Fibrosis Distinguishes Critical Limb Ischemia Patients from Claudicants in a Transcriptomic and Histologic Analysis

Cong, Guangzhi; Cui, Xiangdong; Ferrari, Ricardo; Pipinos, Iraklis I.; Casale, George P.; Chattopadhyay, Ansuman; Sachdev, Ulka

doi:10.3390/jcm9123974

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Fibrosis Distinguishes Critical Limb Ischemia Patients from Claudicants in a Transcriptomic and Histologic Analysis

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Ansuman Chattopadhyay

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Ulka Sachdev

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Department of Surgery, University of Pittsburgh Medical Centre, Pittsburgh, PA 15217, USA

Department of Surgery, University of Nebraska at Medical Center, Omaha, NE 68198, USA

Department of Surgery and VA Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE 68198, USA

⁴

Molecular Biology Information Service, Health Sciences Library System University of Pittsburgh, Pittsburgh, PA 15261, USA

Author to whom correspondence should be addressed.

J. Clin. Med. 2020, 9(12), 3974; https://doi.org/10.3390/jcm9123974

Received: 13 October 2020 / Revised: 24 November 2020 / Accepted: 26 November 2020 / Published: 8 December 2020

(This article belongs to the Special Issue Peripheral Artery Disease: From Diagnosis to Treatment)

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Abstract

Most patients with critical limb ischemia (CLI) from peripheral arterial disease (PAD) do not have antecedent intermittent claudication (IC). We hypothesized that transcriptomic analysis would identify CLI-specific pathways, particularly in regards to fibrosis. Derivation cohort data from muscle biopsies in PAD and non-PAD (controls) was obtained from the Gene Expression Omnibus (GSE120642). Transcriptomic analysis indicated CLI patients (N = 16) had a unique gene expression profile, when compared with non-PAD controls (N = 15) and IC (N = 20). Ninety-eight genes differed between controls and IC, 2489 genes differed between CLI and controls, and 2783 genes differed between CLI and IC patients. Pathway enrichment analysis showed that pathways associated with TGFβ, collagen deposition, and VEGF signaling were enriched in CLI but not IC. Receiver operating curve (ROC) analysis of nine fibrosis core gene expression revealed the areas under the ROC (AUC) were all >0.75 for CLI. Furthermore, the fibrosis area (AUC = 0.81) and % fibrosis (AUC = 0.87) in validation cohort validated the fibrosis discrimination CLI from IC and control (all n = 12). In conclusion, transcriptomic analysis identified fibrosis pathways, including those involving TGFβ, as a novel gene expression feature for CLI but not IC. Fibrosis is an important characteristic of CLI, which we confirmed histologically, and may be a target for novel therapies in PAD. View Full-Text

Keywords: peripheral artery disease (PAD); transcriptomics; fibrosis pathway; claudication; critical limb ischemia (CLI)

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MDPI and ACS Style

Cong, G.; Cui, X.; Ferrari, R.; Pipinos, I.I.; Casale, G.P.; Chattopadhyay, A.; Sachdev, U. Fibrosis Distinguishes Critical Limb Ischemia Patients from Claudicants in a Transcriptomic and Histologic Analysis. J. Clin. Med. 2020, 9, 3974. https://doi.org/10.3390/jcm9123974

AMA Style

Cong G, Cui X, Ferrari R, Pipinos II, Casale GP, Chattopadhyay A, Sachdev U. Fibrosis Distinguishes Critical Limb Ischemia Patients from Claudicants in a Transcriptomic and Histologic Analysis. Journal of Clinical Medicine. 2020; 9(12):3974. https://doi.org/10.3390/jcm9123974

Chicago/Turabian Style

Cong, Guangzhi, Xiangdong Cui, Ricardo Ferrari, Iraklis I. Pipinos, George P. Casale, Ansuman Chattopadhyay, and Ulka Sachdev. 2020. "Fibrosis Distinguishes Critical Limb Ischemia Patients from Claudicants in a Transcriptomic and Histologic Analysis" Journal of Clinical Medicine 9, no. 12: 3974. https://doi.org/10.3390/jcm9123974

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Fibrosis Distinguishes Critical Limb Ischemia Patients from Claudicants in a Transcriptomic and Histologic Analysis

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