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microRNA assays for acute coronary syndromes

  • Omid Shirvani Samani and Benjamin Meder EMAIL logo
Published/Copyright: November 28, 2016
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Diagnosis
From the journal Diagnosis Volume 3 Issue 4

Abstract

microRNAs are promising biomarkers for diverse cardiovascular diseases. While quantification of the small non-coding RNAs is routinely performed in the research laboratory, clinical-grade assessment of microRNAs in central laboratory environments or point-of-care testing is still in its infancy. In this review, we provide an overview on microRNAs as biomarkers for acute coronary syndromes and highlight promising technical approaches for microRNA-based assays systems.

Keywords: acute coronary syndromes (ACS); assay; microRNA; troponin

Introduction

Biochemical assays based on cardiac troponin T (cTnT) and I (cTnI) have become the gold standard for the diagnosis and risk prediction of patients with acute coronary syndromes (ACS) and myocardial necrosis [1]. The latest generation of high-sensitivity cTn immunoassays (hs-cTn) is even superior in terms of their improved diagnostic ability to detect early and even subtle, yet clinically important changes in circulating cTn [2]. Combining this superior sensitivity with dynamic changes over time allows early rule-in as well as rule-out of patients with suspected ACS.

Even though sensitive cardiac troponin assays are cardiac specific, they are not diagnosis specific [3]. The same is true for previous generation troponin assays [4], although the problem was not that obvious. Exemplarily, it has been reported that about 30% of patients admitted with positive troponin test results are actually not affected by an ACS [4]. Cardiomyocyte stress, either physiological or pathological, advanced age as well as impaired renal function [5] are alternative reasons for acute or chronic elevations in cTn levels (Table 1).

Table 1:

Troponin has been reported to be elevated due to different causes (modified from [6]).

ACS-related troponin elevationReferences
Acute myocardial infarction[7]
Open heart surgery[8]
Post-percutaneous coronary intervention[9], [10]
Non-ACS related troponin elevation
Acute heart failure[11]
Acute ischemic stroke[12], [13]
Acute pulmonary embolism[14], [15]
Aortic dissection Stanford A[16]
Asymptomatic patients with end stage renal disease[5], [17]

Cardiac contusion after blunt chest wall trauma[18], [19]

Cardiac infiltrative disorders (amyloidosis)[20]
Cardiotoxic chemotherapy[21]
Chronic heart failure[22], [23]

Heart transplant[24], [25]

High frequency ablation/current cardioversion‐defibrillator shocks[26]
Pericarditis/myocarditis[27], [28], [29]

Rhabdomyolysis[30]
Sepsis/critical ill patients[31], [32]

Strenuous exercise/ultra‐endurance athletes[33], [34], [35]

Subarachnoid hemorrhage[36]

While there is no doubt about the superior sensitivity of cTn assays, the clinical need for biomarkers that are disease specific and have high positive predictive values for ACS has led to the evaluation of additional biomarkers that might replace or supplement the existing assays. While most of these biomarker candidates including microRNAs (miRNAs) are still at the experimental stage, some have already been established in clinical routine and serve as a blueprint for future developments. Copeptin [37], [38] as an example, is the C-terminal part of pro-arginine-vasopressin and is cleaved and secreted from the neurohypophysis into the bloodstream. Arginine-vasopressin (AVP) serves the important function of adapting osmolality, blood pressure and stress response [39]. In patients with acute cardiovascular diseases such as ACS [38], Copeptin is significantly increased in peripheral blood. As Copeptin has a relatively long halftime and stability, it can be reliably measured and interpreted as a surrogate for the activation of the arginine-vasopressin system [40], which occurs in ACS even when patients are still negative for cTn [38]. The statistical power of a combined cTnT and copeptin testing allows improved classification and early rule-out of ACS patients [37], [41]. Copeptin cutoff values, confounders, the accurate point of time for its measurement and pre-test probabilities are under active clinical investigation [42].

microRNAs and their impact as novel biomarkers for cardiovascular diseases

miRNAs as part of the human regulatory transcriptome are expressed intracellularly [43] and released extracellularly, for instance into plasma, urine, saliva and breast milk [44]. Differential miRNA expression plays a role in nearly all physiological and pathophysiological processes [45], [46]. As they are associated with life threatening conditions such as cancer [47] and cardiovascular disease [48], the delineation of their function will potentially bring up a new class of biomarkers. In cardiovascular research, miRNA dysregulation is associated with a wide range of cardiac diseases, covering for instance non-ischemic systolic heart failure [48], atherosclerotic plaque [49], cardiac hypertrophy and failure [50], viral myocarditis and dilated cardiomyopathy [51] as well as arrhythmias [52]. Especially for ACS, miRNAs might provide unambiguous information in addition to cardiac troponins. Hence, hundreds of studies have demonstrated that certain miRNAs are significantly dysregulated within total peripheral blood, serum or plasma of patients with ACS (Table 2). They are transported by blood cells [56], exosomes [57], apoptotic bodies [58], microvesicles [59], lipoproteins [60] or are associated with protein complexes [61].

Table 2:

Significantly dysregulated miRNAs in plasma, serum or total peripheral blood in patients with ACS in comparison to controls.

Significantly dysregulated miRNACase groupControl groupDirection of changeAnalyzed human biomaterialMethod of miRNA expression analysisReferences
miR-30d-5p

miR-125b-5p		AMINon-ACS patientsUpPlasmaMicroarray and qRT-PCR[53]
miR-1

miR-21

miR-146a

miR-208a

miR-499		ACS (UA, NSTEMI)Non-ACS patientsUpSerumqRT-PCR[54]
miR-30c

miR-145

miR-663b

miR-1291		STEMINon-ACS patientsUp



Down		Total peripheral bloodMicroarray and qRT-PCR[55]

By analyzing total peripheral blood samples of patients with ST-segment elevation myocardial infarction (STEMI), which are considered very early ACS patients that were partially negative for troponin at hospital admission, it has been demonstrated that significantly dysregulated single miRNAs such as miR-663b as well as a signature consisting of several other miRNAs have high statistical power [55]. Specifically, non-cardiac specific miR-663b has reached an accuracy of 92.5%, but the signature was even superior in terms of AMI prediction [55]. Additionally, miRNA-30c and -145 correlated with the size of infarction estimated by day 3 troponin levels [55]. By investigating miRNAs and hs-cTnT from serum of suspected ACS patients who were admitted to the emergency department, it has been shown that miR-1, miR-21 or mir-499 in combination with hs-cTnT achieved significant higher diagnostic performance than hs-cTnT alone [54]. Furthermore, these particular miRNAs were already significantly elevated in ACS-diagnosed patients with a symptom commencement of below 3 h or with an initially negative hs-cTnT [54].

Several other studies using serum and plasma have investigated ACS and AMI predictive cardiac-specific miRNAs, an overview is provided in Table 2. Of interest, there is a large heterogeneity between most studies regarding the definition of patients and controls, biosamples, RNA isolation and quantification methods and assays for measuring the small RNA molecules. Nevertheless, miRNA biomarkers might improve the early and specific diagnosis of AMI patients. Likewise, it might increase the diagnostic performance either as a standalone biomarker or by combining miRNAs with troponin. Taking copeptin into consideration for the improved early rule-out of patients [37], [41], upcoming clinical diagnostic procedures might even integrate all three biomarkers in one conjoint index.

Clinical assay technologies for miRNA detection

miRNAs are defined by their particular nucleic acid sequences. The history of the detection of miRNAs includes many methods that more or less recognize this individual base composition, including semiquantitative real-time polymerase chain reaction, quantitative real-time polymerase chain reaction (qRT-PCR), molecular beacons, microarrays and high-throughput sequencing. First attempts for the implementation of such research methods into clinical diagnostics are made and comprise individual or combinations of these technologies [62]. However, each method has not only its advantages, e.g. next-generation sequencing enables the unbiased detection of already known but also novel miRNAs [63], but also carries critical issues that interfere with clinical application. In the case of ACS, the ideal method would be fast (time to result within 1 h), cheap and sensitive as well as specific for targeted miRNA sequences. In the case of NGS, current technologies would not fulfil these requirements, as it normally takes days to receive the expression levels of a certain miRNA. Additionally, the method is still laborious and consumes considerable resources such as consumables, hands-on time and data analysis. While suited for biomarker discovery, the translation of this method into fast turnover diagnostics seems elusive.

Searching for alternatives, recent success was made using a concept named miRNA immunoassay. Kappel et al. have developed such a blood-based immunoassay adapted for quantification of miRNAs instead of proteins. This assay can be applied onto standard immunoassay analyzers that are common in diagnostic laboratories. It has the ability to be immediately integrated into standard diagnostic procedures due to pre-existing expertise, broad implementation and cheap technology. Kappel et al. have reported that the analytical (sequence) specificity of the developed assay reaches 99.4%. Low concentrations of approximately 1 pmol/L miRNA exceed background noise and can be reliably detected. Moreover, the assay has been able to detect very subtle changes in miRNA concentrations and also linearly quantify concentrations of >3 orders of magnitude. Importantly, no time-consuming and bias introducing amplification steps are required. The procedure for quantification of miRNAs is schematically summarized in Figure 1.

Figure 1: A blood-based miRNA immunoassay comprises four main steps.Hybridization: extracted miRNAs and biotinylated catcher DNA oligonucleotides are incubated. Due to complementary matching with a specific miRNA, DNA/miRNA heterohybrids occur. Seperation of heterohybrids: incubation with streptavidin-linked microparticles. The heterohybrids bind to the streptavidin-linked microparticles because of the interaction between streptavidin and biotin. Washing: the supernatant is washed away. Detection: acridinium ester-labled monoclonal antibodies [64] are added. These antibodies bind to the completely complementary matched DNA/miRNA-heterohybrids. The addition of base and acid reagent provokes measurable chemiluminescence, because of their reactions with the acridinium ester attached at the antibodies [65].
Figure 1:

A blood-based miRNA immunoassay comprises four main steps.

Hybridization: extracted miRNAs and biotinylated catcher DNA oligonucleotides are incubated. Due to complementary matching with a specific miRNA, DNA/miRNA heterohybrids occur. Seperation of heterohybrids: incubation with streptavidin-linked microparticles. The heterohybrids bind to the streptavidin-linked microparticles because of the interaction between streptavidin and biotin. Washing: the supernatant is washed away. Detection: acridinium ester-labled monoclonal antibodies [64] are added. These antibodies bind to the completely complementary matched DNA/miRNA-heterohybrids. The addition of base and acid reagent provokes measurable chemiluminescence, because of their reactions with the acridinium ester attached at the antibodies [65].

The total time to the result of the proposed immunoassay is currently little less than 3 h, which is still too long for ACS. An advantage is that all the necessary steps can be automatically carried out by the immunoanalyzer and most of the time-consuming steps comprise not the measurement but the isolation and purification of miRNAs, which means there is large potential for optimization in non-core technologies. Another hurdle is multiplexing and measurement of signatures comprising two to 20 different miRNAs.

Addressing some of these issues, another upcoming assay technology might have considerable advantages. Hoffmann et al. [66] developed a microchip for robust signal measurement of miRNAs at a biochemical interface on a CMOS chip. The method uses a tripartite hybridization complex and simple ligation chemistry to build the measurement complex of targeted miRNA, reporter and capture strands (Figure 2). With a time to results of 30 min, the reported assay achieves a limit of detection below 1 pmol/L of key ACS miRNAs at very high sequence specificity. As for the immunoassays, a nearly linear dynamic range between 1 pM and 1 nM allows quantification of diverse miRNAs (low and highly expressed) that form an ACS signature. The small form factor might additionally allow for point-of-care-testing.

Figure 2: A CMOS chip measures electrical signal from the enzyme conjugated tripartite complex.The ACS-specific miRNA is shown in green. The time to result is approximately 30 min, isolation of miRNAs not included. (Figure modified from [66]).
Figure 2:

A CMOS chip measures electrical signal from the enzyme conjugated tripartite complex.

The ACS-specific miRNA is shown in green. The time to result is approximately 30 min, isolation of miRNAs not included. (Figure modified from [66]).

Conclusions and future challenges

The hunt for novel miRNAs that are dysregulated during disease a or b is over. With more than 10,000 studies devoted to miRNA biomarkers, the field has the obligation to move on and prove that the promise in this new biomarker class holds true. Intricate issues associated with miRNAs are their complex behavior in different analytes, the insufficient knowledge about potential confounders and the immature methodologies used to assess their expression levels. The stringent development of suitable assay technologies for miRNA detection is of ample importance to really propel them to large-scale clinical trials and application.

Corresponding author: PD Dr. Benjamin Meder, Department of Internal Medicine III, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany, Phone: +49 (0) 6221 5639564, Fax: +49 (0) 6221 564645

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: Our work is supported by grants from the German Ministry of Education and Research (“Bundesministerium für Bildung und Forschung”), the German Centre for Cardiovascular Research (“Deutsches Zentrum für Herz-Kreislauf-Forschung e. V.”), CaRNAtion, and the European Union (FP7 BestAgeing).

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

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Received: 2016-7-6
Accepted: 2016-11-4
Published Online: 2016-11-28
Published in Print: 2016-12-1

©2016 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Taking a closer look into the diagnosis of acute coronary syndrome
  4. Reviews
  5. State-of-the-art diagnosis of myocardial infarction
  6. The role of MRI and CT for diagnosis and work-up in suspected ACS
  7. Prehospital diagnosis of patients with acute myocardial infarction
  8. Mini Reviews
  9. Biomarker strategies: the diagnostic and management process of patients with suspected AMI
  10. Do we need to consider age and gender for accurate diagnosis of myocardial infarction?
  11. microRNA assays for acute coronary syndromes
  12. Opinion Paper
  13. Strategies to overcome misdiagnosis of type 1 myocardial infarction using high sensitive cardiac troponin assays
  14. Acknowledgment
https://doi.org/10.1515/dx-2016-0025
Keywords for this article
acute coronary syndromes (ACS); assay; microRNA; troponin

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Taking a closer look into the diagnosis of acute coronary syndrome
  4. Reviews
  5. State-of-the-art diagnosis of myocardial infarction
  6. The role of MRI and CT for diagnosis and work-up in suspected ACS
  7. Prehospital diagnosis of patients with acute myocardial infarction
  8. Mini Reviews
  9. Biomarker strategies: the diagnostic and management process of patients with suspected AMI
  10. Do we need to consider age and gender for accurate diagnosis of myocardial infarction?
  11. microRNA assays for acute coronary syndromes
  12. Opinion Paper
  13. Strategies to overcome misdiagnosis of type 1 myocardial infarction using high sensitive cardiac troponin assays
  14. Acknowledgment
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