Interventional- and amputation-stage muscle proteomes in the chronically threatened ischemic limb.

BACKGROUND: Despite improved surgical approaches for chronic limb-threatening ischemia (CLTI), amputation rates remain high and contributing tissue-level factors remain unknown. The purpose of this study was twofold: (1) to identify differences between the healthy adult and CLTI limb muscle proteome, and (2) to identify differences in the limb muscle proteome of CLTI patients prior to surgical intervention or at the time of amputation. METHODS AND RESULTS: Gastrocnemius muscle was collected from non-ischemic controls (n = 19) and either pre-interventional surgery (n = 10) or at amputation outcome (n = 29) CLTI patients. All samples were subjected to isobaric tandem-mass-tag-assisted proteomics. The mitochondrion was the primary classification of downregulated proteins (> 70%) in CLTI limb muscles and paralleled robust functional mitochondrial impairment. Upregulated proteins (> 38%) were largely from the extracellular matrix. Across the two independent sites, 39 proteins were downregulated and 12 upregulated uniformly. Pre-interventional CLTI muscles revealed a robust upregulation of mitochondrial proteins but modest functional impairments in fatty acid oxidation as compared with controls. Comparison of pre-intervention and amputation CLTI limb muscles revealed mitochondrial proteome and functional deficits similar to that between amputation and non-ischemic controls. Interestingly, these observed changes occurred despite 62% of the amputation CLTI patients having undergone a prior surgical intervention. CONCLUSIONS: The CLTI proteome supports failing mitochondria as a phenotype that is unique to amputation outcomes. The signature of pre-intervention CLTI muscle reveals stable mitochondrial protein abundance that is insufficient to uniformly prevent functional impairments. Taken together, these findings support the need for future longitudinal investigations aimed to determine whether mitochondrial failure is causally involved in amputation outcomes from CLTI.

Impact of Controlling a Nutritional Status Score on Wound Healing in Patients with Chronic Limb-Threatening Ischemia after Endovascular Treatment.

BACKGROUND: Chronic limb-threatening ischemia (CLTI) is the most advanced stage of peripheral artery disease. Therefore, a multidisciplinary approach is necessary to avoid major amputation in CLTI patients. Malnutrition worsens the condition of CLTI patients, and therefore, it may be important to evaluate the nutritional status in patients with CLTI. This study was designed to evaluate the baseline patient characteristics and the influence of the controlling nutritional status (CONUT) score on the clinical results. METHOD AND RESULTS: A retrospective, single-center, non-randomized study was conducted to evaluate the associations of death, major amputation, and wound healing rate at 12 months with the CONUT score on admission. Consecutive CLTI patients (mean age 73.2 ± 10.4 years; 84 males) who underwent endovascular therapy (EVT) for infra-popliteal lesions at Fukuoka University Hospital from January 2014 to May 2019 were enrolled and divided into two groups (higher and lower CONUT score groups). The higher CONUT group showed a higher percentage of dialysis (66.7% vs. 33.9%, p < 0.001) and a higher clinical frailty scale (5.9 ± 1.4 vs. 4.9 ± 1.9, p = 0.005) than the lower CONUT group. Rates of amputation-free survival were 89.5% and 69.8% in the lower and higher CONUT groups, respectively. In addition, rates of wound healing at 12 months were 98.0% and 78.3% in the lower and higher CONUT groups, respectively. Multivariate regression analysis demonstrated that a higher CONUT score was an independent predictor for delayed wound healing (OR: 11.2; 95% CI: 1.29-97.5; p = 0.028). CONCLUSION: An assessment of the nutritional status using the CONUT score could be useful for predicting wound healing, and earlier nutritional intervention may improve the outcome of CLTI patients. Early examination and treatment, along with raising awareness of the issue, may be important for improving the prognosis.