- Email: [email protected]
Prognostic value of microRNAs in acute myocardial infarction: A systematic review and meta-analysis
International Journal of Cardiology 189 (2015) 79–84
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Prognostic value of microRNAs in acute myocardial infarction: A systematic review and meta-analysis Wenzhai Cao a,b,1, Qiang Guo b,1, Ting Zhang a, DeChao Zhong a,⁎, Qian Yu c,⁎ a b c
Department of Cardiology, Zigong First People's Hospital, Zigong 643000, People's Republic of China School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 61000, People's Republic of China Department of Rehabilitation, Sichuan Provincial People's Hospital, Chengdu 61000, People's Republic of China
a r t i c l e
i n f o
Article history: Received 19 March 2015 Accepted 8 April 2015 Available online 10 April 2015 Keywords: MiRNA Prognosis Acute myocardial infarction Meta-analysis
Acute myocardial infarction (AMI) remains the most common and serious cardiovascular disease worldwide. According to the American Heart Association, approximately every 44 s, an American will have an MI. The estimated annual incidence of MI is 515,000 new attacks and 205,000 recurrent attacks [1]. Patients who suffer from MI are at risk for death and illness from several causes including CHF, arrhythmias, sudden death, and recurrent myocardial infarction [2]. Although the mortality of AMI in the U.S. has been declining, prevalence of coronary artery disease and related comorbidity will still increase. Prediction of death and survival after MI is very important in planning interventions (including behavioral change, medication, and revascularization) to improve outcome. Prediction of prognosis after MI can be based on standard clinical parameters including the use of TIMI risk score [3], GRACE score [4] and the CHADS2 score [5]. However, substantial supplementary information should be attained by the use of biomarkers [6]. The value of troponin I, C-reactive protein (CRP), brain-derived natriuretic peptide (BNP) and growth differentiation factor-15 (GDF-15) in post-ACS (Acute Coronary Syndrome) risk stratification were well documented [7]. MicroRNAs (miRNAs) are small non-coding RNA molecules (containing about 22 nucleotides) which function in RNA silencing and post-transcriptional regulation of gene expression [8]. Expression levels of several miRNAs in the heart were altered in response to pathological ⁎ Corresponding authors. E-mail addresses: [email protected] (D. Zhong), [email protected] (Q. Yu). 1 The first two authors contributed equally.
http://dx.doi.org/10.1016/j.ijcard.2015.04.055 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
stress of cardiovascular disease [9]. Because of their tissue- and cellspecific pathological functions, circulating miRNAs in plasma may potentially serve as biomarkers in cardiovascular disease. Altered circulating miRNA concentrations had been detected in patients with stable coronary artery disease [10], essential hypertension [11], acute myocardial infarction [12,13], and heart failure [14]. However, prognostic value of microRNAs in acute myocardial infarction is still unclear. Some studies reported markedly varied results with the same miRNAs. For example, expression of miR-499 did not associate with the outcomes after AMI published by Goretti2013 et al. [15] contrary to other related studies [16]. This study aimed to summarize the existed evidence for prognostic value of miRNAs with the clinical outcomes in AMI patients, focusing on the latest insights in the identification and potential use of circulation miRNAs. Methods are described in the Supplementary material. A total of 1064 potentially relevant articles were identified with our search strategy. After screening by titles or abstracts, 402 replicates and 642 articles irrelevant to our study purpose were eliminated. Of the remaining 20 candidate articles, one was excluded as literature review without data; 5 articles were excluded as lack of clinical outcomes; and 2 articles were dropped from our analysis as insufficient information for calculation HR Therefore, the final meta-analysis was performed for the remaining 12 articles involving 4415 participants (Fig. 1). 21 studies in the included 12 articles covered 13 types of miRNAs with the prognostic values of biomarkers for myocardial infarction [15–26]. Among the 21 studies, 8 studies discussed miRNAs as a prognostic marker of mortality [15,17,24,25], and 14 studies assessed the association of miRNA with major adverse cardiovascular events (MACEs), including death, myocardial infarction and heart failure [18–23,25,26]. The studies were conducted in Germany, Sweden, Luxembourg, Italy, New Zealand and China. All included studies were prospective in design. An average of follow-up was from 1 month to 72 months. The method for detecting miRNA expression was quantitative real-time PCR (qRTPCR) in all included studies. The main features of eligible studies are summarized in Table 1. 8 studies evaluated the prognostic importance of miRNA for mortality in AMI patients. The meta-analysis showed higher expression levels of miRNA significantly predicted poorer survival, with every 1% increase in miRNA, the risk of all-cause mortality increased by 36% (HR 1.48, 95% CI: 1.18–1.85, P b 0.01). Heterogeneity among the studies was observed
80
W. Cao et al. / International Journal of Cardiology 189 (2015) 79–84
Fig. 1. Flow chart of the selection process.
Table 1 Characteristics of included studies on association between miRNAs and clinical outcomes. Author
Year
Origin of population
Number of patient
Widera [17]
2011
Germany
444
Eitel [18] Gidlöf [20]
2012 2013
Germany Sweden
216 424
Devaux [19]
2013
Luxembourg
150
Goretti [15]
2013
Luxembourg.
510
Olivieri [16] Lv [22] Pilbrow [23] He [21] Devaux [24] Dong [25]
2014 2014 2014 2014 2015 2015
Italy China New Zealand China Luxembourg China
142 359 235 359 1155 246
Wang [26]
2015
China
175
miRNA
Mean follow-up (months)
Definition of outcomes and no. of events
HR
6
Mortality: 34
Reported
6 1
MACEs: 28 MACEs: 74
Reported Reported
6
MACEs: 71
Reported
miR-133a miR-208b miR-133a miR-208b miR-499-5p miR-16 miR-27a miR-150 miR-101 miR-208b miR-499-5p miR-499-5p miR-208b miR-34a miR-652 miR-328 miR-134 miR-133a, miR-208b miR-145
72
Mortality: 136
-
24 6 60 6 27 12
Reported Reported Reported Reported Reported
miR-126
24
Mortality: 54 MACEs: 83 MACEs: 70 MACEs: 83 Mortality: 102 MACEs: 72 Mortality: 22 MACEs: –
Reported
W. Cao et al. / International Journal of Cardiology 189 (2015) 79–84
81
Fig. 2. A. Forest plot demonstrating the association between miRNA and mortality in AMI patient. B. Forest plot demonstrating the association between miRNA and MACEs in AMI patient.
for all-cause mortality (I2 = 84.9%) (Fig. 2A). Based on the data displayed in Fig. 2A, we concluded that high expression of miRNA indicated poor survival in AMI patients. Overall HR was pooled to calculate the correlation between miRNA expression and MACEs (death, myocardial infarction and heart failure) from 14 studies. MiRNA expression was significantly associated with MACEs. Elevated expressions of miRNA were involved in dramatically increased risk of MACEs (HR 2.00, 95% CI 1.29–3.11, I2 = 86.3) (Fig. 2B).
Formal tests for publication bias have also carried out using Egger's funnel plot (Fig. 3A–B). No publication bias was detected for the result of meta-analysis of MACEs (Egger's test, p = 0.364). However, there was statistically significant publication bias that existed for the result of Mortality (Egger's test, p = 0.01). Sensitivity analyses were performed to assess the contribution of each study to the pooled estimate by excluding individual studies one at a time and recalculating the pooled HR or OR estimates for the
82
W. Cao et al. / International Journal of Cardiology 189 (2015) 79–84
Fig. 3. A. Funnel plots of studies included in the meta-analysis for mortality. B. Funnel plots of studies included in the meta-analysis for MACEs.
remaining studies (Fig. 4A–B). Eliminating any one study did not substantially change the pooled HR in the result of meta-analysis of MACEs. While excluded from 2 studies [15,24] in the meta-analysis of mortality, the pooled data would change accordingly. When percutaneous coronary revascularization and thrombolysis were widely accepted as a standard therapy for AMI, mortality of AMI patients decreased gradually in the acute phase. However, the mortality from coronary artery disease remains high in the population. The risks of death, heart failure and cardiac arrhythmia persists among the AMI survivors in the long run which contribute to the mortality of coronary artery disease. Therefore, it is crucial to recognize high risk patients after AMI. Substantial information of prognosis could be obtained from the use of biomarkers. MiRNAs were established to be novel biomarkers in various diseases. Recent meta-analyses demonstrated that miRNAs could be suitable for use as diagnostic biomarker for AMI [27]. The prognostic value of miRNAs in AMI is still unclear. The correlation between miRNA expression and clinical outcomes needs to be determined. As far as we know, this is the first meta-analysis of the prognostic value of miRNAs for AMI.
This systematic review and meta-analysis calculated pooled HRs from 4415 patients with acute myocardial infarction in 21 studies. Our result of pooled HR for MACEs was 2.00 (95% CI 1.29–3.11, P b 0.05). The interval of HR did not overlap 1, which demonstrated that the miRNA expression associated with increased risk of adverse clinical outcomes. We also evaluated correlation between miRNA expression and mortality. Pooled HRs from 8 studies was 1.48 (95% CI: 1.18–1.85, P b 0.05), which indicated that over expression of miRNA was positively related to shorter survival time. The association of miRNA expression and clinical outcome could be partly reasoned by their biological functions. MiR-208, one of the most mentioned miRNA in this meta-analysis, was also steadily detected in previous studies. MiR-208 was encoded by the intron of MYH6 (myosin, heavy chain 6, cardiac muscle and alpha) in both human and rat. Meanwhile, this miRNA's sequence was highly conserved between the two species. Existing evidence demonstrated that miR-208 had a positive correlation with cardiac fibrosis by increasing endoglin and collagen I expression in rats [28]. Furthermore, inhibition of miR-208 expression and knock-out miR-208 gene could reduce or even prevent from cardiac
W. Cao et al. / International Journal of Cardiology 189 (2015) 79–84
83
Fig. 4. A. Sensitivity analysis of the result of the meta-analysis for mortality. B. Sensitivity analysis of the result of the meta-analysis for MACEs.
fibrosis in rats [29]. Cardiac fibrosis after myocardial infarction has been identified as a key player in the development of heart failure. Therefore, some miRNAs could be a possible promoter for heart failure and other adverse clinical outcomes. There were also some limitations in the meta-analysis which should be considered. First, substantial heterogeneity was detected among the included studies. The potential sources of heterogeneity could arise from population, sample size, duration of follow-up, miRNAs cut-offs and severity of AMI. Due to various miRNAs included in the metaanalysis, the cut-offs of each miRNAs were divergent. While there is no general consensus on normalization of RT-PCR conditions, cut-off values for the same miRNA even differed among individual researchers. Second, the method of calculation or extraction of data from survival curves might be less reliable, compared to those directly obtained from original article. Third, publication bias was discovered by Egger's test for the result of mortality. Although limited number of studies for analysis on mortality could be a possible source of the publication bias, it was worth noting that positive results were prone to acceptance for publication than negative results. Fourth, due to few articles focusing
on the same miRNAs and incomplete data supplied by original articles, we did not perform further subgroup analysis according to miRNA type, drug therapy and other clinical variables. Finally, on the basis of sensitivity analysis, the result from meta-analysis on mortality was affected mainly by the 2 studies. As the limited number of available studies on mortality, these 2 studies had a large size of study population which constituted a large weight of pooled data. In conclusion, despite some limitations mentioned above, we found that high miRNA expression may be an independent risk factor for patients with AMI. Based on the currently published literature, high miRNA expression was a negative prognostic factor in AMI patients and could be a promising prognostic biomarker. Further large prospective studies using normalized test for miRNA are warranted to validate our conclusion. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2015.04.055.
84
W. Cao et al. / International Journal of Cardiology 189 (2015) 79–84
References [1] A.S. Go, D. Mozaffarian, V.L. Roger, et al., Heart disease and stroke statistics–2014 update: a report from the American Heart Association, Circulation 129 (2014) e28–e292. [2] P.T. O'Gara, F.G. Kushner, D.D. Ascheim, et al., 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the American College of Emergency Physicians and Society for Cardiovascular Angiography and Interventions, Catheter. Cardiovasc. Interv. 82 (2013) E1–27. [3] Q.A. Truong, C.P. Cannon, N.A. Zakai, et al., Thrombolysis in Myocardial Infarction (TIMI) Risk Index predicts long-term mortality and heart failure in patients with ST-elevation myocardial infarction in the TIMI 2 clinical trial, Am. Heart J. 157 (2009) 673–679 (e671). [4] P. de Araujo Goncalves, J. Ferreira, C. Aguiar, et al., TIMI, PURSUIT, and GRACE risk scores: sustained prognostic value and interaction with revascularization in NSTEACS, Eur. Heart J. 26 (2005) 865–872 (Catheter. Cardiovasc. Interv.). [5] S.S. Huang, Y.H. Chen, W.L. Chan, et al., Usefulness of the CHADS2 score for prognostic stratification of patients with acute myocardial infarction, Am. J. Cardiol. 114 (2014) 1309–1314. [6] T.R. Cimato, Emerging strategies to prevent heart failure after myocardial infarction, F1000Research 4 (2015) 37. [7] M.S. Sabatine, D.A. Morrow, J.A. de Lemos, et al., Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes: simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide, Circulation 105 (2002) 1760–1763. [8] D.P. Bartel, MicroRNAs: genomics, biogenesis, mechanism, and function, Cell 116 (2004) 281–297. [9] M.V. Latronico, G. Condorelli, MicroRNAs and cardiac pathology, Nat. Rev. Cardiol. 6 (2009) 419–429. [10] S. Fichtlscherer, S. De Rosa, H. Fox, et al., Circulating microRNAs in patients with coronary artery disease, Circ. Res. 107 (2010) 677–684. [11] S. Li, J. Zhu, W. Zhang, et al., Signature microRNA expression profile of essential hypertension and its novel link to human cytomegalovirus infection, Circulation 124 (2011) 175–184. [12] G.K. Wang, J.Q. Zhu, J.T. Zhang, et al., Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans, Eur. Heart J. 31 (2010) 659–666. [13] J. Zhong, Y. He, W. Chen, et al., Circulating microRNA-19a as a potential novel biomarker for diagnosis of acute myocardial infarction, Int. J. Mol. Sci. 15 (2014) 20355–20364.
[14] A.J. Tijsen, E.E. Creemers, P.D. Moerland, et al., MiR423-5p as a circulating biomarker for heart failure, Circ. Res. 106 (2010) 1035–1039. [15] E. Goretti, M. Vausort, D.R. Wagner, et al., Association between circulating microRNAs, cardiovascular risk factors and outcome in patients with acute myocardial infarction, Int. J. Cardiol. 168 (2013) 4548–4550. [16] F. Olivieri, R. Antonicelli, L. Spazzafumo, et al., Admission levels of circulating miR499-5p and risk of death in elderly patients after acute non-ST elevation myocardial infarction, Int. J. Cardiol. 172 (2014) e276–278. [17] C. Widera, S.K. Gupta, J.M. Lorenzen, et al., Diagnostic and prognostic impact of six circulating microRNAs in acute coronary syndrome, J. Mol. Cell. Cardiol. 51 (2011) 872–875. [18] I. Eitel, V. Adams, P. Dieterich, et al., Relation of circulating MicroRNA-133a concentrations with myocardial damage and clinical prognosis in ST-elevation myocardial infarction, Am. Heart J. 164 (2012) 706–714. [19] Y. Devaux, M. Vausort, G.P. McCann, et al., A panel of 4 microRNAs facilitates the prediction of left ventricular contractility after acute myocardial infarction, PLoS One 8 (2013) e70644. [20] O. Gidlof, J.G. Smith, K. Miyazu, et al., Circulating cardio-enriched microRNAs are associated with long-term prognosis following myocardial infarction, BMC Cardiovasc. Disord. 13 (2013) 12. [21] F. He, P. Lv, X. Zhao, et al., Predictive value of circulating miR-328 and miR-134 for acute myocardial infarction, Mol. Cell. Biochem. 394 (2014) 137–144. [22] P. Lv, M. Zhou, J. He, et al., Circulating miR-208b and miR-34a are associated with left ventricular remodeling after acute myocardial infarction, Int. J. Cardiol. 15 (2014) 5774–5788. [23] A.P. Pilbrow, L. Cordeddu, V.A. Cameron, et al., Circulating miR-323-3p and miR-652: candidate markers for the presence and progression of acute coronary syndromes, Int. J. Cardiol. 176 (2014) 375–385. [24] Y. Devaux, M. Mueller, P. Haaf, et al., Diagnostic and prognostic value of circulating microRNAs in patients with acute chest pain, J. Intern. Med. 277 (2015) 260–271. [25] Y.M. Dong, X.X. Liu, G.Q. Wei, et al., Prediction of long-term outcome after acute myocardial infarction using circulating miR-145, Scand. J. Clin. Lab. Invest. 75 (2015) 85–91. [26] J.H.X. Wang, K.G. Jia, et al., Circulating microRNA-126:a potential role in diagnosis and prognosis of acute myocardial infarction, Chin. J. Clin. 9 (2015) 409–414. [27] C. Cheng, Q. Wang, W. You, et al., MiRNAs as biomarkers of myocardial infarction: a meta-analysis, PLoS One 9 (2014) e88566. [28] Y. Nishimura, C. Kondo, Y. Morikawa, et al., Plasma miR-208 as a useful biomarker for drug-induced cardiotoxicity in rats, J. Appl. Toxicol. 35 (2015) 173–180. [29] B.W. Wang, G.J. Wu, W.P. Cheng, et al., MicroRNA-208a increases myocardial fibrosis via endoglin in volume overloading heart, PLoS One 9 (2014) e84188.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Prognostic value of microRNAs in acute myocardial infarction: A systematic review and meta-analysis Wenzhai Cao a,b,1, Qiang Guo b,1, Ting Zhang a, DeChao Zhong a,⁎, Qian Yu c,⁎ a b c
Department of Cardiology, Zigong First People's Hospital, Zigong 643000, People's Republic of China School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 61000, People's Republic of China Department of Rehabilitation, Sichuan Provincial People's Hospital, Chengdu 61000, People's Republic of China
a r t i c l e
i n f o
Article history: Received 19 March 2015 Accepted 8 April 2015 Available online 10 April 2015 Keywords: MiRNA Prognosis Acute myocardial infarction Meta-analysis
Acute myocardial infarction (AMI) remains the most common and serious cardiovascular disease worldwide. According to the American Heart Association, approximately every 44 s, an American will have an MI. The estimated annual incidence of MI is 515,000 new attacks and 205,000 recurrent attacks [1]. Patients who suffer from MI are at risk for death and illness from several causes including CHF, arrhythmias, sudden death, and recurrent myocardial infarction [2]. Although the mortality of AMI in the U.S. has been declining, prevalence of coronary artery disease and related comorbidity will still increase. Prediction of death and survival after MI is very important in planning interventions (including behavioral change, medication, and revascularization) to improve outcome. Prediction of prognosis after MI can be based on standard clinical parameters including the use of TIMI risk score [3], GRACE score [4] and the CHADS2 score [5]. However, substantial supplementary information should be attained by the use of biomarkers [6]. The value of troponin I, C-reactive protein (CRP), brain-derived natriuretic peptide (BNP) and growth differentiation factor-15 (GDF-15) in post-ACS (Acute Coronary Syndrome) risk stratification were well documented [7]. MicroRNAs (miRNAs) are small non-coding RNA molecules (containing about 22 nucleotides) which function in RNA silencing and post-transcriptional regulation of gene expression [8]. Expression levels of several miRNAs in the heart were altered in response to pathological ⁎ Corresponding authors. E-mail addresses: [email protected] (D. Zhong), [email protected] (Q. Yu). 1 The first two authors contributed equally.
http://dx.doi.org/10.1016/j.ijcard.2015.04.055 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
stress of cardiovascular disease [9]. Because of their tissue- and cellspecific pathological functions, circulating miRNAs in plasma may potentially serve as biomarkers in cardiovascular disease. Altered circulating miRNA concentrations had been detected in patients with stable coronary artery disease [10], essential hypertension [11], acute myocardial infarction [12,13], and heart failure [14]. However, prognostic value of microRNAs in acute myocardial infarction is still unclear. Some studies reported markedly varied results with the same miRNAs. For example, expression of miR-499 did not associate with the outcomes after AMI published by Goretti2013 et al. [15] contrary to other related studies [16]. This study aimed to summarize the existed evidence for prognostic value of miRNAs with the clinical outcomes in AMI patients, focusing on the latest insights in the identification and potential use of circulation miRNAs. Methods are described in the Supplementary material. A total of 1064 potentially relevant articles were identified with our search strategy. After screening by titles or abstracts, 402 replicates and 642 articles irrelevant to our study purpose were eliminated. Of the remaining 20 candidate articles, one was excluded as literature review without data; 5 articles were excluded as lack of clinical outcomes; and 2 articles were dropped from our analysis as insufficient information for calculation HR Therefore, the final meta-analysis was performed for the remaining 12 articles involving 4415 participants (Fig. 1). 21 studies in the included 12 articles covered 13 types of miRNAs with the prognostic values of biomarkers for myocardial infarction [15–26]. Among the 21 studies, 8 studies discussed miRNAs as a prognostic marker of mortality [15,17,24,25], and 14 studies assessed the association of miRNA with major adverse cardiovascular events (MACEs), including death, myocardial infarction and heart failure [18–23,25,26]. The studies were conducted in Germany, Sweden, Luxembourg, Italy, New Zealand and China. All included studies were prospective in design. An average of follow-up was from 1 month to 72 months. The method for detecting miRNA expression was quantitative real-time PCR (qRTPCR) in all included studies. The main features of eligible studies are summarized in Table 1. 8 studies evaluated the prognostic importance of miRNA for mortality in AMI patients. The meta-analysis showed higher expression levels of miRNA significantly predicted poorer survival, with every 1% increase in miRNA, the risk of all-cause mortality increased by 36% (HR 1.48, 95% CI: 1.18–1.85, P b 0.01). Heterogeneity among the studies was observed
80
W. Cao et al. / International Journal of Cardiology 189 (2015) 79–84
Fig. 1. Flow chart of the selection process.
Table 1 Characteristics of included studies on association between miRNAs and clinical outcomes. Author
Year
Origin of population
Number of patient
Widera [17]
2011
Germany
444
Eitel [18] Gidlöf [20]
2012 2013
Germany Sweden
216 424
Devaux [19]
2013
Luxembourg
150
Goretti [15]
2013
Luxembourg.
510
Olivieri [16] Lv [22] Pilbrow [23] He [21] Devaux [24] Dong [25]
2014 2014 2014 2014 2015 2015
Italy China New Zealand China Luxembourg China
142 359 235 359 1155 246
Wang [26]
2015
China
175
miRNA
Mean follow-up (months)
Definition of outcomes and no. of events
HR
6
Mortality: 34
Reported
6 1
MACEs: 28 MACEs: 74
Reported Reported
6
MACEs: 71
Reported
miR-133a miR-208b miR-133a miR-208b miR-499-5p miR-16 miR-27a miR-150 miR-101 miR-208b miR-499-5p miR-499-5p miR-208b miR-34a miR-652 miR-328 miR-134 miR-133a, miR-208b miR-145
72
Mortality: 136
-
24 6 60 6 27 12
Reported Reported Reported Reported Reported
miR-126
24
Mortality: 54 MACEs: 83 MACEs: 70 MACEs: 83 Mortality: 102 MACEs: 72 Mortality: 22 MACEs: –
Reported
W. Cao et al. / International Journal of Cardiology 189 (2015) 79–84
81
Fig. 2. A. Forest plot demonstrating the association between miRNA and mortality in AMI patient. B. Forest plot demonstrating the association between miRNA and MACEs in AMI patient.
for all-cause mortality (I2 = 84.9%) (Fig. 2A). Based on the data displayed in Fig. 2A, we concluded that high expression of miRNA indicated poor survival in AMI patients. Overall HR was pooled to calculate the correlation between miRNA expression and MACEs (death, myocardial infarction and heart failure) from 14 studies. MiRNA expression was significantly associated with MACEs. Elevated expressions of miRNA were involved in dramatically increased risk of MACEs (HR 2.00, 95% CI 1.29–3.11, I2 = 86.3) (Fig. 2B).
Formal tests for publication bias have also carried out using Egger's funnel plot (Fig. 3A–B). No publication bias was detected for the result of meta-analysis of MACEs (Egger's test, p = 0.364). However, there was statistically significant publication bias that existed for the result of Mortality (Egger's test, p = 0.01). Sensitivity analyses were performed to assess the contribution of each study to the pooled estimate by excluding individual studies one at a time and recalculating the pooled HR or OR estimates for the
82
W. Cao et al. / International Journal of Cardiology 189 (2015) 79–84
Fig. 3. A. Funnel plots of studies included in the meta-analysis for mortality. B. Funnel plots of studies included in the meta-analysis for MACEs.
remaining studies (Fig. 4A–B). Eliminating any one study did not substantially change the pooled HR in the result of meta-analysis of MACEs. While excluded from 2 studies [15,24] in the meta-analysis of mortality, the pooled data would change accordingly. When percutaneous coronary revascularization and thrombolysis were widely accepted as a standard therapy for AMI, mortality of AMI patients decreased gradually in the acute phase. However, the mortality from coronary artery disease remains high in the population. The risks of death, heart failure and cardiac arrhythmia persists among the AMI survivors in the long run which contribute to the mortality of coronary artery disease. Therefore, it is crucial to recognize high risk patients after AMI. Substantial information of prognosis could be obtained from the use of biomarkers. MiRNAs were established to be novel biomarkers in various diseases. Recent meta-analyses demonstrated that miRNAs could be suitable for use as diagnostic biomarker for AMI [27]. The prognostic value of miRNAs in AMI is still unclear. The correlation between miRNA expression and clinical outcomes needs to be determined. As far as we know, this is the first meta-analysis of the prognostic value of miRNAs for AMI.
This systematic review and meta-analysis calculated pooled HRs from 4415 patients with acute myocardial infarction in 21 studies. Our result of pooled HR for MACEs was 2.00 (95% CI 1.29–3.11, P b 0.05). The interval of HR did not overlap 1, which demonstrated that the miRNA expression associated with increased risk of adverse clinical outcomes. We also evaluated correlation between miRNA expression and mortality. Pooled HRs from 8 studies was 1.48 (95% CI: 1.18–1.85, P b 0.05), which indicated that over expression of miRNA was positively related to shorter survival time. The association of miRNA expression and clinical outcome could be partly reasoned by their biological functions. MiR-208, one of the most mentioned miRNA in this meta-analysis, was also steadily detected in previous studies. MiR-208 was encoded by the intron of MYH6 (myosin, heavy chain 6, cardiac muscle and alpha) in both human and rat. Meanwhile, this miRNA's sequence was highly conserved between the two species. Existing evidence demonstrated that miR-208 had a positive correlation with cardiac fibrosis by increasing endoglin and collagen I expression in rats [28]. Furthermore, inhibition of miR-208 expression and knock-out miR-208 gene could reduce or even prevent from cardiac
W. Cao et al. / International Journal of Cardiology 189 (2015) 79–84
83
Fig. 4. A. Sensitivity analysis of the result of the meta-analysis for mortality. B. Sensitivity analysis of the result of the meta-analysis for MACEs.
fibrosis in rats [29]. Cardiac fibrosis after myocardial infarction has been identified as a key player in the development of heart failure. Therefore, some miRNAs could be a possible promoter for heart failure and other adverse clinical outcomes. There were also some limitations in the meta-analysis which should be considered. First, substantial heterogeneity was detected among the included studies. The potential sources of heterogeneity could arise from population, sample size, duration of follow-up, miRNAs cut-offs and severity of AMI. Due to various miRNAs included in the metaanalysis, the cut-offs of each miRNAs were divergent. While there is no general consensus on normalization of RT-PCR conditions, cut-off values for the same miRNA even differed among individual researchers. Second, the method of calculation or extraction of data from survival curves might be less reliable, compared to those directly obtained from original article. Third, publication bias was discovered by Egger's test for the result of mortality. Although limited number of studies for analysis on mortality could be a possible source of the publication bias, it was worth noting that positive results were prone to acceptance for publication than negative results. Fourth, due to few articles focusing
on the same miRNAs and incomplete data supplied by original articles, we did not perform further subgroup analysis according to miRNA type, drug therapy and other clinical variables. Finally, on the basis of sensitivity analysis, the result from meta-analysis on mortality was affected mainly by the 2 studies. As the limited number of available studies on mortality, these 2 studies had a large size of study population which constituted a large weight of pooled data. In conclusion, despite some limitations mentioned above, we found that high miRNA expression may be an independent risk factor for patients with AMI. Based on the currently published literature, high miRNA expression was a negative prognostic factor in AMI patients and could be a promising prognostic biomarker. Further large prospective studies using normalized test for miRNA are warranted to validate our conclusion. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2015.04.055.
84
W. Cao et al. / International Journal of Cardiology 189 (2015) 79–84
References [1] A.S. Go, D. Mozaffarian, V.L. Roger, et al., Heart disease and stroke statistics–2014 update: a report from the American Heart Association, Circulation 129 (2014) e28–e292. [2] P.T. O'Gara, F.G. Kushner, D.D. Ascheim, et al., 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the American College of Emergency Physicians and Society for Cardiovascular Angiography and Interventions, Catheter. Cardiovasc. Interv. 82 (2013) E1–27. [3] Q.A. Truong, C.P. Cannon, N.A. Zakai, et al., Thrombolysis in Myocardial Infarction (TIMI) Risk Index predicts long-term mortality and heart failure in patients with ST-elevation myocardial infarction in the TIMI 2 clinical trial, Am. Heart J. 157 (2009) 673–679 (e671). [4] P. de Araujo Goncalves, J. Ferreira, C. Aguiar, et al., TIMI, PURSUIT, and GRACE risk scores: sustained prognostic value and interaction with revascularization in NSTEACS, Eur. Heart J. 26 (2005) 865–872 (Catheter. Cardiovasc. Interv.). [5] S.S. Huang, Y.H. Chen, W.L. Chan, et al., Usefulness of the CHADS2 score for prognostic stratification of patients with acute myocardial infarction, Am. J. Cardiol. 114 (2014) 1309–1314. [6] T.R. Cimato, Emerging strategies to prevent heart failure after myocardial infarction, F1000Research 4 (2015) 37. [7] M.S. Sabatine, D.A. Morrow, J.A. de Lemos, et al., Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes: simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide, Circulation 105 (2002) 1760–1763. [8] D.P. Bartel, MicroRNAs: genomics, biogenesis, mechanism, and function, Cell 116 (2004) 281–297. [9] M.V. Latronico, G. Condorelli, MicroRNAs and cardiac pathology, Nat. Rev. Cardiol. 6 (2009) 419–429. [10] S. Fichtlscherer, S. De Rosa, H. Fox, et al., Circulating microRNAs in patients with coronary artery disease, Circ. Res. 107 (2010) 677–684. [11] S. Li, J. Zhu, W. Zhang, et al., Signature microRNA expression profile of essential hypertension and its novel link to human cytomegalovirus infection, Circulation 124 (2011) 175–184. [12] G.K. Wang, J.Q. Zhu, J.T. Zhang, et al., Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans, Eur. Heart J. 31 (2010) 659–666. [13] J. Zhong, Y. He, W. Chen, et al., Circulating microRNA-19a as a potential novel biomarker for diagnosis of acute myocardial infarction, Int. J. Mol. Sci. 15 (2014) 20355–20364.
[14] A.J. Tijsen, E.E. Creemers, P.D. Moerland, et al., MiR423-5p as a circulating biomarker for heart failure, Circ. Res. 106 (2010) 1035–1039. [15] E. Goretti, M. Vausort, D.R. Wagner, et al., Association between circulating microRNAs, cardiovascular risk factors and outcome in patients with acute myocardial infarction, Int. J. Cardiol. 168 (2013) 4548–4550. [16] F. Olivieri, R. Antonicelli, L. Spazzafumo, et al., Admission levels of circulating miR499-5p and risk of death in elderly patients after acute non-ST elevation myocardial infarction, Int. J. Cardiol. 172 (2014) e276–278. [17] C. Widera, S.K. Gupta, J.M. Lorenzen, et al., Diagnostic and prognostic impact of six circulating microRNAs in acute coronary syndrome, J. Mol. Cell. Cardiol. 51 (2011) 872–875. [18] I. Eitel, V. Adams, P. Dieterich, et al., Relation of circulating MicroRNA-133a concentrations with myocardial damage and clinical prognosis in ST-elevation myocardial infarction, Am. Heart J. 164 (2012) 706–714. [19] Y. Devaux, M. Vausort, G.P. McCann, et al., A panel of 4 microRNAs facilitates the prediction of left ventricular contractility after acute myocardial infarction, PLoS One 8 (2013) e70644. [20] O. Gidlof, J.G. Smith, K. Miyazu, et al., Circulating cardio-enriched microRNAs are associated with long-term prognosis following myocardial infarction, BMC Cardiovasc. Disord. 13 (2013) 12. [21] F. He, P. Lv, X. Zhao, et al., Predictive value of circulating miR-328 and miR-134 for acute myocardial infarction, Mol. Cell. Biochem. 394 (2014) 137–144. [22] P. Lv, M. Zhou, J. He, et al., Circulating miR-208b and miR-34a are associated with left ventricular remodeling after acute myocardial infarction, Int. J. Cardiol. 15 (2014) 5774–5788. [23] A.P. Pilbrow, L. Cordeddu, V.A. Cameron, et al., Circulating miR-323-3p and miR-652: candidate markers for the presence and progression of acute coronary syndromes, Int. J. Cardiol. 176 (2014) 375–385. [24] Y. Devaux, M. Mueller, P. Haaf, et al., Diagnostic and prognostic value of circulating microRNAs in patients with acute chest pain, J. Intern. Med. 277 (2015) 260–271. [25] Y.M. Dong, X.X. Liu, G.Q. Wei, et al., Prediction of long-term outcome after acute myocardial infarction using circulating miR-145, Scand. J. Clin. Lab. Invest. 75 (2015) 85–91. [26] J.H.X. Wang, K.G. Jia, et al., Circulating microRNA-126:a potential role in diagnosis and prognosis of acute myocardial infarction, Chin. J. Clin. 9 (2015) 409–414. [27] C. Cheng, Q. Wang, W. You, et al., MiRNAs as biomarkers of myocardial infarction: a meta-analysis, PLoS One 9 (2014) e88566. [28] Y. Nishimura, C. Kondo, Y. Morikawa, et al., Plasma miR-208 as a useful biomarker for drug-induced cardiotoxicity in rats, J. Appl. Toxicol. 35 (2015) 173–180. [29] B.W. Wang, G.J. Wu, W.P. Cheng, et al., MicroRNA-208a increases myocardial fibrosis via endoglin in volume overloading heart, PLoS One 9 (2014) e84188.