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Cytokine signature of inflammation mediated by autoreactive Th-cells, in calf muscle of claudicating patients with Fontaine stage II peripheral artery disease.

ABSTRACT: Peripheral artery disease (PAD), a severe atherosclerotic condition primarily of the elderly, afflicts 200 million individuals, worldwide, and is associated with lower extremity myopathy. Circulating markers of inflammation have been linked to risk and severity of PAD but the contribution of local inflammation to myopathy remains unknown. We evaluated, by ELISA, calf muscle of PAD patients (N = 23) and control subjects (N = 18) for local expression of inflammatory cytokines including Granulocyte/Monocyte Colony-Stimulating Factor (GM-CSF), Interleukin 17A (IL-17A), Interferon ϒ (IFN-ϒ), tumor necrosis factor α (TNF-α), and Interleukin 6 (IL-6). One or more of these cytokines were expressed in nineteen patients and 2 controls and coordinated expression of GM-CSF, IL-17A, IFN-ϒ, and TNF-α, a signature of activated, MHC Class II dependent autoreactive Th-cells, was unique to 11 patients. GM-CSF is the central driver of tissue-damaging myeloid macrophages. Patients with this cytokine signature had a shorter (P= 0.017) Claudication Onset Distance (17 m) compared with patients lacking the signature (102 m). Transforming Growth Factor β1 (TGFβ1) and Chemokine Ligand 5 (CCL5) were expressed coordinately in all PAD and control muscles, independently of GM-CSF, IL-17A, IFN-ϒ, TNF-α, or IL-6. TGFβ1 and CCL5 and their gene transcripts were increased in PAD muscle, consistent with increased age-associated inflammation in these patients. Serum cytokines were not informative of muscle cytokine expression. We have identified a cytokine profile of autoimmune inflammation in calf muscles of a significant proportion of claudicating PAD patients, in association with decreased limb function, and a second independent profile consistent with increased "inflammaging" in all PAD patients.

SUBMITTER: Casale GP

PROVIDER: S-EPMC7779738 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Cytokine signature of inflammation mediated by autoreactive Th-cells, in calf muscle of claudicating patients with Fontaine stage II peripheral artery disease.

Casale George P GP Thompson Jonathan R JR Carpenter Lauren C LC Kim Julian J Lackner Timothy J TJ Mietus Constance J CJ Ha Duy M DM Myers Sara A SA Brunette Katyarina E KE Li Shuai S Shields Christina C Willcockson Gregory G Pipinos Iraklis I II

Translational research : the journal of laboratory and clinical medicine 20200822

Peripheral artery disease (PAD), a severe atherosclerotic condition primarily of the elderly, afflicts 200 million individuals, worldwide, and is associated with lower extremity myopathy. Circulating markers of inflammation have been linked to risk and severity of PAD but the contribution of local inflammation to myopathy remains unknown. We evaluated, by ELISA, calf muscle of PAD patients (N = 23) and control subjects (N = 18) for local expression of inflammatory cytokines including Granulocyte ...[more]

PMID: 32835907

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Project description:Peripheral artery disease (PAD) remains underdiagnosed and undertreated and is associated with an increased risk for adverse cardiovascular outcomes. Imaging provides an approach to identifying patients with PAD. However, the role of integrating imaging with machine learning to identify PAD patients and potentially assess disease severity remains understudied. A total of 56 participants, including 36 PAD patients with intermittent claudication and 20 matched controls, underwent contrast-enhanced magnetic resonance imaging (CE-MRI) calf muscle perfusion scanning. CE-MRI-derived dynamic muscle perfusion maps were developed to quantify alterations of the microvascular circulation in the calf muscles based on voxel contrast enhancement. These dynamic muscle perfusion maps categorized voxels as hyper-, iso-, or hypo-enhanced and were generated for the anterior (AM), lateral (LM), and deep posterior (DM) muscle groups, and the soleus (SM) and gastrocnemius muscles (GM). An unsupervised block-search algorithm was developed to identify heterogeneous regions of interest based on homogeneity. Machine learning methods were utilized to classify PAD patients from controls, with subgroup analyses performed based on lower extremity function and diabetes. The hypo-enhanced and hyper-enhanced voxel percentages obtained from the dynamic muscle perfusion maps were used to train a decision tree classifier to distinguish PAD patients from controls. The two-group classifier obtained a leave-one-out cross-validation (LOOCV) F1-score of 87.6 and 76.7% with hyper-enhanced and hypo-enhanced perfusion features averaged over all muscle groups, respectively. Hypo-enhanced perfusion features, a marker of microvascular perfusion abnormalities, classified PAD patients who completed a 6-minute treadmill walking test compared to those who did not, with an LOOCV F1-score of 67.6%. Using the same method, hypo-enhanced perfusion features differentiated PAD patients with diabetes versus those without with an LOOCV F1-score of 70.3%. In conclusion, CE-MRI derived measures of skeletal calf muscle perfusion can be used with a decision tree classifier to differentiate PAD patients from matched controls. Machine learning can also identify PAD patients with lower exercise capacity and those with concomitant diabetes. Machine learning and CE-MRI derived measures of the calf microcirculation could be of interest in the study of PAD and disease severity.

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Dataset Information

Cytokine signature of inflammation mediated by autoreactive Th-cells, in calf muscle of claudicating patients with Fontaine stage II peripheral artery disease.

Publications

Cytokine signature of inflammation mediated by autoreactive Th-cells, in calf muscle of claudicating patients with Fontaine stage II peripheral artery disease.

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