.85, P<0.001),30 saphenous vein graft failure for those undergoing coronary artery bypass grafting,31 and cardiovascular mortality.32 In a meta-analysis of eight cohort studies with patients undergoing myocardial revascularization or coronarography, a high NLR increased about twice the risk of cardiovascular and all-cause mortality.33
In patients with stroke, the NLR is an independent mortality predictor in the short and long term.34–36 An NLR ≥5.9 at admission was associated with significant functional dependence (OR 6.72, P=0.025) and predicted mortality at 90 days (OR 6.69, P=0.006) after adjusting for potential confounders.37 In those patients with ischemic stroke who underwent carotid ultrasonography, NLR significantly predicted the degree of carotid stenosis in male patients.37 In a study in Turkey with patients who presented to the emergency service with cerebrovascular accident (stroke and transient ischemic attack), the NLR was significantly higher in patients who died (P<0.001) and in those with ischemic or hemorrhagic stroke than in those with transient ischemic attack (P<0.001).38
The role of NLR seems to begin even before the occurrence of any target organ damage, as was demonstrated in a cohort in which a higher NLR level significantly correlated with an increased risk of developing hypertension compared to participants with lower levels (OR 1.23; 95% confidence interval [CI] 1.06, 1.43).39 In other studies in hypertension, patients with nondipper pattern (that is associated with cardiovascular mortality) presented significantly higher mean NLR than those with dipper pattern (3.1±0.95 vs 1.8±0.52, P<0.001).40 NLR is also associated with resistant hypertension41 and other risk factors for atherosclerosis such as metabolic syndrome42 and diabetes.43 Table 1 summarizes the clinical studies on the predictive value of inflammatory biomarkers in cardiovascular outcomes.
Several studies have demonstrated the association between inflammatory markers and the incidence, severity, response to treatment, and prognosis of PAD.44–47 CRP was, in a cohort, the strongest nonlipidic predictor of PAD (relative risk [RR] 2.8 for the highest quartile in comparison to the lowest).44 In other studies, the CRP was a significant predictor of major adverse limb events (target vessel revascularization, amputation, or disease progression) and major cardiovascular events in patients with PAD who have undergone angioplasty or stent47 and a predictor of mortality.12,48
In patients being treated with statins for PAD, the benefit of reducing mortality from all causes and CVD was only significant in those with baseline CRP above the median and not in those with baseline CRP below the median (HR 0.44; 95% CI 0.23–0.88 vs HR 0.73; 95% CI 0.31–1.75).13 This result suggests that the benefit of statin is closely related to their anti-inflammatory effect, which is in accordance with the findings in patients with CAD, in which the benefit of statins in survival occurs mainly in subjects with high initial CRP, with fall during treatment, independent of lipid level.49,50 It has also been evident in the finding that statin mitigated plaque inflammation, measured by noninvasive imaging with 18F-fluorodeoxyglucose positron emission tomography.51,52 And, even in apparently healthy individuals, with elevated baseline high-sensitive CRP, treatment with statin reduced significantly the incidence of major cardiovascular events.53
Another inflammatory marker associated with PAD and its progression is the IL-6.46,54 In a cohort of 12 years of follow-up, IL-6 was the inflammatory marker that showed the strongest and consistent predictive value for progression of PAD.54 And, in patients with established PAD, persistently high IL-6 levels are associated with faster functional decline25 and greater severity of disease with critical limb ischemia (CLI).46 Table 2 summarizes the clinical studies on the predictive value of general inflammatory biomarkers (other than NLR) in PAD.
In PAD, a high NLR is associated with increased severity of disease,55,56 as was evident in a retrospective cohort of 2,121 patients with PAD in which CLI occurred significantly more in the group with a high NLR (48.5% vs 24.3%, P<0.001).56 In another study including 1,995 patients with PAD, the increase in NLR was associated with a significant increase in CLI rates (20.4%, 26.1%, and 36.1% for the first, second, and third tertiles, respectively).55
In patients who initially received conservative therapy for CLI, a high NLR was an independent predictive factor for amputation and was associated with lower amputation-free survival.57,58 A high NLR was a risk factor for amputation within 30 days in patients who underwent initial embolectomy for acute limb ischemia31 and an independent predictor of graft failure (occlusion or ipsilateral amputation) in those undergoing infrainguinal bypass grafting.59
A high NLR not only predicts disease severity and response to treatment but also is a predictor of mortality.60 In patients followed for PAD, a high NLR predicted independently long-term cardiovascular mortality (HR 2.04, P=0.004).60 A high NLR at admission for chronic CLI is associated with increased mortality.61
In treated patients, a high pre-intervention NLR was an independent predictor of mortality in those who have undergone infrapopliteal percutaneous intervention for CLI (HR 1.95, P<0.03).62 And, even in those undergoing elective revascularization, a high preoperative NLR was independently associated with increased mortality.63,64 Table 3 summarizes the clinical studies that have assessed the role of NLR as a prognostic biomarker in PAD.
Despite substantial epidemiological evidence of the predictive role of NLR in atherosclerotic manifestations, there is a lack of pathophysiological body for such findings. This derived marker is an imbalance of inflammatory cells (disproportionate dominance of neutrophils over lymphocytes), and it may be a reflection of a deeper imbalance in the immunologic response, with the dominance of effectors cells over the regulatory cells, mainly CD4+ T-helper cells.65,66 Some studies have described the domain of subtype T-helper 17 over the regulatory T-cells, resulting in the activation of the interleukin-17 axis that is in turn associated with vascular dysfunction, progression of atherosclerosis, and vascular events.65,67,68 Several other mechanisms may be involved in the link between NLR and atherosclerosis, including endothelial dysfunction69,70 and oxidative stress.71 However, in light of the current literature, there are no sufficient data to support the formulation of a conceptual or pathophysiologic model linking the two. Despite this gap, we know that atherosclerosis is mainly an inflammatory disease,72 and currently effective therapies, particularly statins, are associated with decreasing inflammatory response.49,51,52,73 The most accurate understanding of the mechanisms underlying this emerging evidence from clinical studies should be a substrate of a call to action for future studies in basic science, translational, experimental, and clinical levels.
Some concerns arise regarding the potential use of NLR as a cardiovascular biomarker. NLR is increased in other situations such as nonalcoholic fatty liver disease, metabolic syndrome, psoriasis, and cancer.42,74,75 All these conditions share in common an inflammatory or immune response in a given point of their pathogenesis, and interestingly, most of these have been also associated with CVDs as described by Ganzetti et al76 in his recent review. Despite being a nonspecific marker, NLR has shown consistency in predicting outcomes in atherosclerotic diseases,16–19,23,33–36,58–60 and even in the nationally representative sample of American subjects, NLR was significantly higher in those who reported diabetes, CVD, and smoking than in subjects who did not.23 In addition, NLR has a good correlation with other inflammatory markers such as CRP,77 presenting even better performance as a biomarker in specific conditions.78
There are some important limitations of this study. The first is the use of different cutoff values in different studies and the scarcity of published works validating the normality value in the general population. However, as we just underlined, most studies in atherosclerosis found a higher cutoff than the average NLR value (2.15) found in the only existing study in the general population,23 which suggests the plausibility of the association found in those studies. The second is the absence of studies that have validated the normality value for specific populations. This point is critical because as a derived ratio, it is, of course, affected by changes either in the numerator or the denominator. For example, subjects who have a relative constitutional lymphopenia would easily be classified as having a high NLR, without necessarily an increased inflammatory activity. So, it is prone to potential bias that could lead to false-positive associations. The third is relative to the paucity of studies clarifying the mechanisms underlying the association between NLR and atherosclerosis.
From the available evidence, it is very likely that the presence of a high NLR has predictive value for future vascular events in asymptomatic and symptomatic subjects. This simple, fast, and widely available biomarker can offer an additional noninvasive tool for risk stratification to assess the severity, response to treatment and prognosis of PAD.
More studies are necessary to know and clarify the role of NLR as an additional tool in PAD. This is reinforced because its role has been reproducible and consistent in other vascular beds as cerebral and coronary, especially in the current scenario of growing recognition of various diseases, with chronic inflammatory component as risk factors for atherosclerosis.
Further studies should be addressed to establish the normality value for specific populations to clarify the underlying mechanisms in atherogenesis and should be designed to assess the effectiveness of anti-inflammatory therapies using the fall of NLR as a surrogate outcome and assess its role to guide therapy.
The authors report no conflicts of interest in this work.