Elevated Composite Inflammatory Markers are Associated with Clinical Severity and Long-term Amputation Risk in Patients with Critical Limb Ischemia after Percutaneous Transluminal Angioplasty

Chronic limb-threatening ischemia (CLTI) represents the advanced stages of peripheral arterial disease (PAD) and is caused by atherosclerotic damage in the lower limbs.^1,2 According to the Leriche-Fontaine classification,³ patients with CLTI present the following stages: stage III with rest pain and stage IV with trophic lesions.^1,2,3 Patients with CLTI typically present with advanced age, a higher incidence of comorbidities and risk factors, as well as a greater risk of major amputation.^1,2,4

Patients with CLTI exhibit a higher level of systemic inflammatory status than healthy controls⁵ and those in the initial stages of PAD.^6,7 Recently, intensive research in vascular surgery has been conducted on inflammatory biomarkers derived from blood counts, such as the neutrophil-to-lymphocyte ratio (NLR), the monocyte-to-lymphocyte ratio (MLR), and the platelet-to-lymphocyte ratio (PLR).^{5,6,7,8,9,10,11,12,13,14} Currently, none of the biomarkers mentioned above are used in medical practice. As a result, composite biomarkers have been developed, such as the systemic immune index (SII), the systemic inflammation response index (SIRI), and the aggregate index of systemic inflammation (AISI).⁹ However, few articles have been published on the prognostic role of SII, SIRI, and AISI in vascular surgery, especially in patients with PAD, and to our knowledge, they have not been analyzed in patients with CLTI treated with endovascular interventions.

The aim of this study was to analyze the impact of SII, SIRI, and AISI on the clinical severity and long-term risk of major amputation in patients with CLTI after percutaneous transluminal angioplasty (PTA).

The study included 104 patients with CLTI, with an average age of 70.59 ± 9.13 years. Of these patients, 81 (71.88%) were male. In terms of clinical presentation, 44 patients (42.30%) had stage III Leriche-Fontaine, and 60 patients (57.70%) had stage IV Leriche-Fontaine (Table 1). There were no statistically significant differences between the two groups in terms of demographic data, comorbidities, and risk factors (Table 1). However, patients in stage IV had increased levels of leukocytes (p = 0.005), neutrophils (p = 0.002), and monocytes (p < 0.001), as well as lower levels of hemoglobin (p = 0.030) (Table 1). There was also no significant difference in the risk of major amputation and length of stay between the two groups (Table 1).

Additionally, we analyzed the severity of atherosclerotic lesions in the superficial femoral artery, popliteal artery, and infra-popliteal artery. Patients with stage IV Leriche-Fontaine had a higher incidence of PA occlusion (p = 0.036), subocclusive ATA stenoses (p = 0.007), and peroneal artery occlusion (p = 0.031) (Table 2).

We observed higher levels of three inflammatory biomarkers, the SII (p = 0.027), SIRI (p = 0.0008), and AISI (p = 0.0024) in patients with trophic lesions (Figure 1). Furthermore, the levels of these biomarkers were also higher in patients who underwent major amputation during the follow-up (Figure 2).

FIGURE 1.

Graphical representation of the differences in SII (A), SIRI (B), and AISI (C) inflammatory biomarker values between patients with stage III and stage IV according to the Leriche-Fontaine classification

FIGURE 2.

Graphical representation of the differences in SII (A), SIRI (B), and AISI (C) inflammatory biomarker values between patients with and without major amputation during follow-up

We performed a ROC analysis to determine the correlation between SII, SIRI, and AISI values at baseline and the two endpoints. Our findings indicate that SIRI (AUC, 0.698; p < 0.001 and AUC, 0.712; p < 0.001) and AISI (AUC, 0.680; p = 0.001 and AUC, 0.698; p = 0.003) are useful predictors of clinical severity and the risk of major amputation in the long term. On the other hand, although the findings suggest that SII is a useful prognostic factor of major amputation (AUC, 0.731; p = 0.001), it may not be a reliable predictor of clinical severity (p = 0.052) (Table 3).

According to the Kaplan–Meier graph presented in Figure 3, patients with values of SII (p = 0.008), SIRI (p = 0.022), and AISI (p = 0.006) above the median at the time of admission are at a higher risk of major amputation in the long term, following PTA.

FIGURE 3.

Kaplan–Meier graph showing the incidence of major amputation during follow-up, categorized by the median values of SII (A), SIRI (B), and AISI (C)

We also performed a multivariate regression analysis to identify risk factors that can predict clinical severity. Our findings suggest that high baseline values of SIRI (OR = 2.28; p = 0.017) and AISI (OR = 2.32; p = 0.043), but not SII (OR = 1.71, p = 0.055), are associated with stage IV Leriche-Fontaine (Table 4). Additionally, the results of the Cox regression analysis suggest that SII (HR = 1.56; p = 0.010), SIRI (HR = 1.63; p = 0.009), and AISI (HR = 1.55; p = 0.016) are predictive factors for long-term risk of major amputation after following PTA (Table 4).

The main findings of our study present for the first time, to our knowledge, that composite inflammatory biomarkers SII, SIRI, and AISI can predict the clinical severity and the risk of major amputation in the long term after endovascular treatment for CLTI.

The development of atherosclerotic plaques is influenced by several factors,^{9,12,24,25,26,27,28,29,30,31,32,33,34} including cardiovascular risk factors,^9,12,24,25 changes in local hemodynamics and biomechanics,^{26,27,28,29,30} and high levels of inflammation.^31,32,33,34 Patients with CLTI have a poor prognosis,^1,2 and studies have shown that those with high levels of inflammatory markers are at a greater risk of amputation and long-term mortality.^35,36 There is also evidence that patients with PAD have a more pro-inflammatory genetic profile than healthy individuals, and that this is further potentiated by the severity of the disease.³⁷ Furthermore, Gremmels et al.³⁶ have found that interleukin 6 (HR = 1.35; p = 0.01) and interferon gamma-inducible protein 10 (HR = 1.49; p = 0.006) can predict major events in patients with severe limb ischemia.

In a recent study by Ferreira et al.,³⁸ it was observed that patients with CLTI had a smaller skeletal muscle area (p = 0.013) and higher levels of inflammatory biomarkers, such as C-reactive protein (p < 0.001), fibrinogen (p < 0.001), serum albumin (p = 0.001), and total cholesterol (p = 0.013), than those with claudication. The same authors conducted another study, which showed that in patients with CLTI, more CD45+ leukocyte inflammatory cells were found in muscle biopsies at the level of the sartorius muscle (p = 0.034).³⁹ These changes can have an irreversible effect on the muscles of the lower limb, increasing the risk of major amputation in the long term. Ferreira et al.⁴⁰ conducted a study to examine changes in inflammatory biomarkers at admission, at 3 months, and at 6 months in patients who underwent successful revascularization treatment. The results showed that there was an increase in C-reactive protein and fibrinogen levels and a decrease in serum albumin and total cholesterol levels at 3 months after revascularization, but no significant changes were observed at 6 months.⁴⁰ The study concluded that prompt revascularization can partially reverse the inflammatory status of patients.

Recently, various inflammatory biomarkers have been proposed for cardiovascular disease, including SII, SIRI, and AISI, derived from blood cell counts. In this study, we have demonstrated the predictive role of these biomarkers regarding the clinical severity of PAD and the risk of major amputation in patients with CLTI, following PTA treatment. Studies by Candemir et al.⁴¹ and Mangalesh et al.⁴² have shown that high baseline SII values predict the severity of atherosclerotic lesions in patients with stable⁴¹ or acute coronary syndrome.⁴² On the other hand, Yang et al.⁴³ have found that SII has a prognostic role superior to the usual risk factors in nonfatal myocardial infarctions, nonfatal stroke, and cardiac death in a cohort of 5,602 patients with coronary artery disease. Similarly to our results, Oflar et al.⁴⁴ found a positive correlation between SII values and the severity of PAD (r = 0.363; p < 0.001). Additionally, Aktemur et al.⁴⁵ demonstrated that SII can predict long-term mortality after PTA in patients with iliac artery disease (OR = 3.346; p < 0.001).

There are a few studies on the prognostic value of SIRI in cardiovascular disease.^{46,47,48,49,50,51} Wang et al.⁴⁶ found that high SIRI values are associated with the presence of cardiovascular disease and metabolic disorders. Xia et al.⁴⁷ demonstrated that elevated SII and SIRI are associated with cardiovascular mortality and all-cause mortality. In addition, Dziedzic et al.,⁴⁸ Li et al.,⁴⁹ Liu et al.,⁵⁰ and Han et al.⁵¹ found that high SIRI values are associated with the severity of coronary disease and with the evolution of patients with myocardial infarction after percutaneous coronary intervention. Although AISI has not yet been analyzed in patients with PAD or CLTI, our study marks the first analysis of this biomarker, and we have demonstrated its predictive role in clinical severity and major amputation risk following PTA treatment.

There are some limitations to this study that need to be mentioned. First, it is an observational retrospective study that included patients from a single center. In the future, we need prospective studies that involve multiple centers to validate our findings and establish biomarker threshold values. Second, the study only involved patients with stage III–IV Leriche-Fontaine, therefore our results cannot be extrapolated to patients with stage I–II Leriche-Fontaine. Last, we could not obtain accurate data on the degree of restenosis after PTA because we relied on patients’ self-reporting of major amputations.

This study found elevated levels of SIRI and AISI to be linked with the severity of clinical symptoms and an increased risk of major amputation in the long term in patients with CLTI following PTA. Additionally, higher baseline values for SII were associated with a greater risk of major amputation, but not with clinical severity in the same group of patients. In the future, composite biomarkers derived from blood cell counts could be used to better identify patients at risk and personalize their therapeutic strategies. These biomarkers are highly accessible and cost-effective, making them a promising tool for health-care professionals.