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The Inflammatory Pattern of Chronic Limb-Threatening Ischemia in Muscles: The TNF-α Hypothesis
Diego Caicedo1, Clara V Alvarez2, Sihara Perez-Romero2
1Angiology and Vascular Surgery Department, Complejo Hospitalario de Santiago de Compostela, 15706 Santiago de Compostela, Spain.
Insights
Vascular inflammation mediators like TNF-alpha and NOX4 are key in peripheral arterial disease (PAD) complications, especially in diabetes. Neutrophil-to-lymphocyte ratio (NLR) and TNF-alpha predict mortality in chronic limb-threatening ischemia (CLTI).
Area of Science:
- Investigates the molecular mechanisms underlying vascular inflammation in peripheral arterial disease (PAD).
- Focuses on the interplay between gene expression and plasma biomarkers in chronic limb-threatening ischemia (CLTI).
- Explores the role of specific mediators in the pathogenesis and prognosis of advanced PAD.
Background:
- Vascular inflammation is central to PAD, but involved mediators are not fully understood.
- Chronic limb-threatening ischemia (CLTI) represents an advanced stage of PAD with significant morbidity.
- Identifying key molecular players is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate gene expression and plasma biomarkers in patients with CLTI.
- To correlate molecular findings with clinical outcomes, including mortality.
- To explore the specific roles of TNF-alpha, hsCRP, NOX4, and NLR in PAD.
Main Methods:
- Analysis of plasma markers and mRNA expression from blood and ischemic muscle samples of GHAS trial patients.
- Utilized univariate (Spearman, t-Student, X²) and multivariate (logistic regression) statistical analyses.
- Assessed baseline characteristics, biomarker levels, gene expression, and 12-month cumulative mortality.
Main Results:
- Elevated plasma TNF-alpha (68.6%) and hsCRP (60.5%) were common in CLTI patients.
- Diabetic patients with high inflammation showed increased NOX4 expression (p=0.0346).
- Plasma TNF-alpha correlated negatively with NOS3 expression (p=0.015); hsCRP correlated negatively with VEGFA (p=0.005).
- NOX4 expression paralleled plasma TNF-alpha, particularly in diabetics (p=0.037).
- Neutrophil-to-lymphocyte ratio (NLR) ≥ 3 (p=0.019) and TNF-alpha ≥ 8.1 (p=0.048) predicted 12-month mortality.
- Optimal NLR cutoff for mortality prediction was 3.4.
Conclusions:
- NOX4 and TNF-alpha are critical in lower limb ischemia development and complications, especially in diabetes mellitus (DM).
- hsCRP may negatively impact angiogenesis.
- NLR and TNF-alpha are reliable mortality markers in CLTI, offering potential therapeutic targets.
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.
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