Unique Metabolomic Profile of Skeletal Muscle in Chronic Limb Threatening Ischemia.

Ram B Khattri,Zachary R Salyers,Kyoungrae Kim,Terence E Ryan,Kerri A O’Malley,Trace Thome,Salvatore T Scali,Scott A Berceli

doi:10.3390/jcm10030548

Abstract

Chronic limb threatening ischemia (CLTI) is the most severe manifestation of peripheral atherosclerosis. Patients with CLTI have poor muscle quality and function and are at high risk for limb amputation and death. The objective of this study was to interrogate the metabolome of limb muscle from CLTI patients. To accomplish this, a prospective cohort of CLTI patients undergoing either a surgical intervention (CLTI Pre-surgery) or limb amputation (CLTI Amputation), as well as non-peripheral arterial disease (non-PAD) controls were enrolled. Gastrocnemius muscle biopsy specimens were obtained and processed for nuclear magnetic resonance (NMR)-based metabolomics analyses using solution state NMR on extracted aqueous and organic phases and 1H high-resolution magic angle spinning (HR-MAS) on intact muscle specimens. CLTI Amputation specimens displayed classical features of ischemic/hypoxic metabolism including accumulation of succinate, fumarate, lactate, alanine, and a significant decrease in the pyruvate/lactate ratio. CLTI Amputation muscle also featured aberrant amino acid metabolism marked by elevated branched chain amino acids. Finally, both Pre-surgery and Amputation CLTI muscles exhibited pronounced accumulation of lipids, suggesting the presence of myosteatosis, including cholesterol, triglycerides, and saturated fatty acids. Taken together, these metabolite differences add to a growing body of literature that have characterized profound metabolic disturbance’s in the failing ischemic limb of CLTI patients.

Highlights

Introduction published maps and institutional affilChronic limb threatening ischemia (CLTI) is the most severe manifestation of peripheral arterial disease (PAD) and is clinically characterized by pain at rest, non-healing wounds, gangrene, and a high risk of limb amputation or death
Demographics wasPhysical a prospective cohort study that examined the metabolomic profile of skeletal muscleThis from patients undergoing intervention or amputation, well as a was a prospective cohort study surgical that examined the metabolomic profile ofas skelecohort of non-PAD
CLTI patients present with complex patterns of atherosclerosis and in most cases surgical intervention is often permore complex patterns of atherosclerosis and in most cases surgical intervention is often formed with the primary goal of limb salvage

Summary

Introduction

Chronic limb threatening ischemia (CLTI) is the most severe manifestation of peripheral arterial disease (PAD) and is clinically characterized by pain at rest, non-healing wounds, gangrene, and a high risk of limb amputation or death. These symptoms result in devastating mobility impairment and loss of independence. Current treatment approaches for CLTI include endovascular (atherectomy, angioplasty and/or stenting) and open revascularization (bypass grafting) procedures that directly attempt to restore arterial perfusion. A significant number of CLTI patients that undergo surgical intervention will still require limb amputation despite graft patency and/or improvements in arterial flow by angiography [1,2,3,4]. A critical barrier to developing more effect treatments is a lack of understanding of the resident tissue biology and its contribution to the overall pathobiology of CLTI

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