Background/Purpose: Extracellular microRNAs, circulating in the bloodstream and extracellular space, have been proposed as attractive candidates as both diagnostic and prognostic biomarkers in various diseases, including a spectrum of autoimmune and cardiovascular conditions. Yet, the contribution of circulating miRNAs to the cardiovascular pathogenesis of Rheumatoid Arthitis (RA) patients and their potential role as biomarkers are still unknown. Purpose: To identify circulating miRNAs as potential biomarkers for the presence of cardiovascular disease (CVD) in RA.

Methods: Plasma samples of 80 healthy donors (HDs) and 195 RA patients, including 90 RA patients with cardiovascular events (Ischemic heart disease, Heart failure, Cerebrovascular accident or Peripheral arterial disease) were collected. In the discovery phase, an array of 2,083 human miRNAs was performed by using HTG EdgeSeq miRNA Whole Transcriptome Assay (Next generation sequencing) in 9 plasma samples (3 HDs, 3 RA and 3 RA with CVD). Then, differentially expressed miRNAs, were selected and validated by RT-PCR in the whole cohort of patients. Potential targets of the validated miRNAs, were identified by using Ingenuity Pathway Analysis (IPA) software and analyzed at protein levels (Multiplex Assay). Correlation and association studies of altered miRNAs with analytical and clinical variables such as the type of cardiovascular events, the presence of a pathologic carotid intima-media thickness (CIMT) and the autoimmune and inflammatory profile, were also performed.

Results: The miRNA whole Transcriptome assay showed that 360 miRNAs were differentially expressed in RA patients in relation to HDs, including 261 upregulated and 97 downregulated. Functional classification (IPA) demonstrated that deregulated miRNAs were mainly involved in processes such as inflammatory response, connective tissue development and function, haematological disease, tissue development and immunological disease. RA patients with CVD showed 17 differentially expressed plasma miRNAs in relation to RA patients, including 11 upregulated and 6 downregulated. In silico study identified that these CVD-associated miRNAs had potential targets related to cytokine signaling (TNF, TNFRSF, TNFSF, TRAF, IL1R, IL22, IL33, CCL21, CXCL12), atherosclerosis pathway (iNOS, VEGFA, LDL-R, COL1A1, COL10A1, COL5A3) and intracellular signal transduction (ERK and WNT). Furthermore, the altered levels of several miRNAs and target proteins were validated in the whole cohort of patients, and were linked to the clinical manifestations of the disease, such as the activity of the disease, the occurrence of cardiovascular events, presence of early atherosclerosis and endothelial dysfunction.

Conclusion: Circulating miRNAs levels in plasma of RA patients might be considered useful tools as biomarkers of cardiovascular disease in these patients.Acknowledgements: Supported by FIS (PI01333/2015) and CTS-7940.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/circulating-mirnas-as-potential-biomarkers-of-cardiovascular-disease-in-rheumatoid-arthritis-patients/