Coronary artery disease (CAD) is a leading cause of morbidity and mortality globally, and reliable prognostic tools for identifying subjects at risk of developing a cardiovascular event is currently a great unmet clinical need (1). Despite the considerable effort that has been put into developing risk prediction model, the accuracy of traditional risk factors is insufficient for predicting cardiovascular events in a substantial proportion of patients. The use of coronary imaging holds promise in improving cardiovascular risk prediction, but the technique is costly and unsuitable for population-wide screening. Thus, there is great interest in identifying circulating biomarkers that could complement the assessment of traditional risk factors. In a recent paper, Jakob et al. make a powerful claim for miRNAs as prognostic biomarkers in patients with CAD (2).
MicroRNA (miRNA) is a class of short, non-coding RNAs with a seemingly pervasive role in mammalian biology and disease (3). Through binding to complimentary sequence motifs, mainly in the 3’-untranslated region of target messenger RNAs, miRNAs repress gene expression and play pivotal roles in many essential cellular processes. With the realization that miRNAs are also released from cells upon activation or stress and that circulating miRNAs are protected from RNase-degradation (4), there has been a surging interest in using these molecules as biomarkers in a wide array of human disease states.
In 2010, the first studies showing increased levels of miRNAs of cardiac origin in the circulation of patients with myocardial infarction were published (5-7), providing the first proof-of-principle that miRNAs could have potential clinical use as biomarkers in CAD. Since then, a plethora of papers have been published showing that the miRNA profile in plasma is rapidly and robustly altered as a result of ACS (8-10). However, most studies have been limited in size and have lacked validation in larger cohorts.
Zampetaki et al. published the first large, prospective study investigating the association of circulating miRNAs with incidence of myocardial infarction (11). In this cohort of 820 participants, 47 of which experienced an MI, 3 miRNAs (miR-126, miR-223 and miR-197) were consistently and significantly associated with incident myocardial infarction, with hazard ratios of 2.69, 0.47 and 0.56, respectively. Although the addition of the three miRNAs to the Framingham Risk Score with CAD as an endpoint resulted in an improved C-index, the gain was not statistically significant.
Widera et al. assessed the diagnostic and prognostic value of a select set of cardiac-enriched miRNAs in a large ACS cohort (n=444) and patients were followed for 6 months with regards to all-cause mortality (12). miR-133a and miR-208b levels were significantly and independently associated with risk of death, but association was lost upon adjustment with the established myocardial necrosis marker Troponin T, dampening the expectation on miRNAs as clinically useful biomarkers in CAD.
However, in the first multicenter, prospective study including both a derivation and a validation cohort, Jakob et al. shows that circulating miRNA might still have a clinical value; as independent predictors of adverse cardiovascular outcomes in patients with ST-elevation myocardial infarction (STEMI) (2). Sixty-three patients in a cohort of 1002 STEMI patients experienced a major cardiovascular event (MACE, defined as cardiovascular mortality or recurrent MI) within 1 year of follow-up. A comprehensive profiling of circulating miRNAs in the derivation cohort resulted in 14 dysregulated miRNAs which were carried over to the validation phase. In the subsequent validation cohort of 63 cases and 126 matched controls, miR-26b-5p, miR-660-5p and miR-320a were confirmed to be dysregulated in patients with a MACE within the follow-up period. The area under the receiver operator characteristic curves of Cox regression models could significantly discriminate patients with MACE from controls in the case of all three miRNAs, and a combination of the three yielded an incremental increased in the AUC-ROC. Furthermore, addition of miR-26b-5p, but not miR-660-5p or miR-320a, to the Global Registry of Acute Coronary Events (GRACE)-score increased AUC, and a combination of the three miRNAs increased net reclassification improvement (NRI). Interestingly, these three miRNAs have previously been shown to play roles in cardiomyocyte apoptosis (13), platelet activation (14), and cardiac hypertrophy (15), indicating that the presence of these miRNAs in the circulation is a reflection of underlying disease mechanisms. The study is the first to assess miRNAs related to adverse prognosis in a secondary prevention cohort of STEMI patients, but confirmation of these potential biomarkers in larger cohorts is required if clinical utility is to be established.
The notion of circulating miRNAs as diagnostic and prognostic tools for patients with cardiovascular disease has gained ever-increasing traction in recent years, but clinical implementation still seems distant. Sources of technical and biological variation still need elucidation (16) and the analytical workflow for plasma miRNA samples must be streamlined and standardized. Still, the results of Jakob et al. shows that clinical utility for miRNAs in cardiovascular risk prediction is perhaps not simply a fading “miRage”.
Conflicts of Interest: The author has no conflicts of interest to declare.
- Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2016;37:2315-81. [Crossref] [PubMed]
- Jakob P, Kacprowski T, Briand-Schumacher S, et al. Profiling and validation of circulating microRNAs for cardiovascular events in patients presenting with ST-segment elevation myocardial infarction. Eur Heart J 2017;38:511-5. [PubMed]
- Bartel DP. MicroRNAs: Target Recognition and Regulatory Functions. Cell 2009;136:215-33. [Crossref] [PubMed]
- Mitchell PS, Parkin RK, Kroh EM, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA 2008;105:10513-8. [Crossref] [PubMed]
- Wang GK, Zhu JQ, Zhang JT, et al. Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans. Eur Heart J 2010;31:659-66. [Crossref] [PubMed]
- Ai J, Zhang R, Li Y, et al. Circulating microRNA-1 as a potential novel biomarker for acute myocardial infarction. Biochem Biophys Res Commun 2010;391:73-7. [Crossref] [PubMed]
- D’Alessandra Y, Devanna P, Limana F, et al. Circulating microRNAs are new and sensitive biomarkers of myocardial infarction. Eur Heart J 2010;31:2765-73. [Crossref] [PubMed]
- Vogel B, Keller A, Frese KS, et al. Refining diagnostic MicroRNA signatures by whole-miRNome kinetic analysis in acute myocardial infarction. Clin Chem 2013;59:410-8. [Crossref] [PubMed]
- Gidlöf O, Andersson P, Van Der Pals J, et al. 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. Cardiology 2011;118:217-26. [Crossref] [PubMed]
- Meder B, Keller A, Vogel B, et al. MicroRNA signatures in total peripheral blood as novel biomarkers for acute myocardial infarction. Basic Res Cardiol 2011;106:13-23. [Crossref] [PubMed]
- Zampetaki A, Willeit P, Tilling L, et al. Prospective study on circulating microRNAs and risk of myocardial infarction. J Am Coll Cardiol 2012;60:290-9. [Crossref] [PubMed]
- Widera C, Gupta SK, Lorenzen JM, et al. Diagnostic and prognostic impact of six circulating microRNAs in acute coronary syndrome. J Mol Cell Cardiol 2011;51:872-5. [Crossref] [PubMed]
- Ren XP, Wu J, Wang X, et al. MicroRNA-320 is involved in the regulation of cardiac ischemia/reperfusion injury by targeting heat-shock protein 20. Circulation 2009;119:2357-66. [Crossref] [PubMed]
- Emmrich S, Henke K, Hegermann J, et al. MiRNAs can increase the efficiency of ex vivo platelet generation. Ann Hematol 2012;91:1673-84. [Crossref] [PubMed]
- Han M, Yang Z, Sayed D, et al. GATA4 expression is primarily regulated via a miR-26b-dependent post-transcriptional mechanism during cardiac hypertrophy. Cardiovasc Res 2012;93:645-54. [Crossref] [PubMed]
- Poller W, Dimmeler S, Heymans S, et al. Non-coding RNAs in cardiovascular diseases: diagnostic and therapeutic perspectives. Eur Heart J 2017. [Epub ahead of print]. [Crossref] [PubMed]
Cite this article as: Gidlöf O. Circulating microRNAs as predictors of cardiovascular disease—more than a miRage? J Lab Precis Med 2017;2:22.