The authors have declared that no competing interests exist.
Conceived and designed the experiments: CC QW. Performed the experiments: CC QW. Analyzed the data: CC QW MC JX. Contributed reagents/materials/analysis tools: MC JX. Wrote the paper: CC QW WY JX. Proofread the manuscript: WY. Paid for some articles: MC.
Recent studies have demonstrated that acute myocardial infarction induces a distinctive miRNA signature, suggesting that miRNAs may serve as diagnostic markers. Although many studies have investigated the use of miRNAs in the detection of cardiac injury, some had small sample sizes (<100 patients) or reported different results for the same miRNA. Here, the role of circulating miRNAs for use as biomarkers of myocardial infarction is summarized and analyzed.
Medline, SCI, Embase, and Cochrane databases were searched up to January 2013 for studies that evaluated associations between miRNAs and myocardial infarction. Relevant publications were identified by searching for combinations of “myocardial infarction,” “miRNAs,” and their synonyms. Methodological quality was scored using a standardized list of criteria, and diagnostic performance was assessed using estimates of test sensitivity and specificity. These values were summarized using summary receiver-operating characteristic curves. Nineteen studies met the inclusion criteria: 15 studies reported sensitivity, specificity, and AUC, but 4 studies did not.
MiRNAs, especially miR-499 and miR-133a, may be suitable for use as diagnostic biomarkers of myocardial infarction.
Coronary artery disease (CAD) and acute myocardial infarction (AMI) are the leading causes of death in developed and developing countries
In this review, recent information on biomarkers for AMI is summarized, focusing on the latest insights in the identification and potential use of miRNAs in the plasma and serum. The specificity and sensitivity of miRNAs were evaluated to assess the feasibility of using them as biomarkers of AMI.
Sources of studies included the Medline, SCI, Embase, and Cochrane library databases. The databases were searched from inception to January 28, 2013 for relevant studies using the terms “myocardial infarction,” “heart infarction,” “heart injury,” and “cardiovascular infarction” in combination with “miRNAs” and “microRNA” and synonyms for all five terms. Potentially associated publications were assessed by checking their titles and abstracts and the most relevant publications were subjected to closer examination. The reference lists of the selected papers were also screened for articles that might have been missed in the initial search, and references cited in the identified articles were searched manually. A manual search of abstracts from 44th Annual Scientific Meeting of the European Society for Clinical Investigation, BAS/BSCR Poster Abstracts of the HEART, the Circulation Research, the ESC Congress 2012 was conducted.
The following criteria were used for the literature selection in the meta-analysis.
All eligible studies satisfied the following inclusion criteria:
1. miRNAs and myocardial infarctions were used in outcome analysis.
2. Sample size, sensitivity, specificity, AUC, and their 95% confidence intervals (CIs) or other information that might help assess the results was required.
3. Cohort studies and case-control studies were included.
4. There were no language restrictions.
5. A sample size of more than four subjects was required for each comparison group.
Accordingly, studies were excluded based on the following criteria:
1. Studies not conducted on humans.
2. Studies not mentioning myocardial infarction in the abstract.
3. Studies without comparison groups.
4. Studies that did not explicitly state that the control group consisted of human control subjects.
5. Studies those were designed or defined markedly differently from the selected papers.
6. Review articles, abstracts presented at conferences, editorials, commentaries, and studies without complete data.
Variations in methodological quality of diagnostic studies may influence the results and conclusions of a systematic review. For this reason, the quality of each included study was assessed as follows. Two reviewers, Qiang Wang and Chao Cheng, independently scored the quality of the selected studies using a standardized set of criteria (study selection). These criteria have been used in previous reviews of diagnostic studies, and they were reported by Whiting et al. (10). Nine identical methodological criteria and three additional criteria were used in the present study (
The sensitivity, specificity, AUC, and diagnostic OR of each miRNA associated with the diagnostic value of myocardial infarction were estimated for each study. For detection of sample size bias, the sensitivity, specificity, AUC, and diagnostic OR and their 95% confidence intervals (CI) were plotted against the number of participants. The statistical heterogeneity was analyzed (χ2-based Q statistic test) and presented when I squared (I2) exceeded 50% or
A total of 935 potentially relevant abstracts were identified. After duplicates were removed, 642 unique abstracts remained. Abstracts and full-text articles were screened, and 19 publications seemed to meet all of the inclusion criteria and none of the exclusion criteria
The 19 studies included 15 studies that reported the sensitivity, specificity, and AUC clearly
Almost all the studies included here, excepting only 1
Study | Comparison | miRNA | Comparison vs. miRNAs |
Adachi, T. et al. | CKMB | miR-499 | |
2010 |
Log10[miR-499] = 3.65+0.0044 * CKMB | ||
Ai, J. et al. | QRS | miR-1 | |
2010 |
ST segment | miR-1 | |
CKMB | miR-1 | ||
cTnI | miR-1 | ||
Cheng, Y. et al. | CKMB | miR-1 | |
2010 |
CKMB = 97.89+101.84* miR-1 | ||
Corsten, M.F. et al. | CPK | miR-208b | |
2010 |
CPK | miR-499 | |
cTnT | miR-208b | ||
cTnT | miR-499 | ||
Gidlof, O. et al. | cTnT | miR-208b | |
2011 |
|||
Kuwabara, Y. et al. | cTnT | miR-1 | |
2011 |
Log[miR-1] = 0.1849×Log [cTnT] -38.618 | ||
cTnT | miR-133a | ||
Log[miR-133a] = 0.5009×Log[ cTnT] -35.51 | |||
Meder B. et al. | hsTnT | miR-30c miR-145 | |
2011 |
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Devaux, Y. et al. | hsTnT | miR-208b | ALL: |
2012 |
<3 h: |
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3–6 h: |
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6–12 h: |
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hsTnT | miR-499 | ALL: |
|
<3 h: |
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3–6 h: |
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6–12 h: |
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CK | miR-208b | ||
CK | miR-499 | ||
cTnT | miR-208b | ||
cTnT | miR-499 |
Eight studies reporting the correlations between miRNAs and other biomarkers with line charts are displayed in the table.
Study | Comparison | miRNAs | Comparison + miRNAs | Comparison vs miRNAs | |||||||||
Type | Sensitivity | Specificity | AUC(95%Cl) | Type | Sensitivity | Specificity | AUC (95%Cl) | Type | Sensitivity | Specificity | AUC (95%Cl) | ||
Oerlemans, | hsTnT | — | — | 0.86 | miR-1 | ALL | ALL | 0.75 (0.70–0.81) | hsTnT +miR-1 | 0.92 (0.90–0.95) | |||
M.I.F.J. et al. | (0.82–0.91) | miR-208a | — | — | 0.61 (0.54–9.67) | hsTnT +miR-208a | 0.89 (0.85–0.93) | _ | |||||
2012 |
miR-499 | 0.79 (0.74–0.84) | hsTnT +miR-499 | 0.92 (0.89–0.95) | |||||||||
miR-21 | 0.76 (0.71–0.82) | hsTnT +miR-21 | 0.92 (0.89–0.95) | ||||||||||
miR-146a | 0.68 (0.62–0.74) | hsTnT +miR-146a | 0.90 (0.87–0.94) | _ | |||||||||
miR-1+ miR-499 | 0.89 (0.85–0.94) | hsTnT+miR-1+ | 0.94 (0.92–0.97) | ||||||||||
+miR-21 | miR-499 +miR-21 | ||||||||||||
Olivieri, F. et al. | cTnT | — | — | 1.00 | miR-499-5p | 1.00 | 1.00 | 1.00 | |||||
2012 |
|||||||||||||
Wang, G.K. et | cTnI | <4 h: | _ | 0.987 | miR-1 | — | ALL | 0.847 (0.751–0.943) | |||||
al. 2010 |
0.85 | (0.966–1.000) | miR-133a | — | — | 0.867 (0.771–0.963) | |||||||
>4 h: | miR-499 | — | 0.822 (0.717–0.927) | ||||||||||
1.00 | miR-208a | miR-208a | 0.965 (0.92–1.00) | ||||||||||
Total: | <4 h:1.00 | ||||||||||||
0.909 | >4 h:0.846 | ||||||||||||
Total:0.909 | |||||||||||||
Devaux, Y. et | hsTnT | 0.93 | 0.98 | ALL: 0.97 | miR-208b | 0.79 | 1.00 | ALL: 0.90 | hsTnT +miR-499 | 0.95 | 0.98 | ALL: |
|
al. | <3 h: 0.94 | <3 h: 0.83 | <3 h: |
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2012 |
3–6 h: 0.98 | 3–6 h: 0.91 | 3–6 h: |
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6–12 h: 0.99 | 6–12 h: 0.95 | 6–12 h: |
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miR-499 | 0.95 | 1.00 | ALL: 0.97 | ALL: |
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<3 h: 0.96 | <3 h: |
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3–6 h: 0.99 | 3–6 h: |
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6–12 h: 0.99 | 6–12 h: |
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Gidlof, O. et al. | cTnT | 0.95 | 0.95 | 0.95 | miR-1 | 0.55 | 0.60 | 0.57 | |||||
2013 |
miR-208b | 0.75 | 0.82 | 0.82 | |||||||||
miR-499-5p | 0.78 | 0.75 | 0.79 | ||||||||||
Li, C. J. et al. | cTnT | 0.62 | 0.98 | 0.800 | miR-1 | 0.60 | 0.70 | 0.696 (0.593–0.799); | |||||
2013 |
(0.714–0.887) | miR-134 | 0.55 | 0.75 | 0.657 (0.551–0.763); | ||||||||
miR-186 | 0.78 | 0.58 | 0.715 (0.614–0.817); | ||||||||||
miR-208 | 0.78 | 0.76 | 0.778 (0.686–0.869); | ||||||||||
miR-223 | 0.78 | 0.68 | 0.741 (0.645–0.838) | ||||||||||
CKMB | 0.62 | 0.75 | 0.683 | miR-499 | 0.75 | 0.72 | 0.755 (0.662–0.849) | ||||||
(0.579–0.786) | |||||||||||||
Li, Y. Q. et al. | cTnT | 0.95 | 1.00 | 0.9820 | miR-1 | 0.78 | 0.85 | 0.8265 | |||||
2013 |
(0.9289–0.997 | (0.7441–0.9088), | |||||||||||
5) | miR-133a | 0.88 | 0.96 | 0.9468 | |||||||||
(0.9057–0.9879), | |||||||||||||
miR-208b | 0.82 | 1.00 | 0.8899 | ||||||||||
(0.8259–0.9540), | |||||||||||||
miR-499 | 0.80 | 0.94 | 0.8841 | ||||||||||
(0.8187–0.9495), |
Seven studies reporting the correlations between miRNAs and cardiac troponin with sensitivity, specificity, and AUC values charts are displayed in the table.
Study | Biomarkers | Time and fold change/max change | |||||||
D'Alessandra, Y. et al. | T0 |
3 h | 9 h | 15 h | 21 h | 33 h | 45 h | 69 h | |
2010 |
cTnI | 0.65 | 0.80 | 0.58 | 0.35 | 0.4 | 0.32 | 0.2 | 0.18 |
miR-1 | 1.0 | 0.35 | 0.1 | 0.06 | 0.05 | 0.05 | 0.06 | 0.04 | |
miR-133a | 1.0 | 0.18 | 0.05 | 0.04 | 0.03 | 0.02 | 0.03 | 0.02 | |
miR-133b | 0.9 | 0.55 | 0.2 | 0.1 | 0.07 | 0.05 | 0.05 | 0.05 | |
miR-499-5p | 0.58 | 0.65 | 0.88 | 0.5 | 0.3 | 0.1 | 0.01 | 0.01 | |
miR-122 | 0.8 | 0.4 | 0.4 | 0.3 | 0.45 | 0.4 | 0.2 | 0.4 | |
miR-375 | 1.0 | 0.3 | 0.2 | 0.19 | 0.21 | 0.1 | 0.2 | 0.4 | |
Long, G. et al. | 4 h | 8 h | 12 h | 24 h | 48 h | 721h | 1 w | ||
2012 |
cTnI | 0.8 | 0.8 | 0.55 | 0.6 | 0.3 | 0.2 | 0 | |
miR-1 | 0.2 | 1.0 | 0.35 | 0.1 | 0.3 | 0.3 | 0.2 | ||
miR-126 | 0.4 | 1.0 | 0.7 | 0.2 | 0.8 | 0.3 | 0.1 | ||
Long, G. et al. | 4 h | 8 h | 12 h | 24 h | 48 h | 72 h | 1 w | ||
2012 |
cTnI | 0.8 | 0.8 | 0.5 | 0.6 | 0.3 | 0.2 | 0 | |
miR-30a | 0.15 | 1.0 | 0.15 | 0 | 0.1 | 0.1 | 0 | ||
miR-195 | 0.1 | 1.0 | 0.15 | 0.1 | 0.05 | 0.05 | 0.05 | ||
Wang, R. et al. | Control | T0 |
20 h | 7 d | |||||
2011 |
cTnI |
1 | 15 | 18 | 1 | ||||
miR-133 |
0.4 | 0.15 | 0.2 | 0.35 | |||||
miR-328 |
0.2 | −0.2 | 0.05 | 0.1 |
Four studies reporting the fold changes/max changes or fold changes of miRNAs and cTnI with time are displayed in the table.
* T0 indicates 156±72 min after the onset of symptoms.
T0 indicates 5.24±1.38 hours after AMI.
Fold changes.
Log2 relative expression levels.
Mean score of risk for bias of all 19 included studies was 7.789, ranging from 5.00 to 10.00. In the 19 studies, only two studies had scores below 7
Some 15 studies covering 13 types of miRNA and involving a total of 2136 participants investigated the diagnostic values of miRNAs as the biomarkers of myocardial infarction
(A) Sensitivity. (B) Specificity. (C) Diagnostic OR. (D) SROC curve with AUC. (E) Funnel plot. Df, degree of freedom; OR, odds ratio; SROC, summary receiver operator characteristics; AUC, area under the curve; SE, standard error; Q*, Q index. Balls, estimated respectively the sensitivity, specificity, diagnostic OR, AUC; Bars, 95% confidence intervals (CIs); Width of diamonds, pooled CIs. The size of each ball is proportional to the weight of each study in the meta-analysis. The SROC show all values of AUC and the area between the upper left and lower right curves represent the CIs of AUC for total miRNA levels. Values that cross the borders are not shown in these figures. Boxes in the funnel plot indicated the studies included in this meta- analysis.
Eight studies covering 1634 participants evaluated the diagnostic value of miR-499 as a biomarker of myocardial infarction
(A) Sensitivity. (B) Specificity. (C) Diagnostic OR. (D) SROC curve with AUC. (E) Funnel plot. Df, degree of freedom; OR, odds ratio; SROC, summary receiver operator characteristics; AUC, area under the curve; SE, standard error; Q*, Q index. Balls, estimated respectively the sensitivity, specificity, diagnostic OR, AUC; Bars, 95% confidence intervals (CIs); Width of diamonds, pooled CIs. The size of each ball is proportional to the weight of each study in the meta-analysis. The SROC show all values of AUC and the area between the upper left and lower right curves represent the CIs of AUC for total miRNA levels. Values that cross the borders are not shown in these figures. Boxes in the funnel plot indicated the studies included in this meta- analysis.
Seven studies involving of 1031 participants investigated the diagnostic values of miR-1 as the biomarkers for myocardial infarction
(A) Sensitivity. (B) Specificity. (C) Diagnostic OR. (D) SROC curve with AUC. (E) Funnel plot. Df, degree of freedom; OR, odds ratio; SROC, summary receiver operator characteristics; AUC, area under the curve; SE, standard error; Q*, Q index. Balls, estimated respectively the sensitivity, specificity, diagnostic OR, AUC; Bars, 95% confidence intervals (CIs); Width of diamonds, pooled CIs. The size of each ball is proportional to the weight of each study in the meta-analysis. The SROC show all values of AUC and the area between the upper left and lower right curves represent the CIs of AUC for total miRNA levels. Values that cross the borders are not shown in these figures. Boxes in the funnel plot indicated the studies included in this meta- analysis.
Four studies involving 285 participants investigated the diagnostic values of miR-133a as the biomarkers for myocardial infarction
(A) Sensitivity. (B) Specificity. (C) Diagnostic OR. (D) SROC curve with AUC. (E) Funnel plot. Df, degree of freedom; OR, odds ratio; SROC, summary receiver operator characteristics; AUC, area under the curve; SE, standard error; Q*, Q index. Balls, estimated respectively the sensitivity, specificity, diagnostic OR, AUC; Bars, 95% confidence intervals (CIs); Width of diamonds, pooled CIs. The size of each ball is proportional to the weight of each study in the meta-analysis. The SROC show all values of AUC and the area between the upper left and lower right curves represent the CIs of AUC for total miRNA levels. Values that cross the borders are not shown in these figures. Boxes in the funnel plot indicated the studies included in this meta- analysis.
Six studies involving 1424 participants evaluated the diagnostic value of miR-208b as a biomarker of myocardial infarction
(A) Sensitivity. (B) Specificity. (C) Diagnostic OR. (D) SROC curve with AUC. (E) Funnel plot. Df, degree of freedom; OR, odds ratio; SROC, summary receiver operator characteristics; AUC, area under the curve; SE, standard error; Q*, Q index. Balls, estimated respectively the sensitivity, specificity, diagnostic OR, AUC; Bars, 95% confidence intervals (CIs); Width of diamonds, pooled CIs. The size of each ball is proportional to the weight of each study in the meta-analysis. The SROC show all values of AUC and the area between the upper left and lower right curves represent the CIs of AUC for total miRNA levels. Values that cross the borders are not shown in these figures. Boxes in the funnel plot indicated the studies included in this meta- analysis.
In the present study, the diagnostic value of miRNAs as biomarkers of myocardial infarction was evaluated based on observations made in relevant previous studies. Sensitivity and specificity are basic standards used to estimate the suitability of one diagnostic method. The diagnostic OR and SROC curve (AUC) values can be used to describe the characteristics of index test and its suitability as a diagnostic method. The results described above show that miRNAs are suitable for use as diagnostic biomarkers of myocardial infarction. Total miRNA levels: sensitivity: 0.78 (95%CI: 0.77–0.80;
Among all miRNAs investigated in this study, miR-499 was found to be most significantly associated with myocardial infarction. The results given above show not only the sensitivity and specificity of miR-499 to be satisfied but also highlight certain other characteristics. In the study published by Devaux et al., miR-499 levels were evaluated within hours of the onset of symptoms, which is helpful for early diagnosis
Other miRNAs in the studies included here have their own characteristics. In a study by Vogel et al., the reported miRNAs changed greatly not only early during myocardial infarction, but also during mild infarction
CKMB and cardiac troponin have been widespread used in the diagnosis of myocardial infarction. Correlations between miRNAs and other diagnostic biomarker of myocardial infarction are presented in the current study. Although some studies have used lines chart to show these relationships, some have used the AUC value and others showed their changes over time. In either case, obvious correlations are easily discovered. Ten studies reported the correlation between miRNAs and cTnT. Six studies discussed cTnI. Five studies showed the relationship between miRNAs and CKMB. The results shown in these line charts indicate that some miRNAs, like miR-1, miR122, miR375, and miR-328, changed concentration earlier than cardiac troponin I, and levels of change of some miRNAs were more obvious than others
The correlations between miR-499 and CKMB, cTnT, hs-cTnT, cTnI, and CPK merit concern. The line charts of the related studies showed the obvious correlations between miR-499 and CKMB, cTnT, hs-cTnT, and CPK
MiRNA profiles may be useful in the early detection of AMI. Early detection biomarkers may indicate the onset of a disease and often play a role in the disease
There are some shortcomings in the research for warranting a meta-analysis. The sample sizes the cases and controls are often poorly matched and there is a lack of standardization. For example, different normalization procedures have been used without taking effects of medication into consideration. Another limitation of our study is that it is based on a limited number of articles. There are two reasons for it. For one, in some article the patients included are ACS which contains AMI, the specific number of AMI is unclear in the groups. We once asked the author for the data, however we failed to get the information. For another, although some studies detected the variation of miRNA in the AMI, the data did not meet our demand because of the different purposes of research. To make sure the reliability of our study, we excluded several articles
It is possible that the miRNAs, particularly miR-499 and miR-133a, may be suitable for use as diagnostic biomarkers of myocardial infarction. MiR-208b suggests that it may also be usable, but it requires further evaluation. Other miRNAs may also be available, but more clinical studies are required to prove this.
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