Heart, Lung and Circulation

Circulating Levels of MicroRNAs in Hypertrophic Cardiomyopathy: The Relationship With Left Ventricular Hypertrophy, Left Atrial Dilatation and Ventricular Depolarisation-Repolarisation Parameters


      MicroRNAs are small, endogenous, non-coding RNAs that regulate the expression of many genes. It has recently been shown that circulating microRNAs may be biomarkers of hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy (HCM).


      To determine whether circulating levels of microRNAs involved in HCM are associated with electrocardiographic and echocardiographic parameters.


      This study enrolled 20 patients with familial HCM and 20 blood donors. Peripheral serum levels of miR-29a-3p, miR-199a-5p and miR-451a were assessed by quantitative real-time polymerase chain reaction and compared with levels in the control group. Whether circulating levels of miRNAs in HCM patients correlated with electrocardiographic and echocardiographic parameters was also assessed.


      Median circulating levels of miR-29a and miR-451a were significantly higher in HCM than the control group. Median miR-199a levels did not differ between groups. However, circulating levels of miR-199a negatively correlated with corrected QT duration (Bazett formula). Median miR-29a levels positively correlated with QRS duration. In addition, circulating levels of miR-29a correlated with maximal wall thickness, left ventricular mass index and left atrial volume index.


      The data suggested that serum levels of miR-29a and miR-451a were significantly increased in HCM patients. As the circulating level of miR-29a correlated with QRS duration, left ventricular hypertrophy and left atrial dilatation, the serum miR-199a level negatively correlated with corrected QT duration. These miRNAs may be seen as potential biomarkers for further research in HCM pathophysiology.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Heart, Lung and Circulation
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Maron B.J.
        • Maron M.S.
        Hypertrophic cardiomyopathy.
        Lancet. 2013; 381: 242-255
        • Fatkin D.
        • Graham R.M.
        Molecular mechanisms of inherited cardiomyopathies.
        Physiol Rev. 2002; 82: 945-980
        • Van Der Velden J.
        • Ho C.Y.
        • Tardiff J.C.
        • Olivotto I.
        • Knollmann B.C.
        • Carrier L.
        Research priorities in sarcomeric cardiomyopathies.
        Cardiovasc Res. 2015; 105: 449-456
        • Roma-Rodrigues C.
        • Raposo L.R.
        • Fernandes A.R.
        MicroRNAs-based therapy of hypertrophic cardiomyopathy: the road traveled so far.
        Biomed Res Int. 2015; 2015: 983290
        • Van Rooij E.
        • Olson E.N.
        MicroRNAs: powerful new regulators of heart disease and provocative therapeutic targets.
        J Clin Invest. 2007; 117: 2369-2376
        • Da Costa Martins P.A.
        • De Windt L.J.
        MicroRNAs in control of cardiac hypertrophy.
        Cardiovasc Res. 2012; 93: 563-572
        • Roncarati R.
        • Viviani Anselmi C.
        • Losi M.A.
        • Papa L.
        • Cavarretta E.
        • Da Costa Martins P.
        • et al.
        Circulating miR-29a, among other up-regulated microRNAs, is the only biomarker for both hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy.
        J Am Coll Cardiol. 2014; 63: 920-927
        • Wang G.K.
        • Zhu J.Q.
        • Zhang J.T.
        • Li Q.
        • Li Y.
        • He J.
        • et al.
        Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans.
        Eur Heart J. 2010; 31: 659-666
        • Shieh J.T.C.
        • Huang Y.
        • Gilmore J.
        • Srivastava D.
        Elevated miR-499 levels blunt the cardiac stress response.
        PLoS One. 2011; 6: e19481
        • Fichtlscherer S.
        • De Rosa S.
        • Fox H.
        • Schwietz T.
        • Fischer A.
        • Liebetrau C.
        • et al.
        Circulating microRNAs in patients with coronary artery disease.
        Circ Res. 2010; 107: 677-684
        • Song L.
        • Su M.
        • Wang S.
        • Zou Y.
        • Wang X.
        • Wang Y.
        • et al.
        MiR-451 is decreased in hypertrophic cardiomyopathy and regulates autophagy by targeting TSC1.
        J Cell Mol Med. 2014; 18: 2266-2274
        • Gersh B.J.
        • Maron B.J.
        • Bonow R.O.
        • Dearani J.A.
        • Fifer M.A.
        • Link M.S.
        • et al.
        2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
        Circulation. 2011; 124: 2761-2796
        • Pescador N.
        • Pérez-Barba M.
        • Ibarra J.M.
        • Corbatón A.
        • Martínez-Larrad M.T.
        • Serrano-Ríos M.
        Serum circulating microRNA profiling for identification of potential type 2 diabetes and obesity biomarkers.
        PLoS One. 2013; 8: e77251
        • Roberts T.C.
        • Coenen-Stass A.M.L.
        • Wood M.J.A.
        Assessment of RT-qPCR normalization strategies for accurate quantification of extracellular microRNAs in murine serum.
        PLoS One. 2014; 9: e89237
        • Gharbi S.
        • Shamsara M.
        • Khateri S.
        • Soroush M.R.
        • Ghorbanmehr N.
        • Tavallaei M.
        • et al.
        Identification of reliable reference genes for quantification of MicroRNAs in serum samples of sulfur mustard-exposed veterans.
        Cell J. 2015; 17: 494-501
        • Lang R.M.
        • Badano L.P.
        • Mor-Avi V.
        • Afilalo J.
        • Armstrong A.
        • Ernande L.
        • et al.
        Chamber quantification.
        J Am Soc Echocardiogr. 2015; 28: 1-39
        • Nagueh S.F.
        • Smiseth O.A.
        • Appleton C.P.
        • Byrd 3rd, B.F.
        • Dokainish H.
        • Edvardsen T.
        • et al.
        Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
        Eur Heart J Cardiovasc Imaging. 2017; 17: 1321-1360
        • Zoghbi W.A.
        • Adams D.
        • Bonow R.O.
        • Enriquez-Sarano M.
        • Foster E.
        • Grayburn P.A.
        • et al.
        Recommendations for noninvasive evaluation of native valvular regurgitation.
        J Am Soc Echocardiogr. 2017; 30: 303-371
        • van Rooij E.
        • Sutherland L.B.
        • Thatcher J.E.
        • DiMaio J.M.
        • Naseem R.H.
        • Marshall W.S.
        • et al.
        Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis.
        Proc Natl Acad Sci U S A. 2008; 105: 13027-13032
        • Boon R.A.
        • Seeger T.
        • Heydt S.
        • Fischer A.
        • Hergenreider E.
        • Horrevoets A.J.
        • et al.
        MicroRNA-29 in aortic dilation: implications for aneurysm formation.
        Circ Res. 2011; 109: 1115-1119
        • Zhang P.
        • Huang A.
        • Ferruzzi J.
        • Mecham R.P.
        • Starcher B.C.
        • Tellides G.
        • et al.
        Inhibition of MicroRNA-29 enhances elastin levels in cells haploinsufficient for elastin and in bioengineered vessels-brief report.
        Arterioscler Thromb Vasc Biol. 2012; 32: 756-759
        • Sassi Y.
        • Avramopoulos P.
        • Ramanujam D.
        • Grüter L.
        • Werfel S.
        • Giosele S.
        • et al.
        Cardiac myocyte miR-29 promotes pathological remodeling of the heart by activating Wnt signaling.
        Nat Commun. 2017; 8: 1614
        • Wang X.
        • Zhu H.
        • Zhang X.
        • Liu Y.
        • Chen J.
        • Medvedovic M.
        • et al.
        Loss of the miR-144/451 cluster impairs ischaemic preconditioning-mediated cardioprotection by targeting Rac-1.
        Cardiovasc Res. 2012; 94: 379-390
        • Zhang X.
        • Wang X.
        • Zhu H.
        • Zhu C.
        • Wang Y.
        • Pu W.T.
        • et al.
        Synergistic effects of the GATA-4-mediated miR-144/451 cluster in protection against simulated ischemia/reperfusion-induced cardiomyocyte death.
        J Mol Cell Cardiol. 2010; 49: 841-850
        • Rane S.
        • He M.
        • Sayed D.
        • Vashistha H.
        • Malhotra A.
        • Sadoshima J.
        • et al.
        Downregulation of MiR-199a depresses hypoxia-inducible factor-1α and sirtuin 1 and recapitulates hypoxia preconditioning in cardiac myocytes.
        Circ Res. 2009; 104: 879-886
        • Song X.W.
        • Li Q.
        • Lin L.
        • Wang X.C.
        • Li D.F.
        • Wang G.K.
        • et al.
        MicroRNAs are dynamically regulated in hypertrophic hearts, and miR-199a is essential for the maintenance of cell size in cardiomyocytes.
        J Cell Physiol. 2010; 225: 37-43
        • Haghikia A.
        • Missol-Kolka E.
        • Tsikas D.
        • Venturini L.
        • Brundiers S.
        • Castoldi M.
        • et al.
        Signal transducer and activator of transcription 3-mediated regulation of miR-199a-5p links cardiomyocyte and endothelial cell function in the heart: a key role for ubiquitin-conjugating enzymes.
        Eur Heart J. 2011; 32: 1287-1297
        • An M.
        • Kwon K.
        • Park J.
        • Ryu D.R.
        • Shin J.A.
        • Lee Kang J.
        • et al.
        Extracellular matrix-derived extracellular vesicles promote cardiomyocyte growth and electrical activity in engineered cardiac atria.
        Biomaterials. 2017; 146: 49-59
        • Batkai S.
        • Thum T.
        Analytical approaches in microRNA therapeutics.
        J Chromatogr B Anal Technol Biomed Life Sci. 2014; 964: 146-152