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Human enterovirus in the gastrocnemius of patients with peripheral arterial disease.

ABSTRACT: Peripheral arterial disease (PAD) is characterized by myofiber degeneration and loss of function in muscles of the lower limbs. Human enterovirus (HEV) infection has been implicated in the pathogenesis of a number of muscle diseases. However, its association with PAD has not been studied. In this study, we tested the hypothesis that infectious HEV is present in skeletal muscle of patients with PAD and is associated with severity of disease.Gastrocnemius biopsies from 37 patients with PAD and 14 controls were examined for the presence of HEV RNA, viral capsid protein, viral RNA copy number, and viral infectivity. HEV RNA was detected in 54% of the biopsies from patients with PAD but was not detected in muscle biopsies from control patients. This difference in prevalence among PAD and control patients was significant at P<0.001. Viral RNA copy numbers were increased significantly at the later stages of disease; Fontaine Stage IV (10(5.50) copies/mg muscle wet weight, at P<0.005) and Stage III (10(4.87) copies/mg, at P<0.010) compared to Stage II (10(2.50) copies/mg). Viral replication was confirmed by the presence of the negative-strand of viral RNA in all specimens positive for HEV RNA. Cultures of HeLa and human skeletal muscle cells treated with muscle homogenates showed HEV replication and the presence of HEV capsid protein.Our data identified infectious HEV in the gastrocnemius of PAD patients but not in controls. Viral copy number and prevalence of infection were higher in the later stages of disease. Our data point to the need for further studies to determine the contribution of HEV infection to the pathophysiology of PAD.

SUBMITTER: Kim JK

PROVIDER: S-EPMC3828788 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Human enterovirus in the gastrocnemius of patients with peripheral arterial disease.

Kim Julian K S JK Zhu Zhen Z Casale George G Koutakis Panagiotis P McComb Rodney D RD Swanson Stanley S Thompson Jonathan J Miserlis Dimitrios D Johanning Jason M JM Haynatzki Gleb G Pipinos Iraklis I II

Journal of the American Heart Association 20130806 4

<h4>Background</h4>Peripheral arterial disease (PAD) is characterized by myofiber degeneration and loss of function in muscles of the lower limbs. Human enterovirus (HEV) infection has been implicated in the pathogenesis of a number of muscle diseases. However, its association with PAD has not been studied. In this study, we tested the hypothesis that infectious HEV is present in skeletal muscle of patients with PAD and is associated with severity of disease.<h4>Methods and results</h4>Gastrocne ...[more]

PMID: 23920231

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Project description:Peripheral arterial disease (PAD) is a relatively common manifestation of systemic atherosclerosis that leads to progressive narrowing of the lumen of leg arteries. Circulating monocytes are in contact with the arterial wall and can serve as reporters of vascular pathology in the setting of PAD. We performed gene expression analysis of peripheral blood mononuclear cells (PBMC) in patients with PAD and controls without PAD to identify differentially regulated genes. We identified 87 genes differentially expressed in the setting of PAD; 40 genes were upregulated and 47 genes were downregulated. We employed an integrated bioinformatics pipeline coupled with literature curation to characterize the functional coherence of differentially regulated genes. Notably, upregulated genes mediate immune response, inflammation, apoptosis, stress response, phosphorylation, hemostasis, platelet activation and platelet aggregation. Downregulated genes included several genes from the zinc finger family that are involved in transcriptional regulation. These results provide insights into molecular mechanisms relevant to the pathophysiology of PAD. PAD was defined as an ankle brachial index (ABI) <= 0.9 (n = 19) while age and gender matched controls had an ABI > 1.0 (n = 18). Microarray analysis was performed using Affymetrix HG-U133 plus 2.0 gene chips and analyzed using GeneSpring GX 11.0. Gene expression data was normalized using Robust Multichip Analysis (RMA) normalization method, differential expression was defined as a fold change [greater than or equal to]1.5, followed by unpaired Mann-Whitney test (P < 0.05) and correction for multiple testing by Benjamini and Hochberg False Discovery Rate. Meta-analysis of differentially expressed genes was performed using an integrated bioinformatics pipeline with tools for enrichment analysis using Gene Ontology (GO) terms, pathway analysis using Kyoto Encyclopedia of Genes and Genomes (KEGG), molecular event enrichment using Reactome annotations and network analysis using Ingenuity Pathway Analysis suite. Extensive biocuration was also performed to understand the functional context of genes.

Project description:BACKGROUND: We investigated the association of process of care measures with adverse limb and systemic events in patients with peripheral arterial disease (PAD). METHODS: We conducted a retrospective cohort study of patients with PAD, as defined by an ankle-brachial index (ABI) <0.9. The index date was defined as the date, during 1995 to 1998, when the patient was seen in the Michael E. DeBakey VA Medical Center noninvasive vascular laboratory and found to have PAD. We conducted a chart review for process of care variables starting 3 years before the index date and ending at the time of the first event or the final visit (December 31, 2001), whichever occurred first. We examined the association between PAD process of care measures, including risk factor control, and prescribing of medication, with time of the patient's first major limb event or death. RESULTS: Of the 796 patients (mean age, 65 +/- 9.9 years), 230 (28.9% experienced an adverse limb event (136 lower-extremity bypass, 94 lower-extremity amputation), and 354 (44.5%) died. Of the patients who died, 247 died without a preceding limb event. Glucose control was protective against death or a limb event with a hazard ratio (HR) of 0.74 (95% confidence limits [CL] 0.60, 0.91, P = 0.004). African Americans were at 2.8 (95% CL 1.7, 4.5) times the risk of Whites or Hispanics for an adverse limb event. However, this risk was no longer significant if their glucose was controlled. For process measures, the dispensing of PAD specific medication (HR 1.4, 95% CL 1.1, 1.7) was associated an increased risk for an adverse outcome. CONCLUSIONS: Our data suggest that glucose control is key to reducing the risk for adverse outcomes, particularly limb events in African Americans. Certain process of care measures, as markers of disease severity and disease management, are associated with poor outcomes in patients with PAD. Further work is needed to determine the role of early disease intervention to reduce poor outcomes in patients with PAD.

Project description:BackgroundLower extremity peripheral artery disease (PAD) is a growing epidemic with limited effective treatment options. Here, we provide a single-nuclei atlas of PAD limb muscle to facilitate a better understanding of the composition of cells and transcriptional differences that comprise the diseased limb muscle.MethodsWe obtained gastrocnemius muscle specimens from 20 patients with PAD and 12 non-PAD controls. Nuclei were isolated and single-nuclei RNA-sequencing was performed. The composition of nuclei was characterized by iterative clustering via principal component analysis, differential expression analysis, and the use of known marker genes. Bioinformatics analysis was performed to determine differences in gene expression between PAD and non-PAD nuclei, as well as subsequent analysis of intercellular signaling networks. Additional histological analyses of muscle specimens accompany the single-nuclei RNA-sequencing atlas.ResultsSingle-nuclei RNA-sequencing analysis indicated a fiber type shift with patients with PAD having fewer type I (slow/oxidative) and more type II (fast/glycolytic) myonuclei compared with non-PAD, which was confirmed using immunostaining of muscle specimens. Myonuclei from PAD displayed global upregulation of genes involved in stress response, autophagy, hypoxia, and atrophy. Subclustering of myonuclei also identified populations that were unique to PAD muscle characterized by metabolic dysregulation. PAD muscles also displayed unique transcriptional profiles and increased diversity of transcriptomes in muscle stem cells, regenerating myonuclei, and fibro-adipogenic progenitor cells. Analysis of intercellular communication networks revealed fibro-adipogenic progenitors as a major signaling hub in PAD muscle, as well as deficiencies in angiogenic and bone morphogenetic protein signaling which may contribute to poor limb function in PAD.ConclusionsThis reference single-nuclei RNA-sequencing atlas provides a comprehensive analysis of the cell composition, transcriptional signature, and intercellular communication pathways that are altered in the PAD condition.

Dataset Information

Human enterovirus in the gastrocnemius of patients with peripheral arterial disease.

Publications

Human enterovirus in the gastrocnemius of patients with peripheral arterial disease.

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