miRNome in myocardial infarction: Future directions and perspective

Table 1 miRNAs with suggested role in experimental models of myocardial infarction and in myocardial infarction in humans

miRNA	Role/function	Expression in MI	Target genes	Species	Ref.
miR-1	After heat-shock up, protective against I/R	Nd	Repressing pro-apoptotic and up-regulating anti-apoptotic genes	Mouse	[40]
	Nd	Down	Nd	Mouse	[59]
	Pro-apoptotic	Up	IGF1	Rat	[45]
	Pro-arrhythmogenic	Up	Ion channels: Cx43, Kir2.1	Rat	[46]
	Predictive	Down, up	Predictive	Human	[55,56]
miR-15b	Anti-angiogenic	Down	Suggested VEGF and Ang2	Endothelial cells	[30]
miR-21	H2O2 induced cell injury	Up	PDCD4	Cardiomyocytes	[29]
	After heat-shock up, protective against I/R	Nd	Repressing pro-apoptotic and up-regulating anti-apoptotic genes	Mouse	[40]
	Response to I/R	Up in cardiac fibroblasts	PTEN	Mouse	[23]
	Anti-apoptotic	Down, up	PDCD4	Rat	[47]
	Pro-arrhythmogenic	Up	Sprouty-1, collagen I, collagen III	Rat	[48]
miR-24	Anti-fibrotic	Down	Furin	Mouse	[35]
	Anti-angiogenic, induce endothelial cell apoptosis	Down in cardiomyocytes and fibroblasts, up in endothelial cells	GATA2, PAK4 eNOS	Mouse Mouse	[36] [37]
	After heat-shock up, protective against I/R	Nd	Repressing pro-apoptotic and up-regulating anti-apoptotic genes	Mouse	[40]
miR-29 family	Anti-fibrotic	Down	Proteins involved in fibrosis (COL1A1-2, COL3A1, FBN1, ELN)	Mouse, human	[34]
miR-29b	Anti-fibrotic	Down	Proteins involved in fibrosis (COL1A1, COL3A1, αSMA)	Rat	[52]
miR-34a	Pro-apoptotic	Up	ALDH2	Rat	[49]
miR-92a	Anti-angiogenic	Up	ITGA5	Mouse	[38]
miR-101a/b	Anti-fibrotic	Down	c-Fos	Rat	[50]
miR-106b	Anti-apoptotic	Up	p21	Cardiomyocytes	[30]
miR-133a	Nd	Down	Nd	Mouse	[59]
	Predictive	Down	Predictive	Human	[55,56]
miR-133b	Predictive	Down	Predictive	Human	[55,56]
miR-146a	Predictive: inflammation and VR	Up	Predictive	Human	[57]
miR-150	Predictive: inflammation and VR	Down	Predictive	Human	[57]
miR-155	Predictive: inflammation and VR	Down	Predictive	Human	[57]
miR-206	Pro-apoptotic	Up	IGF1	Rat	[45]
miR-208a	Nd	Down	Nd	Mouse	[59]
	Predictive	Up	Predictive	Human	[55]
miR-320	Pro-apoptotic	Down	HSP20	Mouse	[41]
miR-494	Activation of Akt pathway	Down	Pro- and anti-apoptotic proteins (PTEN, ROCK1, CaMKII; FGFR2, LIF)	Mouse	[42]
miR-499	Nd	Down	Nd	Mouse	[59]
miR-711	Involved in anti-fibrotic effect of pioglitazone	Down	SP1	Rat	[51]
miR-874	Regulated by Foxo3a in necrosis	Up	Caspase 8	Mouse	[39]

I/R: Ischemia/reperfusion; MI: Myocardial infarction; Nd: Not determinate; VR: Ventricular rupture.

Table 2 miRNAs as potential diagnostic and prognostic biomarkers in myocardial infarction

miRNAs as potential biomarker	Role of biomarker	Expression in body fluid	Species and body fluid	Ref.
let-7b	Potential diagnostic value	Up	Plasma; human	[72]
let-7f	Differentiating TTC and MI	Down	Plasma; human	[79]
miR-1	Detection of AMI and AP	Up	Exosome, serum; human and mouse	[59]
	Correlation with MI size	Up	Serum; rat and human	[60]
	Differentiating AMI and AP	Up	Serum; human	[61]
	Differentiating AMI and other cardiovascular diseases	Up	Plasma; rat and human	[67]
	Similar time course to cTnI and the same trend to cTnI concentration	Up	Plasma and tissue; human and mouse	[68,70]
	Differentiating AMI and non-AMI	Up	Plasma; human	[69]
	AMI biomarkers, not superior to cTnT	Up	Plasma; human	[71]
	Associated with various degree of cardiovascular damage (AMI, viral myocarditis, diastolic dysfunction, acute HF)	Up	Plasma; human	[76]
	No association with 30 d mortality post-MI and diagnosis of HF	Up	Plasma; human	[81]
	Biomarker for AMI, correlated with renal elimination	Up	Plasma, urine; human, pig	[85]
	Detected in urine	Up	Urine; rat	[86]
miR-16	Differentiating TTC and MI	Down	Plasma; human	[79]
	Higher risk of impaired LV contractility	Up	Plasma; human	[83]
miR-21	Associated with various degree of cardiovascular damage (AMI, viral myocarditis, diastolic dysfunction, acute HF)	Nd	Plasma; human	[76]
	Differentiating NSTEMI and CHF	Up	Plasma; human	[78]
	Time-dependent changes 2-90 d post-MI	Down, up	Plasma; human	[80]
miR-26a	Differentiating TTC and MI	Down	Plasma; human	[79]
miR-27a	High risk of impaired LV contractility	Up	Plasma; human	[83]
miR-29a	Time-dependent changes 2-90 d post MI	Up	Plasma; human	[80]
miR-29b	Associated with various degree of cardiovascular damage (AMI, viral myocarditis, diastolic dysfunction, acute HF)	Nd	Plasma; human	[76]
miR-30a	Potential diagnostic value	Up	Plasma; human	[72]
miR-30c	Correlation with MI size	Up	Whole blood; human	[64]
miR-34a	Prognostic: correlated with LV end diastolic dimension	Up	Exosomes, serum; human	[62]
miR-101	Higher risk of impaired LV contractility	Down	Plasma; human	[83]
miR-126	The same trend to cTnI expression	Down	Plasma; human	[70]
	Positive association to the risk for MI	Nd	Plasma; human	[84]
miR-133a	Detection of AMI, AP: biomarker for cardiomyocyte death	Up	Exosome, serum; human and mouse	[59]
	AMI biomarker, correlation to cTnI	Up	Plasma and whole blood; human	[66]
	Differentiating AMI and other cardiovascular diseases	Up	Plasma; rat and human	[67]
	Similar time-course to cTnI	Up	Plasma and tissue; human and mouse	[68]
	AMI biomarkers, not superior to cTnT	Up	Plasma; human	[71]
	Differentiating AMI and AP, positive correlation to severity of coronary stenosis	Up	Plasma; human	[75]
	Associated with various degree of cardiovascular damage (AMI, viral myocarditis, diastolic dysfunction, acute HF)	Up	Plasma; human	[76]
	Differentiating TCC and MI	Up	Plasma; human	[79]
	Biomarker for AMI, correlated with renal elimination	Up	Plasma, urine; human, pig	[85]
miR-133b	Similar time-course to cTnI	Up	Plasma and tissue; human and mouse	[68]
miR-134	Differentiating AMI and AP	Up	Serum; human	[61]
miR-145	Correlation with MI size	Up	Whole blood; human	[64]
miR-146a	Associated with various degree of cardiovascular damage (AMI, viral myocarditis, diastolic dysfunction, acute HF)	Nd	Plasma; human	[76]
miR-150	Associated with LV remodeling	Down	Plasma; human	[82]
	Higher risk of impaired LV contractility	Down	Plasma; human	[83]
miR-155	Prognostic for cardiac death within 1 yr after MI	Up	Serum; human	[63]
	Associated with various degree of cardiovascular damage (AMI, viral myocarditis, diastolic dysfunction, acute HF)	Nd	Plasma; human	[76]
miR-181c*	Novel mirna dysregulated during MI	Nd	Whole blood; human	[65]
miR-186	Differentiating AMI and AP	Up	Serum; human	[61]
miR-192	Prognostic for development of ischemic HF	Up	Exosomes, serum; human	[62]
miR-194	Prognostic: correlated with LV end diastolic dimension	Up	Exosomes, serum; human	[62]
miR-195	Potential diagnostic value	Up	Plasma; human	[72]
miR-197	Negative association to the risk for MI	Nd	Plasma; human	[84]
miR-208	Differentiating AMI and AP	Up in AP compared to AMI	Serum; human	[61]
	Differentiating AMI and other cardiovascular diseases	Up	Plasma; rat and human	[67]
	Time-dependent changes 2-90 d post MI	Up	Plasma; human	[80]
	Detected in urine	Up	Urine; rat	[86]
miR-208b	AMI biomarkers, correlation to cTnT but not superior to cTnT	Up	Plasma; human	[71,76]
	Differentiating STEMI and NSTEMI	Higher in STEMI	Plasma; human	[73]
	Associated with various degree of cardiovascular damage (AMI, viral myocarditis, diastolic dysfunction, acute HF)	Up	Plasma; human	[76]
	Higher risk for 30 d mortality post-MI and HF	Up	Plasma; human	[81]
	Biomarker for AMI, correlated with troponin	Up	Plasma, urine; human, pig	[85]
miR-223	Differentiating AMI and AP	Up	Serum; human	[61]
	Associated with various degree of cardiovascular damage (AMI, viral myocarditis, diastolic dysfunction, acute HF)	Down	Plasma; human	[76]
	Negative association to the risk for MI	Nd	Plasma; human	[84]
miR-328	AMI biomarker, correlation to cTnI	Up	Plasma and whole blood; human	[66]
miR-380*	Prognostic for cardiac death within 1 yr after MI	Up	Serum; human	[63]
miR-423-5p	Before PCI compared to after	Up	Plasma; human	[77]
miR-499	Differentiating AMI and AP	Up in AP compared to AMI	Serum; human	[61]
	Differentiating AMI and other cardiovascular diseases	Up	Plasma; rat and human	[67]
	Similar time course to cTnI	Up	Plasma and tissue; human and mouse	[68]
	AMI biomarkers, correlation to cTnT but not superior to cTnT	Up	Plasma; human	[71,76]
	Differentiating STEMI and NSTEMI	Higher in STEMI	Plasma; human	[73]
	Differentiating MI, CHF and unstable AP	Up	Plasma; human	[74]
	Associated with various degree of cardiovascular damage (AMI, viral myocarditis, diastolic dysfunction, acute HF)	Up and also in acute HF	Plasma; human	[76]
	Differentiating NSTEMI and CHF	Up	Plasma; human	[78]
	Higher risk for 30 d mortality post MI and HF	Up	Plasma; human	[81]
	Biomarker for AMI, correlated with renal elimination	Up	Plasma, urine; human, pig	[85]
miR-1915	Novel miRNA dysregulated during MI	Nd	Whole blood; human	[65]
11 miRNAs	Prognosis after MI	Up and down	Serum; human	[63]
20 miRNAs	Predicting AMI (96% specificity; 90% sensitivity; 93% accuracy)	Up and down	Whole blood; human	[64]
A subset of miRNAs	Dysregulated during AMI course	Nd	Whole blood; human	[65]
34 miRNAs	AMI biomarkers	20 up, 14 down	Plasma and tissue; human and mouse	[68]
19 candidate miRNAs	Prediction for risk of MI	Nd	Plasma; human	[84]

AMI: Acute myocardial infarction; AP: Angina pectoris; cTnI: Cardiac troponin I; CHF: Chronic heart failure; cTnT: Cardiac troponin T; HF: Heart failure; LV: Left ventricle; MI: Myocardial infarction; Nd: Not determine; NSTEMI: Non-ST-elevation MI; PCI: Percutaneous coronary intervention; STEMI: ST-elevation MI; TTC: Takotsubo cardiomyopathy.