The Inflammatory Pattern of Chronic Limb-Threatening Ischemia in Muscles: The TNF-α Hypothesis

Abstract

Background: Vascular inflammation plays a crucial role in peripheral arterial disease (PAD), although the role of the mediators involved has not yet been properly defined. The aim of this work is to investigate gene expression and plasma biomarkers in chronic limb-threating ischemia (CLTI). Methods: Using patients from the GHAS trial, both blood and ischemic muscle samples were obtained to analyze plasma markers and mRNA expression, respectively. Statistical analysis was performed by using univariate (Spearman, t-Student, and X2) and multivariate (multiple logistic regression) tests. Results: A total of 35 patients were available at baseline (29 for mRNA expression). Baseline characteristics (mean): Age: 71.4 ± 12.4 years (79.4% male); TNF-α: 10.7 ± 4.9 pg/mL; hsCRP:1.6 ± 2.2 mg/dL; and neutrophil-to-lymphocyte ratio (NLR): 3.5 ± 2.8. Plasma TNF-α was found elevated (≥8.1) in 68.6% of patients, while high hsCRP (≥0.5) was found in 60.5%. Diabetic patients with a high level of inflammation showed significantly higher levels of NOX4 expression at baseline (p = 0.0346). Plasma TNF-α had a negative correlation with NOS3 (eNOS) expression (−0.5, p = 0.015) and plasma hsCRP with VEGFA (−0.63, p = 0.005). The expression of NOX4 was parallel to that of plasma TNF-α (0.305, p = 0.037), especially in DM. Cumulative mortality at 12 months was related to NLR ≥ 3 (p = 0.019) and TNF-α ≥ 8.1 (p = 0.048). The best cutoff point for NLR to predict mortality was 3.4. Conclusions: NOX4 and TNF-α are crucial for the development and complications of lower limb ischemia, especially in DM. hsCRP could have a negative influence on angiogenesis too. NLR and TNF-α represent suitable markers of mortality in CLTI. These results are novel because they connect muscle gene expression and plasma information in patients with advanced PAD, deepening the search for new and accurate targets for this condition.

Inflammatory Markers Used as Predictors of Subclinical Atherosclerosis in Patients with Diabetic Polyneuropathy

“…An analysis of recently published articles reveals that among these inflammatory markers, NLR, MLR, PLR, and SII have emerged as valuable predictors of vascular disease. Numerous works have highlighted their predictive potential in this context [ 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ].…”

Narrative Review of Biological Markers in Chronic Limb-Threatening Ischemia

“…Caicedo et al [35] studied TNF-α in 35 patients with CLTI and found increased levels (≥8.1) in 68.6% of patients and concluded that this marker is very important in the progression of ischemia, especially in diabetic patients.…”

Growth hormone (GH) benefits for the treatment of lower limbs ischemia

“… La rhGH aplicada a los animales pareció mostrar ventajas de recuperación tras la isquemia en los animales, medidas por la PPG y escalas clínicas y funcional de valoración, si bien ninguna de ellas resultó ser significativa. En nuestro estudio, el TNF-α estaba aumentado en el 70 % de los pacientes con CLTI (22). Y, aunque finalmente no pudieron medirse los niveles en sangre de IL-6, debemos señar que la producción de IL-6 es también en gran parte dependiente de TNF-α y, por tanto, esta última molécula debe desempeñar un rol principal en la isquemia (23), aunque pueda haber diferencias con la enfermedad coronaria (24).…”