Differential metabolomes in claudicating and chronic limb-threatening ischemia limb muscles

Peripheral artery disease presents clinically as intermittent claudication (IC) and chronic limb-threatening ischemia (CLTI; pain at rest with or without tissue necrosis or gangrene). Patients with CLTI exhibit high morbidity and mortality rates, which is compounded by our lack of understanding of their unique tissue biology. This study compared limb tissue metabolomic profiles across patients with differing clinical presentations of peripheral artery disease (PAD).

Gastrocnemius muscles were obtained from healthy adults (HA; n = 23), patients with IC (n = 15), and patients with CLTI (n = 24) and analyzed using ultrahigh performance liquid chromatography-tandem mass spectroscopy.

We identified 1114 biochemicals through global metabolomic profiling. The IC muscle metabolome largely reflected the HA profile (P ≤ .05; 117 increased and 67 decreased biochemicals). The CLTI metabolome differentially presented 531 metabolites (P ≤ .05) vs HA, which was defined by a majority of increasing (343 vs 188 decreased) biochemicals. The IC and CLTI groups only shared 77 decreased and 127 increased metabolites, which were largely defined by alterations in lipids (including fatty acid and dicarboxylate species). Altered (P ≤ .05) metabolites in IC/HA and CLTI/HA comparisons reflect substantial changes in muscle amino acid and lipid profiles, but particularly in the CLTI presentation (220 lipid species increased or decreased). Direct comparisons of the CLTI and IC groups revealed 159 increased (P < .1) and 90 decreased (P < .1) biochemicals, including large changes in amino acids, lipids, and nucleotides.

The limb muscle metabolome of patients with CLTI is unique and reflects novel biochemical characteristics that underlie disease pathophysiology.

Metabolomic profiling of the lateral gastrocnemius muscle revealed unique alterations in the metabolic pathways of patients with chronic limb-threatening ischemia (CLTI) compared with patients with intermittent claudication (IC) and HA. This finding points to metabolic targets that may influence disease severity and patient outcomes. The most significantly changed metabolites were related to pain and inflammation, and energy and lipid metabolism, which reflect the primary symptoms (pain, inflammation, myopathy, and myosteatosis) of the CLTI patient population. These data provide critical information that can aid in identifying the CLTI etiology and may be leveraged for the development of adjuvant therapies to supplement surgical intervention.