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Circulating miRNAs and Vascular Injury Markers Associate with Cardiovascular Function in Older Patients Reaching End-Stage Kidney Disease.

ABSTRACT: The prevalence of end-stage kidney disease (ESKD) is rapidly increasing and mostly occurring in patients aged 65 years or older. The main cause of death in these patients is cardiovascular disease (CVD). Novel markers of vascular integrity may thus be of clinical value for identifying patients at high risk for CVD. Here we associated the levels of selected circulating angiogenic miRNAs, angiopoietin-2 (Ang-2) and asymmetric dimethylarginine (ADMA) with cardiovascular structure and function (as determined by cardiovascular MRI) in 67 older patients reaching ESKD that were included from 'The Cognitive decline in Older Patients with End stage renal disease' (COPE) prospective, multicentered cohort study. We first determined the association between the vascular injury markers and specific heart conditions and observed that ESKD patients with coronary heart disease have significantly higher levels of circulating ADMA and miR-27a. Moreover, circulating levels of miR-27a were higher in patients with atrial fibrillation. In addition, the circulating levels of the vascular injury markers were associated with measures of cardiovascular structure and function obtained from cardiovascular MRI: pulse wave velocity (PWV), ejection fraction (EF) and cardiac index (CI). We found Ang-2 and miR-27a to be strongly correlated to the PWV, while Ang-2 also associated with ejection fraction. Finally, we observed that in contrast to miR-27a, Ang-2 was not associated with a vascular cause of the primary kidney disease, suggesting Ang-2 may be an ESKD-specific marker of vascular injury. Taken together, among older patients with ESKD, aberrant levels of vascular injury markers (miR-27a, Ang-2 and ADMA) associated with impaired cardiovascular function. These markers may serve to identify individuals at higher risk of CVD, as well as give insight into the underlying (vascular) pathophysiology.

SUBMITTER: Zhao Q

PROVIDER: S-EPMC8788543 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionProteomic profiling of end-stage renal disease (ESRD) patients could lead to improved risk prediction and novel insights into cardiovascular disease mechanisms. Plasma levels of 92 cardiovascular disease-associated proteins were assessed by proximity extension assay (Proseek Multiplex CVD-1, Olink Bioscience, Uppsala, Sweden) in a discovery cohort of dialysis patients, the Mapping of Inflammatory Markers in Chronic Kidney disease cohort [MIMICK; n?=?183, 55% women, mean age 63 years, 46 cardiovascular deaths during follow-up (mean 43 months)]. Significant results were replicated in the incident and prevalent hemodialysis arm of the Salford Kidney Study [SKS dialysis study, n?=?186, 73% women, mean age 62 years, 45 cardiovascular deaths during follow-up (mean 12 months)], and in the CKD5-LD-RTxcohort with assessments of coronary artery calcium (CAC)-score by cardiac computed tomography (n?=?89, 37% women, mean age 46 years).ResultsIn age and sex-adjusted Cox regression in MIMICK, 11 plasma proteins were nominally associated with cardiovascular mortality (in order of significance: Kidney injury molecule-1 (KIM-1), Matrix metalloproteinase-7, Tumour necrosis factor receptor 2, Interleukin-6, Matrix metalloproteinase-1, Brain-natriuretic peptide, ST2 protein, Hepatocyte growth factor, TNF-related apoptosis inducing ligand receptor-2, Spondin-1, and Fibroblast growth factor 25). Only plasma KIM-1 was associated with cardiovascular mortality after correction for multiple testing, but also after adjustment for dialysis vintage, cardiovascular risk factors and inflammation (hazard ratio) per standard deviation (SD) increase 1.84, 95% CI 1.26-2.69, p?=?0.002. Addition of KIM-1, or nine of the most informative proteins to an established risk-score (modified AROii CVM-score) improved discrimination of cardiovascular mortality risk from C?=?0.777 to C?=?0.799 and C?=?0.823, respectively. In the SKS dialysis study, KIM-1 predicted cardiovascular mortality in age and sex adjusted models (hazard ratio per SD increase 1.45, 95% CI 1.03-2.05, p?=?0.034) and higher KIM-1 was associated with higher CACscores in the CKD5-LD-RTx-cohort.ConclusionsOur proteomics approach identified plasma KIM-1 as a risk marker for cardiovascular mortality and coronary artery calcification in three independent ESRD-cohorts. The improved risk prediction for cardiovascular mortality by plasma proteomics merit further studies.

Project description:AimThe study was designed to assess the possibility of using circulating miRNAs (serum miRNAs) as diagnostic biomarkers in colorectal cancer (CRC) and to identify their possibility as candidates for targeted therapy.MethodsThe study involved two sample sets: 1- a training set which included 90 patients with colorectal related disease (30 with CRC, 18 with inflammatory bowel disease (IBD), 18 with colonic polyps (CP) and 24 with different colonic symptoms but without any colonoscopic abnormality who were enrolled as control group) and 2- a validation set which included 100 CRC patients. Serum miRNAs were extracted from all subjects to assess the expression profiles for the following miRNAs (miR-17, miR-18a, miR-19a, miR-19b, miR-20a, miR-21, miR-146a, miR-223, miR-24, miR-454, miR-183, miR-135a, miR- 135b and miR- 92a) using the custom miScript miRNA PCR-based sybergreen array. The area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnostic performance of the studied miRNAs for colorectal cancer diagnosis.ResultsData analysis of miRNA from the training set showed that; compared to control group, only miR-19b was significantly up-regulated in patients with IBD group (fold change = 5.24, p = 0.016), whereas in patients with colonic polyps, miR-18a was significantly up-regulated (fold change = 3.49, p-value = 0.018). On the other hand, miR-17, miR-19a, miR-20a and miR-223 were significantly up-regulated (fold change = 2.35, 3.07, 2.38 and 10.35; respectively and p-value = 0.02, 0.015, 0.017 and 0.016; respectively in CRC patients. However, the validation set showed that only miR-223 was significantly up-regulated in CRC patients (fold change = 4.06, p-value = 0.04).ConclusionAberrant miRNA expressions are highly involved in the cascade of colorectal carcinogenesis. We have found that (miR-17, miR-19a, miR-20a and miR-223) could be used as diagnostic biomarkers for CRC. On the other hand, miR-19b and miR-18a could be used as diagnostic biomarkers for CP and IBD respectively.

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Circulating miRNAs and Vascular Injury Markers Associate with Cardiovascular Function in Older Patients Reaching End-Stage Kidney Disease.

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