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. 2019 Sep 14;8(9):1463.
doi: 10.3390/jcm8091463.

Altered Metabolomic Profile in Patients with Peripheral Artery Disease

Ahmed Ismaeel  1 , Marco E Franco  2 , Ramon Lavado  2 , Evlampia Papoutsi  1 , George P Casale  3 , Matthew Fuglestad  3 , Constance J Mietus  3 , Gleb R Haynatzki  4 , Robert S Smith  5 , William T Bohannon  5 , Ian Sawicki  5 , Iraklis I Pipinos  3 , Panagiotis Koutakis  6
Affiliations

Altered Metabolomic Profile in Patients with Peripheral Artery Disease

Ahmed Ismaeel et al. J Clin Med. .

Abstract

Peripheral artery disease (PAD) is a common atherosclerotic disease characterized by narrowed or blocked arteries in the lower extremities. Circulating serum biomarkers can provide significant insight regarding the disease progression. Here, we explore the metabolomics signatures associated with different stages of PAD and investigate potential mechanisms of the disease. We compared the serum metabolites of a cohort of 26 PAD patients presenting with claudication and 26 PAD patients presenting with critical limb ischemia (CLI) to those of 26 non-PAD controls. A difference between the metabolite profiles of PAD patients from non-PAD controls was observed for several amino acids, acylcarnitines, ceramides, and cholesteryl esters. Furthermore, our data demonstrate that patients with CLI possess an altered metabolomic signature different from that of both claudicants and non-PAD controls. These findings provide new insight into the pathophysiology of PAD and may help develop future diagnostic procedures and therapies for PAD patients.

Keywords: claudication; critical limb ischemia (CLI); metabolomics; peripheral artery disease (PAD).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Discriminant function analysis model. Note: On the basis of metabolomic parameters, patient discriminant function scores can separate non-peripheral artery disease (PAD) control from PAD patients (A), and intermittent claudication (IC) patients from critical limb ischemia (CLI) patients (B).
Figure 2
Figure 2
Potential mechanism (oxidative stress and inflammation) operating to produce decreased arginine and ornithine, increased phenylalanine to tyrosine ratio, and decreased nitric oxide bioavailability in PAD. Note: Tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide synthase (NOS) and phenylalanine hydroxylase (PAH), is depleted by oxidative stress and inflammation. Therefore, reduced BH4 may explain the decreased turnover of phenylalanine to tyrosine observed in IC and CLI patients. Reduced BH4, as well as a lack of arginine availability, may play a role in impairing production of NO in PAD patients, leading to endothelial dysfunction. * denotes a significant difference from non-PAD controls and † denotes a significant difference from IC.
Figure 3
Figure 3
Potential mechanism (oxidative stress and inflammation) operating to produce decreased tryptophan levels in CLI. Note: Accelerated conversion of tryptophan to kynurenine is induced by inflammatory cytokines. Tryptophan is converted to kynurenine by the enzyme indoleamine 2,3 dioxygenase (IDO). IDO expression and activity are enhanced by tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ). Elevations in these cytokines may explain an increased conversion of tryptophan to kynurenine in CLI patients. * denotes a significant difference from non-PAD controls and † denotes a significant difference from IC.
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