Diagnostic and prognostic value of circulating microRNAs in heart failure with preserved and reduced ejection fraction

Table 1 Systematic overview of microRNAs dysregulated in heart failure

miRNA	Study type	Bio-material	Group/size	Detection method	Effect	Value as biomarker	Ref.
Single miRNAs
Let-7	Clinical	Tissue	ICM n = 10	qRT-PCR	Up-regulated in DCM and ICM	Diagnostic	[90]
			DCM n = 25
			AS n = 13
			HC n = 10
miR-1	Clinical	Tissue	ICM n = 10	qRT-PCR	Down-regulated in DCM	Diagnostic	[90]
			DCM n = 25
			AS n = 13
			HC n = 10
miR-15b	Clinical	Tissue	ICM n = 10	qRT-PCR	Up-regulated in DCM	Diagnostic	[90]
			DCM n = 25
			AS n = 13
			HC n = 10
miR-16	Experimental	Plasma	Rats, hypertension-induced HF	qRT-PCR	Up-regulated in HF	Diagnostic	[107]
miR-17-5p	Clinical	Tissue	ICM n = 10	qRT-PCR	Down-regulated in DCM	Diagnostic	[90]
			DCM n = 25
			AS n = 13
			HC n = 10
miR-18b	Clinical	Plasma	HF n = 30	qRT-PCR	Up-regulated in HF	Diagnostic	[108]
			Dyspnea n = 20
			HC n = 20
miR-20b	Experimental	Plasma	Rats, hypertension-induced HF	qRT-PCR	Up-regulated in HF	Diagnostic	[107]
miR-211	Clinical	Tissue	LVAD-patients	Micro-array	Up-regulated in HF	Experimental	[89]
miR-22	Clinical	Serum	HFrEF n = 30	qRT-PCR	Up-regulated in HFrEF	Diagnostic/	[110]
			HC n = 30			prognostic
miR-23a	Clinical	Tissue	LVAD-patients	Micro-array	Up-regulated in HF	Experimental	[89]
miR-24	Experimental	Tissue	Mice, human hearts	Micro-array	Up-regulated in HF, CH	Experimental	[36]
miR-26b-5p	Clinical	Plasma	HF n = 81	qRT-PCR	Down-regulated	Diagnostic	[114]
			HC n = 15
miR-28	Clinical	Tissue	ICM n = 10	qRT-PCR	Down-regulated in DCM	Diagnostic	[90]
			DCM n = 25
			AS n = 13
			HC n = 10
miR-29a-3p	Clinical	Plasma	HF n = 81	qRT-PCR	Down-regulated	Diagnostic	[114]
			HC n = 15
miR-30b	Clinical	Plasma	HF n = 44	RT-PCR	Down-regulated in HF	Diagnostic	[113]
			COPD n = 32
			Dyspnea n = 59
			HC n = 15
miR-30e-5p	Clinical	Plasma	HF n = 81	qRT-PCR	Down-regulated	Diagnostic	[114]
			HC n = 15
miR-92b	Clinical	Serum	HFrEF n = 30	qRT-PCR	Up-regulated in HFrEF	Diagnostic/	[110]
			HC n = 30			prognostic
miR-92a-3p	Clinical	Plasma	HF n = 81	qRT-PCR	Down-regulated	Diagnostic	[114]
			HC n = 15
miR-93	Experimental	Plasma	Rats, hypertension-induced HF	qRT-PCR	Up-regulated in HF	Diagnostic	[107]
miR-103	Clinical	Plasma	HF n = 44	RT-PCR	Down-regulated in HF	Diagnostic	[113]
			COPD n = 32
			Dyspnea n = 59
			HC n = 15
miR-106a	Clinical	Tissue	ICM n = 10	qRT-PCR	Down-regulated in DCM	Diagnostic	[90]
			DCM n = 25
			AS n = 13
			HC n = 10
miR-106b	Experimental	Plasma	Rats, hypertension-induced HF	qRT-PCR	Up-regulated in HF	Diagnostic	[107]
miR-125b	Experimental	Tissue	Mice, human hearts	Micro-array	Up-regulated in HF, CH	Experimental	[36]
miR-126	Clinical	Plasma	HF n = 10	qRT-PCR	Down-regulated in HF	Diagnostic	[150]
			HC n = 17
miR-133	Clinical	Tissue	LVAD-patients	Micro-array	Up-regulated in HF	Experimental	[89]
miR-138	Clinical	PBMC	DCM n = 44	qRT-PCR	Up-regulated in DCM	Diagnostic	[117]
			HC n = 48
miR-142-3p	Clinical	Plasma	HF n = 44	RT-PCR	Down-regulated in HF	Diagnostic	[113]
			COPD n = 32
			Dyspnea n = 59
			HC n = 15
	Clinical	Plasma	HFpEF n = 8	qRT-PCR	Down-regulated in stable and	Diagnostic	[121]
			Stable DCM n = 10		decompensated DCM
			Decompensated DCM n = 13
			HC n = 8
miR-145-5p	Clinical	Plasma	HF n = 81	qRT-PCR	Down-regulated	Diagnostic	[114]
			HC n = 15
miR-182	Clinical	Serum	HF n = 42	Micro-array	Up-regulated in HF	Prognostic	[119]
			HC n = 15
miR-183-3p1	Clinical	Plasma	HF n = 60 (HFpEF n = 30; HFrEF n = 30)	qRT-PCR	Down-regulated in HF	Diagnostic	[115]
			HC n = 28
miR-190a	Clinical	Plasma	HF n = 60 (HFpEF n = 30; HFrEF n = 30)	qRT-PCR	Down-regulated in HF	Diagnostic	[115]
			HC n = 28
miR-193b-3p1	Clinical	Plasma	HF n = 60 (HFpEF n = 30; HFrEF n = 30)	qRT-PCR	Down-regulated in HF	Diagnostic	[115]
			HC n = 28
miR-193b-5p1	Clinical	Plasma	HF n = 60 (HFpEF n = 30; HFrEF n = 30)	qRT-PCR	Down-regulated in HF	Diagnostic	[115]
			HC n = 28
miR-195	Experimental	Tissue	Mice, human hearts	Micro-array	Up-reglated in HF, CH	Experimental	[36]
	Clinical	Tissue	ICM n = 10	qRT-PCR	Down-regulated in DCM	Diagnostic	[90]
			DCM n = 25		and ICM
			AS n = 13
			HC n = 10
miR-199a	Experimental	Tissue	Mice, human hearts	Micro-array	Up-reglated in HF, CH	Experimental	[36]
	Clinical	Tissue	ICM n = 10	qRT-PCR	Down-regulated in	Diagnostic	[90]
			DCM n = 25		DCM and ICM
			AS n = 13
			HC n = 10
miR-208	Experimental	Tissue	Mice	Micro-array	Up-regulated in HF, CF, CH	Experimental	[57]
	Clinical	Tissue	DCM n = 82	qRT-PCR	Up-regulated in DCM	Diagnostic/	[92]
			HC n = 21			prognostic
miR-208b	Clinical	Tissue	DCM n = 82	qRT-PCR	Up-regulated in DCM	Diagnostic	[92]
			HC n = 21
miR-211-5p1	Clinical	Plasma	HF n = 60 (HFpEF n = 30; HFrEF n = 30)	qRT-PCR	Down-regulated in HF	Diagnostic	[115]
			HC n = 28
miR-214	Experimental	Tissue	Mice, human hearts	Micro-array	Up-reglated in HF, CH	Experimental	[36]
miR-222	Clinical	Tissue	ICM n = 10	qRT-PCR	Down-regulated in	Diagnostic	[90]
			DCM n = 25		DCM and ICM
			AS n = 13
			HC n = 10
miR-223	Experimental	Plasma	Rats, hypertension-induced HF	qRT-PCR	Up-regulated in HF	Diagnostic	[107]
miR-320a	Clinical	Serum	HFrEF n = 30	qRT-PCR	Up-regulated in HFrEF	Diagnostic/	[110]
			HC n = 30			prognostic
miR-342-3p	Clinical	Plasma	HF n = 44	RT-PCR	Down-regulated in HF	Diagnostic	[113]
			COPD n = 32
			Dyspnea n = 59
			HC n = 15
miR-422b	Clinical	Tissue	ICM n = 10	qRT-PCR	Down-regulated in	Diagnostic	[90]
			DCM n = 25		DCM and ICM
			AS n = 13
			HC n = 10
miR-423-5p	Experimental	Plasma	Rats, hypertension-induced HF	qRT-PCR	Up-regulated in HF	Diagnostic	[107]
	Clinical	Plasma	HF n = 30	qRT-PCR	Up-regulated in HF	Diagnostic/	[108]
			Dyspnea n = 20			prognostic
			HC n = 20
	Clinical	Serum	HFrEF n = 30	qRT-PCR	Up-regulated in HFrEF	Diagnostic/	[110]
			HC n = 30			prognostic
	Clinical	Plasma	HF n = 44	RT-PCR	Down-regulated in HF	Prognostic when	[113]
			COPD n = 32			combined with
			Dyspnea n = 59			NT-proBNP
			HC n = 15
miR-4941	Clinical	Plasma	HF n = 60 (HFpEF n = 30; HFrEF n = 30)	qRT-PCR	Down-regulated in HF	Diagnostic	[115]
			HC n = 28
miR-499	Clinical	Tissue	DCM n = 82	qRT-PCR	Up-regulated in DCM	Diagnostic	[92]
			HC n = 21
	Clinical	Plasma	Acute HF n = 33	qRT-PCR	Up-regulation in acute HF	Diagnostic	[10]
			HC n = 34
miR-548c	Clinical	PBMC	DCM n = 44	qRT-PCR	Down-regulated in DCM	Diagnostic	[117]
			HC n = 48
miR-548i	Clinical	PBMC	DCM n = 44	qRT-PCR	Down-regulated in DCM	Diagnostic	[117]
			HC n = 48
miR-671-5p1	Clinical	Plasma	HF n = 60 (HFpEF n = 30; HFrEF n = 30)	qRT-PCR	Up-regulated in HF	Diagnostic	[115]
			HC n = 28
miR-675	Clinical	Plasma	HF n = 30	qRT-PCR	Up-regulated in HF	Diagnostic	[108]
			Dyspnea n = 20
			HC n = 20
miR-12331	Clinical	Plasma	HF n = 60 (HFpEF n = 30; HFrEF n = 30)	qRT-PCR	Up-regulated in HF	Diagnostic	[115]
			HC n = 28
miRNA signatures
miR-520d-5p	Clinical	Whole blood	HFrEF n = 53	qRT-PCR	Dysregulated in HF - superior to	Diagnostic	[120]
miR-558			HC n = 39		single miRNAs
miR-122*
miR-200b*
miR-622
miR-519e*
miR-1231
miR-1228*

¹See also Table 2;

^*Most microRNAs have two mature products, one derives from the 5’ arm of the miRNAs hairpin and the other from the 3’ arm of the hairpin; the latter is marked “*”. miRNA: microRNA; HF: Heart failure; CF: Cardiac fibrosis; CH: Cardiac hypertrophy; HC: Healthy control; ICM: Ischemic cardiomyopathy; DCM: Dilated cardiomyopathy; AS: Aortic stenosis; COPD: Chronic obstructive pulmonary disease; MI: Myocardial infarction; HFpEF: Heart failure with preserved ejection fraction; HFrEF: Heart failure with reduced ejection fraction; PBMC: Peripheral blood mononuclear cell; LVAD: Left ventricular assist device; qRT-PCR: Quantitative real time polymerase chain reaction.

Table 2 microRNAs in the diagnosis and differentiation of heart failure with preserved ejection fraction and heart failure with reduced ejection fraction

miRNA	Study type	Bio-material	Groups/size	Detection method	Effect	Value as biomarker	Ref.
miR-211	Experimental	Tissue	Mice - HFpEF vs HC	qRT-PCR	Up-regulated in HFpEF	Diagnostic	[67]
miR-30c	Clinical	Serum	HFpEF n = 90	qRT-PCR	AUC analyses	Differentiating	[122]
			HFrEF n = 90			HFrEF from HFpEF
			HC n = 90
miR-125a-5p	Clinical	Plasma	HFpEF n = 30	qRT-PCR	Up-regulated in HFrEF,	Diagnostic in HFrEF +	[115]
			HFrEF n = 30		unchanged in HFpEF	differentiating HFrEF
			HC n = 28			from HFpEF
miR-146a	Clinical	Serum	HFpEF n = 90	qRT-PCR	AUC analyses	Differentiating HFrEF	[122]
			HFrEF n = 90			from HFpEF
			HC n = 90
miR-183-3p1	Clinical	Plasma	HFpEF n = 30	qRT-PCR	Down-regulated in	Diagnostic	[115]
			HFrEF n = 30		HFrEF and HFpEF
			HC n = 28
miR-190a*	Clinical	Plasma	HFpEF n = 30	qRT-PCR	Down-regulated in	Diagnostic in HFpEF +	[115]
			HFrEF n = 30		HFpEF, unchanged in	differentiating
			HC n = 28		HFrEF	HFrEF from HFpEF
miR-193b-3p1	clinical	Plasma	HFpEF n = 30	qRT-PCR	Down-regulated in	Diagnostic	[115]
			HFrEF n = 30		HFrEF and HFpEF
			HC n = 28
miR-193b-5p1	Clinical	Plasma	HFpEF n = 30	qRT-PCR	Down-regulated in HFpEF	Diagnostic	[115]
			HFrEF n = 30
			HC n = 28
miR-211-5p1	Clinical	Plasma	HFpEF n = 30	qRT-PCR	Down-regulated in HFrEF	Diagnostic	[115]
			HFrEF n = 30
			HC n = 28
miR-221	Clinical	Serum	HFpEF n = 90	qRT-PCR	AUC analyses	Differentiating	[122]
			HFrEF n = 90			HFrEF from HFpEF
			HC n = 90
miR-328	Clinical	Serum	HFpEF n = 90	qRT-PCR	AUC analyses	Differentiating	[122]
			HFrEF n = 90			HFrEF from HFpEF
			HC n = 90
miR-375	Clinical	Serum	HFpEF n = 90	qRT-PCR	AUC analyses	Differentiating	[122]
			HFrEF n = 90			HFrEF from HFpEF
			HC n = 90
miR-454	Clinical	Plasma	HFpEF n = 8	qRT-PCR	Down-regulated in HFpEF	Diagnostic	[121]
			Stable DCM n = 10
			Decompensated DCM n = 13
			HC n = 8
miR-4941	Clinical	Plasma	HFpEF n = 30	qRT-PCR	Down-regulated in HFrEF	Diagnostic	[115]
			HFrEF n = 30
			HC n = 28
miR-500	Clinical	Plasma	HFpEF n = 8	qRT-PCR	Down-regulated in HFpEF	Diagnostic	[121]
			Stable DCM n = 10
			Decompensated DCM n = 13
			HC n = 8
miR-545-5p	Clinical	Plasma	HFpEF n = 30	qRT-PCR	Up-regulated in HFpEF	Diagnostic	[115]
			HFrEF n = 30
			HC n = 28
miR-550a-5p	Clinical	Plasma	HFpEF n = 30	qRT-PCR	Up-regulated in HFrEF	Differentiating	[115]
			HFrEF n = 30		Down-regulation in HFpEF	HFrEF from HFpEF
miR-638	Clinical	Plasma	HFpEF n = 30	qRT-PCR	Down-regulated in HFrEF,	Diagnostic in HFrEF +	[115]
			HFrEF n = 30		unchanged in HFpEF	differentiating HFrEF
			HC n = 28			from HFpEF
miR-671-5p1	Clinical	Plasma	HFpEF n = 30	qRT-PCR	Up-regulated in HFrEF	Diagnostic	[115]
			HFrEF n = 30
			HC n = 28
miR-12331	Clinical	Plasma	HFpEF n = 30	qRT-PCR	Up-regulated in HFpEF	Diagnostic	[115]
			HFrEF n = 30
			HC n = 28
miR-1246	Clinical	Plasma	HFpEF n = 8	qRT-PCR	Down-regulated in HFpEF	Diagnostic	[121]
			Stable DCM n = 10
			Decompensated DCM n = 13
			HC n = 8

¹See also Table 1. HC: Healthy control; miRNA: microRNAs; DCM: Dilated cardiomyopathy; HFpEF: Heart failure with preserved ejection fraction; HFrEF: Heart failure with reduced ejection fraction; qRT-PCR: Quantitative real time polymerase chain reaction; AUC: Area under the operating receiver curve.