Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Genetics of Vascular Inflammation in Lower Limb Ischemia: The TNF-α Hypothesis in Peripheral Arterial Disease

Version 1 : Received: 30 November 2021 / Approved: 3 December 2021 / Online: 3 December 2021 (09:44:42 CET)

A peer-reviewed article of this Preprint also exists.

Caicedo, D.; Alvarez, C.V.; Perez-Romero, S.; Devesa, J. The Inflammatory Pattern of Chronic Limb-Threatening Ischemia in Muscles: The TNF-α Hypothesis. Biomedicines 2022, 10, 489. Caicedo, D.; Alvarez, C.V.; Perez-Romero, S.; Devesa, J. The Inflammatory Pattern of Chronic Limb-Threatening Ischemia in Muscles: The TNF-α Hypothesis. Biomedicines 2022, 10, 489.

Journal reference: Biomedicines 2022, 10, 489
DOI: 10.3390/biomedicines10020489

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 analy-sis was performed by using univariate (Spearman, t-Student, X2) and multivariate (multiple lo-gistic regression) tests. Results: 35 patients were available at baseline (29 for mRNA expression). Baseline characteristics (mean): Age:71.4±12.4 (79.4% male); TNF-α:10.7±4.9; hs-CRP:1.6±2.2; Neutrophil-to-lymphocyte ratio (NLR):3.5±2.8. Plasma TNF-α was found elevated (≥8.1) in 68.6% of patients, while high hs-CRP (≥0.5) in 60.5%. Diabetic patients with high level of inflammation showed significantly higher levels of NOX4 expression at baseline (p=0.0346). Plasma TNF-α had a negative correlation with eNOS expression (-0.5, p=0.015) and hs-CRP with VEGF-A (-0.63, p=0.005). The expression of NOX4 was parallel to that of plasma TNF-α (0.305, p=0.037), especial-ly in DM. Cumulative mortality at 12-month was related to NLR ≥3 (p=0.019) and TNF-α ≥8.1 (p=0.048). The best cut-off 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. hs-CRP could have a negative influence on angiogenesis too. NLR and TNF-α represent suita-ble markers of mortality in CLTI. These results are novel because they connect muscle gene expres-sion and plasma information in patients with advanced PAD, deepening the search of new and ac-curate targets for this condition.

Keywords

Vascular inflammation; Peripheral arterial disease (PAD); Chronic limb-threatening ischemia (CLTI); GHAS trial; TNF-α; hs-CRP; Neutrophil-to-lymphocyte ratio (NLR); NOX4; eNOS; VEGF-A.

Subject

MEDICINE & PHARMACOLOGY, General Medical Research

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