Diagnostic Potential of Plasmatic MicroRNA Signatures in Stable and Unstable Angina

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Abstract

Purpose

We examined circulating miRNA expression profiles in plasma of patients with coronary artery disease (CAD) vs. matched controls, with the aim of identifying novel discriminating biomarkers of Stable (SA) and Unstable (UA) angina.

Methods

An exploratory analysis of plasmatic expression profile of 367 miRNAs was conducted in a group of SA and UA patients and control donors, using TaqMan microRNA Arrays. Screening confirmation and expression analysis were performed by qRT-PCR: all miRNAs found dysregulated were examined in the plasma of troponin-negative UA (n=19) and SA (n=34) patients and control subjects (n=20), matched for sex, age, and cardiovascular risk factors. In addition, the expression of 14 known CAD-associated miRNAs was also investigated.

Results

Out of 178 miRNAs consistently detected in plasma samples, 3 showed positive modulation by CAD when compared to controls: miR-337-5p, miR-433, and miR-485-3p. Further, miR-1, -122, -126, -133a, -133b, and miR-199a were positively modulated in both UA and SA patients, while miR-337-5p and miR-145 showed a positive modulation only in SA or UA patients, respectively. ROC curve analyses showed a good diagnostic potential (AUC ≥ 0.85) for miR-1, -126, and -483-5p in SA and for miR-1, -126, and -133a in UA patients vs. controls, respectively. No discriminating AUC values were observed comparing SA vs. UA patients. Hierarchical cluster analysis showed that the combination of miR-1, -133a, and -126 in UA and of miR-1, -126, and -485-3p in SA correctly classified patients vs. controls with an efficiency ≥ 87%. No combination of miRNAs was able to reliably discriminate patients with UA from patients with SA.

Conclusions

This work showed that specific plasmatic miRNA signatures have the potential to accurately discriminate patients with angiographically documented CAD from matched controls. We failed to identify a plasmatic miRNA expression pattern capable to differentiate SA from UA patients.

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Most cited references 14

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Circulating microRNAs are new and sensitive biomarkers of myocardial infarction

Yuri D’Alessandra, Paolo Devanna, Federica Limana … (2010)

Aims Circulating microRNAs (miRNAs) may represent a novel class of biomarkers; therefore, we examined whether acute myocardial infarction (MI) modulates miRNAs plasma levels in humans and mice. Methods and results Healthy donors (n = 17) and patients (n = 33) with acute ST-segment elevation MI (STEMI) were evaluated. In one cohort (n = 25), the first plasma sample was obtained 517 ± 309 min after the onset of MI symptoms and after coronary reperfusion with percutaneous coronary intervention (PCI); miR-1, -133a, -133b, and -499-5p were ∼15- to 140-fold control, whereas miR-122 and -375 were ∼87–90% lower than control; 5 days later, miR-1, -133a, -133b, -499-5p, and -375 were back to baseline, whereas miR-122 remained lower than control through Day 30. In additional patients (n = 8; four treated with thrombolysis and four with PCI), miRNAs and troponin I (TnI) were quantified simultaneously starting 156 ± 72 min after the onset of symptoms and at different times thereafter. Peak miR-1, -133a, and -133b expression and TnI level occurred at a similar time, whereas miR-499-5p exhibited a slower time course. In mice, miRNAs plasma levels and TnI were measured 15 min after coronary ligation and at different times thereafter. The behaviour of miR-1, -133a, -133b, and -499-5p was similar to STEMI patients; further, reciprocal changes in the expression levels of these miRNAs were found in cardiac tissue 3–6 h after coronary ligation. In contrast, miR-122 and -375 exhibited minor changes and no significant modulation. In mice with acute hind-limb ischaemia, there was no increase in the plasma level of the above miRNAs. Conclusion Acute MI up-regulated miR-1, -133a, -133b, and -499-5p plasma levels, both in humans and mice, whereas miR-122 and -375 were lower than control only in STEMI patients. These miRNAs represent novel biomarkers of cardiac damage.

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Circulating microRNAs: biomarkers or mediators of cardiovascular diseases?

Stephan Fichtlscherer, Andreas Zeiher, Stefanie Dimmeler (2011)

MicroRNAs (miRs) are small, noncoding RNAs that posttranscriptionally control gene expression by inhibiting protein translation or inducing target mRNA destabilization. Besides their intracellular function, recent studies demonstrate that miRs can be exported or released by cells and circulate with the blood in a remarkably stable form. The discovery of circulating miRs opens up intriguing possibilities to use the circulating miR patterns as biomarker for cardiovascular diseases. Cardiac injury as it occurs after acute myocardial infarction increases the circulating levels of several myocardial-derived miRs (eg, miR-1, miR-133, miR-499, miR-208), whereas patients with coronary artery disease or diabetes showed reduced levels of endothelial-enriched miRs, such as miR-126. This review article summarizes the current clinical and experimental studies addressing the role of circulating miRs as a diagnostic or prognostic biomarker in cardiovascular disease. In addition, the mechanisms by which miRs are released and their putative function as long-distance communicators are discussed.

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Cardiospecific microRNA Plasma Levels Correlate with Troponin and Cardiac Function in Patients with ST Elevation Myocardial Infarction, Are Selectively Dependent on Renal Elimination, and Can Be Detected in Urine Samples

Olof Gidlöf, Patrik Andersson, Jesper van der Pals … (2011)

Objectives: Circulating microRNAs (miRNAs) are promising as biomarkers for various diseases. We examined the release patterns of cardiospecific miRNAs in a closed-chest, large animal ischemia-reperfusion model and in patients with ST elevation myocardial infarction (STEMI). Methods: Six anesthetized pigs were subjected to coronary occlusion-reperfusion. Plasma, urine, and clinical parameters were collected from 25 STEMI patients undergoing primary percutaneous coronary intervention. miRNA was extracted and measured with qPCR. Results: In the pig reperfusion model miR-1, miR-133a, and miR-208b increased rapidly in plasma with a peak at 120 min, while miR-499-5p remained elevated longer. In patients with STEMI all 4 miRNAs increased abruptly from 70-fold to 3,000-fold in plasma, with a peak within 12 h (p < 0.01). miR-1 and miR-133a both correlated strongly with the glomerular filtration rate (GFR), indicating renal elimination. This was confirmed by detection of miR-1 and miR-133a, but not miR-208b or miR-499-5p, in urine. Peak values of miR-208b correlated with peak troponin and the ejection fraction. Conclusion: We demonstrate a distinct and rapid increase in levels of cardiospecific miRNA in the circulation after myocardial infarction. Release of miRNAs correlated with cardiomyocyte necrosis markers, the ejection fraction, and the GFR, indicating a possible role for these molecules as biomarkers for the diagnosis of STEMI as well as the prediction of long-term complications.

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Author and article information

Contributors

Partha Mukhopadhyay: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 15 November 2013

Volume: 8

Issue: 11

Electronic Location Identifier: e80345

Affiliations

[1 ]Laboratory of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino, IRCCS, Milan, Italy

[2 ]Department of Vascular Surgery, Centro Cardiologico Monzino, IRCCS, Milan, Italy

[3 ]Cardiac Intensive Care Unit - UTIC, Centro Cardiologico Monzino, IRCCS, Milan, Italy

[4 ]Laboratory of Immunology and Functional Genomics, Centro Cardiologico Monzino, IRCCS, Milan, Italy

[5 ]Statistical Center, I.N.R.C.A. National Institute, Ancona, Italy

[6 ]Cardiology Department, San Gerardo Hospital, Monza, Italy

[7 ]Division of Cardiology, S.L. Mandic Hospital, Merate, Italy

[8 ]Laboratory of Vascular Pathology, Istituto Dermopatico dell'Immacolata, IDI - IRCCS, Rome, Italy

[9 ]Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy

National Institutes of Health, United States of America

Author notes

* E-mail: ydalessa@ 123456ccfm.it

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: YD M. Carena MR GM GIC FA SM M. Capogrossi GP. Performed the experiments: YD M. Carena PD. Analyzed the data: YD M. Carena LS FM BB PD MR GM GIC FA SM M. Capogrossi GP. Wrote the manuscript: YD M. Carena LS FM BB PD MR GM GIC FA SM M. Capogrossi GP.

Article

Publisher ID: PONE-D-13-28739

DOI: 10.1371/journal.pone.0080345

PMC ID: 3829878

PubMed ID: 24260372

SO-VID: 1d243c08-41bb-49b0-90e8-8e8cae987549

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 12 July 2013

Date accepted : 1 October 2013

Funding

The present study was supported by the following grants: from the Italian Health Ministry: Centro Cardiologico “Monzino” - Programma Strategico (ex art.12 D.Lgs.n.502/92 e s.m.i.), RFPS-2007-2-634780; from Regione Lombardia: Centro Cardiologico “Monzino”, Ospedale di Lecco, Ospedale di Merate - Progetti di Ricerca Indipendente 2009; and from Fondazione Umberto Veronesi : Yuri D'Alessandra - Young Investigator Programme 2013. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Diagnostic Potential of Plasmatic MicroRNA Signatures in Stable and Unstable Angina

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Abstract

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Results

Conclusions

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Most cited references 14

Circulating microRNAs are new and sensitive biomarkers of myocardial infarction

Circulating microRNAs: biomarkers or mediators of cardiovascular diseases?

Cardiospecific microRNA Plasma Levels Correlate with Troponin and Cardiac Function in Patients with ST Elevation Myocardial Infarction, Are Selectively Dependent on Renal Elimination, and Can Be Detected in Urine Samples

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