ssmuБюллетень сибирской медициныBulletin of Siberian Medicine1682-03631819-3684Siberian State Medical University, the Ministry of Healthcare of the Russian Federation10.20538/1682-0363-2021-3-203-212ssmu-4498Research ArticleОБЗОРЫ И ЛЕКЦИИREVIEW AND LECTURESМикроРНК: роль в патофизиологии фибрилляции предсердий и возможности использования в качестве биомаркераMicrorna: the role in the pathophysiology of atrial fibrillation and potential use as a biomarkerhttps://orcid.org/0000-0002-2712-0227ЧаулинА. М.ChaulinA. M.

 аспирант, ассистент, кафедра гистологии и эмбриологии 

 Россия, 443099, г. Самара, ул. Чапаевская, 89 

 89, Chapaevskaya Str., Samara, 443099, Russian Federation 

alekseymichailovich22976@gmail.comhttps://orcid.org/0000-0002-6453-2976ДупляковД. В.DuplyakovD. V.

 д-р мед. наук, профессор, кафедра кардиологии и сердечно-сосудистой хирургии

 Россия, 443099, г. Самара, ул. Чапаевская, 89 

 89, Chapaevskaya Str., Samara, 443099, Russian Federation 

Самарский государственный медицинский университетРоссияSamara State Medical UniversityRussian Federation202122102021203203212Copyright © Чаулин А.М., Дупляков Д.В., 20212021Чаулин А.М., Дупляков Д.В.Chaulin A.M., Duplyakov D.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://bulletin.ssmu.ru/jour/article/view/4498

Проведен анализ современной медицинской литературы по базе данных PubMed – NCBI. Фибрилляция предсердий является широко распространенным и серьезным сердечно-сосудистым заболеванием. Патофизиологические механизмы, лежащие в основе развития фибрилляции предсердий, не совсем ясны. Кроме того, отсутствуют оптимальные биомаркеры для раннего выявления и оценки прогноза пациентов с фибрилляцией предсердий.В последнее время внимание исследователей привлекли молекулы микрорибонуклеиновой кислоты (микроРНК). Накоплено немало данных, согласно которым они участвует в патогенезе неврологических, онкологических и сердечно-сосудистых заболеваний. Рассмотрена роль микроРНК в патофизиологии фибрилляции предсердий. Также обсуждается возможность использования микроРНК в качестве биомаркеров для диагностики и прогнозирования фибрилляции предсердий.

The aim of the study was to analyze medical literature on the role of microRNA in the pathophysiology of atrial fibrillation and the possibilities of using microRNAs as biomarkers.The analysis of modern medical literature was carried out using the PubMed – NCBI database.

Atrial fibrillation (AF) is a common and serious cardiovascular disease. The pathophysiological mechanisms underlying the development of atrial fibrillation are not entirely clear. In addition, there are no optimal biomarkers for early detection and assessment of the prognosis for patients with atrial fibrillation. Recently, the attention of researchers has been directed to the molecules of microRNA. There is a lot of evidence that they are involved in the pathogenesis of neurological, oncological, and cardiovascular diseases. This review examines the role of microRNAs in the pathophysiology of atrial fibrillation. The possibility of using microRNA as a biomarker for the diagnosis and prediction of atrial fibrillation is also discussed.MicroRNAs play a crucial role in the pathophysiology of atrial fibrillation, regulating the mechanisms of atrial remodeling, such as electrical remodeling, structural remodeling, remodeling of the autonomic nervous system, and impaired regulation of calcium levels. The stability of microRNAs and the possibility to study them in various biological fluids and tissues, including blood, make these molecules a promising diagnostic biomarker for various cardiovascular diseases. The presented data clearly indicate that AF is associated with changes in the expression level of various microRNAs, which can be quantified using a polymerase chain reaction. Further research is required to assess the role of microRNAs as biomarkers for atrial fibrillation, in particular to establish precise reference limits.

микроРНКфибрилляция предсердийпатофизиологиябиомаркерлабораторная диагностика.microRNAatrial fibrillationpathophysiologybiomarkerlaboratory diagnosticsReferencesLee S.H., Park S.J., Byeon K., On Y.K., Kim J.S., Shin D.G., Cho J.G., Kim Y.N., Kim Y.H., KORAF Investigators. Risk factors between patients with lone and non-lone atrial fibrillation. J. Korean Med Sci. 2013; 28 (8): 1174–1180. DOI: 10.3346/jkms.2013.28.8.1174.Lee S.H., Park S.J., Byeon K., On Y.K., Kim J.S., Shin D.G., Cho J.G., Kim Y.N., Kim Y.H., KORAF Investigators. Risk factors between patients with lone and non-lone atrial fibrillation. J. Korean Med Sci. 2013; 28 (8): 1174–1180. DOI: 10.3346/jkms.2013.28.8.1174.Pellman J., Sheikh F. Atrial fibrillation: mechanisms, therapeutics, and future directions. Compr. Physiol. 2015; 5 (2): 649–665. DOI: 10.1002/cphy.c140047.Pellman J., Sheikh F. Atrial fibrillation: mechanisms, therapeutics, and future directions. Compr. Physiol. 2015; 5 (2): 649–665. DOI: 10.1002/cphy.c140047.Ko D., Rahman F., Martins M.A., Hylek E.M., Ellinor P.T., Schnabel R.B., Benjamin E.J., Christophersen I.E. Atrial fibrillation in women: treatment. Nat. Rev. Cardiol. 2017; 14 (2): 113–124. DOI: 10.1038/nrcardio.2016.171.Ko D., Rahman F., Martins M.A., Hylek E.M., Ellinor P.T., Schnabel R.B., Benjamin E.J., Christophersen I.E. Atrial fibrillation in women: treatment. Nat. Rev. Cardiol. 2017; 14 (2): 113–124. DOI: 10.1038/nrcardio.2016.171.Turagam M.K., Mirza M., Werner P.H., Sra J., Kress D.C., Tajik A.J., Jahangir A. Circulating biomarkers predictive of postoperative atrial fibrillation. Cardiol Rev. 2016; 24 (2): 76–87. DOI: 10.1097/CRD.0000000000000059.Turagam M.K., Mirza M., Werner P.H., Sra J., Kress D.C., Tajik A.J., Jahangir A. Circulating biomarkers predictive of postoperative atrial fibrillation. Cardiol Rev. 2016; 24 (2): 76–87. DOI: 10.1097/CRD.0000000000000059.Чаулин А.М., Карслян Л.С., Григорьева Е.В., Нурбалтаева Д.А., Дупляков Д.В. Клинико-диагностическая ценность кардиомаркеров в биологических жидкостях человека. Кардиология. 2019; 59 (11): 66–75. DOI: 10.18087/cardio.2019.11.n414.Чаулин А.М., Карслян Л.С., Григорьева Е.В., Нурбалтаева Д.А., Дупляков Д.В. Клинико-диагностическая ценность кардиомаркеров в биологических жидкостях человека. Кардиология. 2019; 59 (11): 66–75. DOI: 10.18087/cardio.2019.11.n414.Чаулин А.М., Дупляков Д.В. Повышение кардиальных тропонинов, не ассоциированное с острым коронарным синдромом. Часть 1. Кардиология: новости, мнения, обучение. 2019; 7 (2): 13–23. DOI: 10.24411/2309-1908-2019-12002.Чаулин А.М., Дупляков Д.В. Повышение кардиальных тропонинов, не ассоциированное с острым коронарным синдромом. Часть 1. Кардиология: новости, мнения, обучение. 2019; 7 (2): 13–23. DOI: 10.24411/2309-1908-2019-12002.Чаулин А.М., Дупляков Д.В. Повышение кардиальных тропонинов, не ассоциированное с острым коронарным синдромом. Часть 2. Кардиология: новости, мнения, обучение. 2019; 7 (2): 24–35. DOI: 10.24411/2309-1908-2019-12003.Чаулин А.М., Дупляков Д.В. Повышение кардиальных тропонинов, не ассоциированное с острым коронарным синдромом. Часть 2. Кардиология: новости, мнения, обучение. 2019; 7 (2): 24–35. DOI: 10.24411/2309-1908-2019-12003.Gonzalez-Del-Hoyo M., Cediel G., Carrasquer A., Bonet G., Vasquez-Nunez K., Boque C., Ali S., Bardaji A. Prognostic implications of troponin I elevation in emergency department patients with tachyarrhythmia. Clin. Cardiol. 2019; 42 (5): 546–552. DOI: 10.1002/clc.23175.Gonzalez-Del-Hoyo M., Cediel G., Carrasquer A., Bonet G., Vasquez-Nunez K., Boque C., Ali S., Bardaji A. Prognostic implications of troponin I elevation in emergency department patients with tachyarrhythmia. Clin. Cardiol. 2019; 42 (5): 546–552. DOI: 10.1002/clc.23175.Zellweger M.J., Schaer B.A., Cron T.A., Pfisterer M.E., Osswald S. Elevated troponin levels in the absence of coronary artery disease after supraventricular tachycardia. Swiss Med. Wkly. 2003; 133 (31–32): 439–441.Zellweger M.J., Schaer B.A., Cron T.A., Pfisterer M.E., Osswald S. Elevated troponin levels in the absence of coronary artery disease after supraventricular tachycardia. Swiss Med. Wkly. 2003; 133 (31–32): 439–441.Fox C.S., Parise H., D’Agostino R.B. Sr., Lloyd-Jones D.M., Vasan R.S., Wang T.J., Levy D., Wolf P.A., Benjamin E.J. Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. JAMA. 2004; 291 (23): 2851–2855. DOI: 10.1001/jama.291.23.2851.Fox C.S., Parise H., D’Agostino R.B. Sr., Lloyd-Jones D.M., Vasan R.S., Wang T.J., Levy D., Wolf P.A., Benjamin E.J. Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. JAMA. 2004; 291 (23): 2851–2855. DOI: 10.1001/jama.291.23.2851.Low S.K., Takahashi A., Ebana Y., Ozaki K., Christophersen I.E., Ellinor P.T., AFGen Consortium, Ogishima S., Yamamoto M., Satoh M., Sasaki M., Yamaji T., Iwasaki M., Tsugane S., Tanaka K., Naito M., Wakai K., Tanaka H., Furukawa T., Kubo M., Ito K., Kamatani Y., Tanaka T. Identification of six new genetic loci associated with atrial fibrillation in the Japanese population. Nat. Genet. 2017; 49 (6): 953–958. DOI: 10.1038/ng.3842.Low S.K., Takahashi A., Ebana Y., Ozaki K., Christophersen I.E., Ellinor P.T., AFGen Consortium, Ogishima S., Yamamoto M., Satoh M., Sasaki M., Yamaji T., Iwasaki M., Tsugane S., Tanaka K., Naito M., Wakai K., Tanaka H., Furukawa T., Kubo M., Ito K., Kamatani Y., Tanaka T. Identification of six new genetic loci associated with atrial fibrillation in the Japanese population. Nat. Genet. 2017; 49 (6): 953–958. DOI: 10.1038/ng.3842.Lee R.C., Feinbaum R.L., Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993; 75 (5): 843–854. DOI: 10.1016/0092-8674(93)90529-y.Lee R.C., Feinbaum R.L., Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993; 75 (5): 843–854. DOI: 10.1016/0092-8674(93)90529-y.Kozomara A., Griffiths-Jones S. miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic. Acids Res. 2014; 42: 68–73. DOI: 10.1093/nar/gkt1181.Kozomara A., Griffiths-Jones S. miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic. Acids Res. 2014; 42: 68–73. DOI: 10.1093/nar/gkt1181.MacFarlane L.A., Murphy P.R. MicroRNA: biogenesis, function and role in cancer. Curr Genomics. 2010; 11 (7): 537–561. DOI: 10.2174/138920210793175895.MacFarlane L.A., Murphy P.R. MicroRNA: biogenesis, function and role in cancer. Curr Genomics. 2010; 11 (7): 537–561. DOI: 10.2174/138920210793175895.Ardekani A.M., Naeini M.M. The role of microRNAs in human diseases. Avicenna J. Med. Biotechnol. 2010; 2 (4): 161–179.Ardekani A.M., Naeini M.M. The role of microRNAs in human diseases. Avicenna J. Med. Biotechnol. 2010; 2 (4): 161–179.Ha T.Y. MicroRNAs in human diseases: from cancer to cardiovascular disease. Immune Netw. 2011; 11 (3): 135–154. DOI: 10.4110/in.2011.11.3.135.Ha T.Y. MicroRNAs in human diseases: from cancer to cardiovascular disease. Immune Netw. 2011; 11 (3): 135–154. DOI: 10.4110/in.2011.11.3.135.Van den Berg N.W.E., Kawasaki M., Berger W.R., Neefs J., Meulendijks E., Tijsen A.J., de Groot J.R. MicroRNAs in atrial fibrillation: from expression signatures to functional implications. Cardiovasc. Drugs Ther. 2017; 31 (3): 345–365. DOI: 10.1007/s10557-017-6736-z.Van den Berg N.W.E., Kawasaki M., Berger W.R., Neefs J., Meulendijks E., Tijsen A.J., de Groot J.R. MicroRNAs in atrial fibrillation: from expression signatures to functional implications. Cardiovasc. Drugs Ther. 2017; 31 (3): 345–365. DOI: 10.1007/s10557-017-6736-z.Liu Z., Zhou C., Liu Y., Wang S., Ye P., Miao X., Xia J. The expression levels of plasma micoRNAs in atrial fibrillation patients. PLoS One. 2012; 7 (9): e44906. DOI: 10.1371/journal.pone.0044906.Liu Z., Zhou C., Liu Y., Wang S., Ye P., Miao X., Xia J. The expression levels of plasma micoRNAs in atrial fibrillation patients. PLoS One. 2012; 7 (9): e44906. DOI: 10.1371/journal.pone.0044906.Hodgkinson C.P., Kang M.H., Dal-Pra S., Mirotsou M., Dzau V.J. MicroRNAs and сardiac regeneration. Circ. Res. 2015; 116 (10): 1700–1711. DOI: 10.1161/CIRCRESAHA.116.304377.Hodgkinson C.P., Kang M.H., Dal-Pra S., Mirotsou M., Dzau V.J. MicroRNAs and сardiac regeneration. Circ. Res. 2015; 116 (10): 1700–1711. DOI: 10.1161/CIRCRESAHA.116.304377.Neudecker V., Brodsky K.S., Kreth S., Ginde A.A., Eltzschig H.K. Emerging roles for microRNAs in perioperative medicine. Anesthesiology. 2016; 124 (2): 489–506. DOI: 10.1097/ALN.0000000000000969.Neudecker V., Brodsky K.S., Kreth S., Ginde A.A., Eltzschig H.K. Emerging roles for microRNAs in perioperative medicine. Anesthesiology. 2016; 124 (2): 489–506. DOI: 10.1097/ALN.0000000000000969.Chaldoupi S.M., Loh P., Hauer R.N., de Bakker J.M., van Rijen H.V. The role of connexin40 in atrial fibrillation. Cardiovasc. Res. 2009; 84 (1): 15–23. DOI: 10.1093/cvr/cvp203.Chaldoupi S.M., Loh P., Hauer R.N., de Bakker J.M., van Rijen H.V. The role of connexin40 in atrial fibrillation. Cardiovasc. Res. 2009; 84 (1): 15–23. DOI: 10.1093/cvr/cvp203.Chen J.F., Mandel E.M., Thomson J.M., Wu Q., Callis T.E., Hammond S.M., Conlon F.L., Wang D.Z. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat. Genet. 2006; 38(2): 8228–8833. DOI: 10.1038/ng1725.Chen J.F., Mandel E.M., Thomson J.M., Wu Q., Callis T.E., Hammond S.M., Conlon F.L., Wang D.Z. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat. Genet. 2006; 38(2): 8228–8833. DOI: 10.1038/ng1725.Jia X., Zheng S., Xie X., Zhang Y., Wang W., Wang Z., Zhang Y., Wang J., Gao M., Hou Y. MicroRNA-1 accelerates the shortening of atrial effective refractory period by regulating KCNE1 and KCNB2 expression: an atrial tachypacing rabbit model. PLoS One. 2013; 8 (12): e85639. DOI: 10.1371/journal.pone.0085639.Jia X., Zheng S., Xie X., Zhang Y., Wang W., Wang Z., Zhang Y., Wang J., Gao M., Hou Y. MicroRNA-1 accelerates the shortening of atrial effective refractory period by regulating KCNE1 and KCNB2 expression: an atrial tachypacing rabbit model. PLoS One. 2013; 8 (12): e85639. DOI: 10.1371/journal.pone.0085639.Tsoporis J.N., Fazio A., Rizos I.K., Izhar S., Proteau G., Salpeas V., Rigopoulos A., Sakadakis E., Toumpoulis I.K., Parker T.G. Increased right atrial appendage apoptosis is associated with differential regulation of candidate MicroRNAs 1 and 133A in patients who developed atrial fibrillation after cardiac surgery. J. Mol. Cell Cardiol. 2018; 121: 25–32. DOI: 10.1016/j.yjmcc.2018.06.005.Tsoporis J.N., Fazio A., Rizos I.K., Izhar S., Proteau G., Salpeas V., Rigopoulos A., Sakadakis E., Toumpoulis I.K., Parker T.G. Increased right atrial appendage apoptosis is associated with differential regulation of candidate MicroRNAs 1 and 133A in patients who developed atrial fibrillation after cardiac surgery. J. Mol. Cell Cardiol. 2018; 121: 25–32. DOI: 10.1016/j.yjmcc.2018.06.005.Li Y.D., Hong Y.F., Yusufuaji Y., Tang B.P., Zhou X.H., Xu G.J., Li J.X., Sun L., Zhang J.H., Xin Q., Xiong J., Ji Y.T., Zhang Y. Altered expression of hyperpolarization-activated cyclic nucleotide-gated channels and microRNA-1 and -133 in patients with age-associated atrial fibrillation. Mol. Med. Rep. 2015; 12 (3): 3243–3248. DOI: 10.3892/mmr.2015.3831.Li Y.D., Hong Y.F., Yusufuaji Y., Tang B.P., Zhou X.H., Xu G.J., Li J.X., Sun L., Zhang J.H., Xin Q., Xiong J., Ji Y.T., Zhang Y. Altered expression of hyperpolarization-activated cyclic nucleotide-gated channels and microRNA-1 and -133 in patients with age-associated atrial fibrillation. Mol. Med. Rep. 2015; 12 (3): 3243–3248. DOI: 10.3892/mmr.2015.3831.Girmatsion Z., Biliczki P., Bonauer A., Wimmer-Greinecker G., Scherer M., Moritz A., Bukowska A., Goette A., Nattel S., Hohnloser S.H., Ehrlich J.R. Changes in microRNA-1 expression and IK1 up-regulation in human atrial fibrillation. Heart Rhythm. 2009; 6 (12): 1802–1809. DOI: 10.1016/j.hrthm.2009.08.035.Girmatsion Z., Biliczki P., Bonauer A., Wimmer-Greinecker G., Scherer M., Moritz A., Bukowska A., Goette A., Nattel S., Hohnloser S.H., Ehrlich J.R. Changes in microRNA-1 expression and IK1 up-regulation in human atrial fibrillation. Heart Rhythm. 2009; 6 (12): 1802–1809. DOI: 10.1016/j.hrthm.2009.08.035.Lu Y., Hou S., Huang D., Luo X., Zhang J., Chen J., Xu W. Expression profile analysis of circulating microRNAs and their effects on ion channels in Chinese atrial fibrillation patients. Int. J. Clin. Exp. Med. 2015; 8 (1): 845–853.Lu Y., Hou S., Huang D., Luo X., Zhang J., Chen J., Xu W. Expression profile analysis of circulating microRNAs and their effects on ion channels in Chinese atrial fibrillation patients. Int. J. Clin. Exp. Med. 2015; 8 (1): 845–853.Santulli G., Iaccarino G., De Luca N., Trimarco B., Condorelli G. Atrial fibrillation and microRNAs. Front. Physiol. 2014; 5: 15. DOI: 10.3389/fphys.2014.00015.Santulli G., Iaccarino G., De Luca N., Trimarco B., Condorelli G. Atrial fibrillation and microRNAs. Front. Physiol. 2014; 5: 15. DOI: 10.3389/fphys.2014.00015.Lu Y., Zhang Y., Wang N., Pan Z., Gao X., Zhang F., Zhang Y., Shan H., Luo X., Bai Y., Sun L., Song W., Xu C., Wang Z., Yang B. MicroRNA-328 contributes to adverse electrical remodeling in atrial fibrillation. Circulation. 2010; 122 (23): 2378–2387. DOI: 10.1161/CIRCULATIONAHA.110.958967.Lu Y., Zhang Y., Wang N., Pan Z., Gao X., Zhang F., Zhang Y., Shan H., Luo X., Bai Y., Sun L., Song W., Xu C., Wang Z., Yang B. MicroRNA-328 contributes to adverse electrical remodeling in atrial fibrillation. Circulation. 2010; 122 (23): 2378–2387. DOI: 10.1161/CIRCULATIONAHA.110.958967.Kim G.H. MicroRNA regulation of cardiac conduction and arrhythmias. Transl. Res. 2013; 161 (5): 381–392. DOI: 10.1016/j.trsl.2012.12.004.Kim G.H. MicroRNA regulation of cardiac conduction and arrhythmias. Transl. Res. 2013; 161 (5): 381–392. DOI: 10.1016/j.trsl.2012.12.004.Soeki T., Matsuura T., Bando S., Tobiume T., Uematsu E., Ise T., Kusunose K., Yamaguchi K., Yagi S., Fukuda D., Yamada H., Wakatsuki T., Shimabukuro M., Sata M. Relationship between local production of microRNA-328 and atrial substrate remodeling in atrial fibrillation. J. Cardiol. 2016; 68 (6): 472–477. DOI: 10.1016/j.jjcc.2015.12.007.Soeki T., Matsuura T., Bando S., Tobiume T., Uematsu E., Ise T., Kusunose K., Yamaguchi K., Yagi S., Fukuda D., Yamada H., Wakatsuki T., Shimabukuro M., Sata M. Relationship between local production of microRNA-328 and atrial substrate remodeling in atrial fibrillation. J. Cardiol. 2016; 68 (6): 472–477. DOI: 10.1016/j.jjcc.2015.12.007.Ling T.Y., Wang X.L., Chai Q., Lau T.W., Koestler C.M., Park S.J., Daly R.C., Greason K.L., Jen J., Wu L.Q., Shen W.F., Shen W.K., Cha Y.M., Lee H.C. Regulation of the SK3 channel by microRNA-499-potential role in atrial fibrillation. Heart Rhythm. 2013; 10 (7): 1001–1009. DOI: 10.1016/j.hrthm.2013.03.005.Ling T.Y., Wang X.L., Chai Q., Lau T.W., Koestler C.M., Park S.J., Daly R.C., Greason K.L., Jen J., Wu L.Q., Shen W.F., Shen W.K., Cha Y.M., Lee H.C. Regulation of the SK3 channel by microRNA-499-potential role in atrial fibrillation. Heart Rhythm. 2013; 10 (7): 1001–1009. DOI: 10.1016/j.hrthm.2013.03.005.Ling T.Y., Wang X.L., Chai Q., Lu T., Stulak J.M., Joyce L.D., Daly R.C., Greason K.L., Wu L.Q., Shen W.K., Cha Y.M., Lee H.C. Regulation of cardiac CACNB2 by microRNA-499: Potential role in atrial fibrillation. BBA Clin. 2017; 7: 78–84. DOI: 10.1016/j.bbacli.2017.02.002.Ling T.Y., Wang X.L., Chai Q., Lu T., Stulak J.M., Joyce L.D., Daly R.C., Greason K.L., Wu L.Q., Shen W.K., Cha Y.M., Lee H.C. Regulation of cardiac CACNB2 by microRNA-499: Potential role in atrial fibrillation. BBA Clin. 2017; 7: 78–84. DOI: 10.1016/j.bbacli.2017.02.002.Da Silva A.M.G., de Araujo J.N.G., de Oliveira K.M., Novaes A.E.M., Lopes M.B., de Sousa J.C.V., Filho A.A.A., Luchessi A.D., de Rezende A.A., Hirata M.H., Silbiger V.N. Circulating miRNAs in acute new-onset atrial fibrillation and their target mRNA network. J. Cardiovasc. Electrophysiol. 2018; 29 (8): 1159–1166. DOI: 10.1111/jce.13612.Da Silva A.M.G., de Araujo J.N.G., de Oliveira K.M., Novaes A.E.M., Lopes M.B., de Sousa J.C.V., Filho A.A.A., Luchessi A.D., de Rezende A.A., Hirata M.H., Silbiger V.N. Circulating miRNAs in acute new-onset atrial fibrillation and their target mRNA network. J. Cardiovasc. Electrophysiol. 2018; 29 (8): 1159–1166. DOI: 10.1111/jce.13612.Xu J., Cui G., Esmailian F., Plunkett M., Marelli D., Ardehali A., Odim J., Laks H., Sen L. Atrial extracellular matrix remodeling and the maintenance of atrial fibrillation. Circulation. 2004; 109 (3): 363–368. DOI: 10.1161/01.CIR.0000109495.02213.52.Xu J., Cui G., Esmailian F., Plunkett M., Marelli D., Ardehali A., Odim J., Laks H., Sen L. Atrial extracellular matrix remodeling and the maintenance of atrial fibrillation. Circulation. 2004; 109 (3): 363–368. DOI: 10.1161/01.CIR.0000109495.02213.52.Liu H., Chen G.X., Liang M.Y., Qin H., Rong J., Yao J.P., Wu Z.K. Atrial fibrillation alters the microRNA expression profiles of the left atria of patients with mitral stenosis. BMC Cardiovasc. Disord. 2014; 14: 10. DOI: 10.1186/1471-2261-14-10.Liu H., Chen G.X., Liang M.Y., Qin H., Rong J., Yao J.P., Wu Z.K. Atrial fibrillation alters the microRNA expression profiles of the left atria of patients with mitral stenosis. BMC Cardiovasc. Disord. 2014; 14: 10. DOI: 10.1186/1471-2261-14-10.Barana A., Matamoros M., Dolz-Gaiton P., Pérez-Hernández M., Amoros I., Nunez M., Sacristán S., Pedraz Á., Pinto Á., Fernández-Avilés F., Tamargo J., Delpón E., Caballero R. Chronic atrial fibrillation increases microRNA-21 in human atrial myocytes decreasing L-type calcium current. Circ. Arrhythm. Electrophysiol. 2014; 7 (5): 861–868. DOI: 10.1161/CIRCEP.114.001709.Barana A., Matamoros M., Dolz-Gaiton P., Pérez-Hernández M., Amoros I., Nunez M., Sacristán S., Pedraz Á., Pinto Á., Fernández-Avilés F., Tamargo J., Delpón E., Caballero R. Chronic atrial fibrillation increases microRNA-21 in human atrial myocytes decreasing L-type calcium current. Circ. Arrhythm. Electrophysiol. 2014; 7 (5): 861–868. DOI: 10.1161/CIRCEP.114.001709.Adam O., Lohfelm B., Thum T., Gupta S.K., Puhl S.L., Schafers H.J., Böhm M., Laufs U. Role of miR-21 in the pathogenesis of atrial fibrosis. Basic. Res. Cardiol. 2012; 107 (5): 278. DOI: 10.1007/s00395-012-0278-0.Adam O., Lohfelm B., Thum T., Gupta S.K., Puhl S.L., Schafers H.J., Böhm M., Laufs U. Role of miR-21 in the pathogenesis of atrial fibrosis. Basic. Res. Cardiol. 2012; 107 (5): 278. DOI: 10.1007/s00395-012-0278-0.Thum T., Gross C., Fiedler J., Fischer T., Kissler S., Bussen M., Galuppo P., Just S., Rottbauer W., Frantz S., Castoldi M., Soutschek J., Koteliansky V., Rosenwald A., Basson M.A., Licht J.D., Pena J.T., Rouhanifard S.H., Muckenthaler M.U., Tuschl T., Martin G.R., Bauersachs J., Engelhardt S. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature. 2008; 456 (7224): 980–984. DOI: 10.1038/nature07511Thum T., Gross C., Fiedler J., Fischer T., Kissler S., Bussen M., Galuppo P., Just S., Rottbauer W., Frantz S., Castoldi M., Soutschek J., Koteliansky V., Rosenwald A., Basson M.A., Licht J.D., Pena J.T., Rouhanifard S.H., Muckenthaler M.U., Tuschl T., Martin G.R., Bauersachs J., Engelhardt S. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature. 2008; 456 (7224): 980–984. DOI: 10.1038/nature07511Zhang K., Zhao L., Ma Z., Wang W., Li X., Zhang Y., Yuan M, Liang X., Li G. Doxycycline attenuates atrial remodeling by interfering with microRNA-21 and downstream phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K) signaling pathway. Med. Sci. Monit. 2018; 24: 5580–5587. DOI: 10.12659/MSM.909800.Zhang K., Zhao L., Ma Z., Wang W., Li X., Zhang Y., Yuan M, Liang X., Li G. Doxycycline attenuates atrial remodeling by interfering with microRNA-21 and downstream phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K) signaling pathway. Med. Sci. Monit. 2018; 24: 5580–5587. DOI: 10.12659/MSM.909800.Kriegel A.J., Liu Y., Fang Y., Ding X., Liang M. The miR-29 family: genomics, cell biology, and relevance to renal and cardiovascular injury. Physiol. Genomics. 2012; 44 (4): 237–244. DOI: 10.1152/physiolgenomics.00141.2011.Kriegel A.J., Liu Y., Fang Y., Ding X., Liang M. The miR-29 family: genomics, cell biology, and relevance to renal and cardiovascular injury. Physiol. Genomics. 2012; 44 (4): 237–244. DOI: 10.1152/physiolgenomics.00141.2011.Dawson K., Wakili R., Ordog B., Clauss S., Chen Y., Iwasaki Y., Voigt N., Qi X.Y., Sinner M.F., Dobrev D., Kääb S., Nattel S. MicroRNA29: a mechanistic contributor and potential biomarker in atrial fibrillation. Circulation. 2013; 127 (14): 1466–1475, 1475e1–28. DOI: 10.1161/CIRCULATIONAHA.112.001207.Dawson K., Wakili R., Ordog B., Clauss S., Chen Y., Iwasaki Y., Voigt N., Qi X.Y., Sinner M.F., Dobrev D., Kääb S., Nattel S. MicroRNA29: a mechanistic contributor and potential biomarker in atrial fibrillation. Circulation. 2013; 127 (14): 1466–1475, 1475e1–28. DOI: 10.1161/CIRCULATIONAHA.112.001207.Ishizaki T., Tamiya T., Taniguchi K., Morita R., Kato R., Okamoto F., Saeki K., Nomura M., Nojima Y., Yoshimura A. miR126 positively regulates mast cell proliferation and cytokine production through suppressing Spred1. Genes. Cells. 2011; 16 (7): 803–814. DOI: 10.1111/j.1365-2443.2011.01529.x.Ishizaki T., Tamiya T., Taniguchi K., Morita R., Kato R., Okamoto F., Saeki K., Nomura M., Nojima Y., Yoshimura A. miR126 positively regulates mast cell proliferation and cytokine production through suppressing Spred1. Genes. Cells. 2011; 16 (7): 803–814. DOI: 10.1111/j.1365-2443.2011.01529.x.Wei X.J., Han M., Yang F.Y., Wei G.C., Liang Z.G., Yao H., Ji C.W., Xie R.S., Gong C.L., Tian Y. Biological significance of miR-126 expression in atrial fibrillation and heart failure. Braz. J. Med. Biol. Res. 2015; 48 (11): 983–989. DOI: 10.1590/1414-431X20154590.Wei X.J., Han M., Yang F.Y., Wei G.C., Liang Z.G., Yao H., Ji C.W., Xie R.S., Gong C.L., Tian Y. Biological significance of miR-126 expression in atrial fibrillation and heart failure. Braz. J. Med. Biol. Res. 2015; 48 (11): 983–989. DOI: 10.1590/1414-431X20154590.Goren Y., Meiri E., Hogan C., Mitchell H., Lebanony D., Salman N., Schliamser J.E., Amir O. Relation of reduced expression of MiR-150 in platelets to atrial fibrillation in patients with chronic systolic heart failure. Am. J. Cardiol. 2014; 113 (6): 976–981. DOI: 10.1016/j.amjcard.2013.11.060.Goren Y., Meiri E., Hogan C., Mitchell H., Lebanony D., Salman N., Schliamser J.E., Amir O. Relation of reduced expression of MiR-150 in platelets to atrial fibrillation in patients with chronic systolic heart failure. Am. J. Cardiol. 2014; 113 (6): 976–981. DOI: 10.1016/j.amjcard.2013.11.060.McManus D.D., Tanriverdi K., Lin H., Esa N., Kinno M., Mandapati D., Tam S., Okike O.N., Ellinor P.T., Keaney J.F. Jr., Donahue J.K., Benjamin E.J., Freedman J.E. Plasma microRNAs are associated with atrial fibrillation and change after catheter ablation (the miRhythm study). Heart Rhythm. 2015; 12 (1): 3–10. DOI: 10.1016/j.hrthm.2014.09.050.McManus D.D., Tanriverdi K., Lin H., Esa N., Kinno M., Mandapati D., Tam S., Okike O.N., Ellinor P.T., Keaney J.F. Jr., Donahue J.K., Benjamin E.J., Freedman J.E. Plasma microRNAs are associated with atrial fibrillation and change after catheter ablation (the miRhythm study). Heart Rhythm. 2015; 12 (1): 3–10. DOI: 10.1016/j.hrthm.2014.09.050.Harling L., Lambert J., Ashrafian H., Darzi A., Gooderham N.J., Athanasiou T. Elevated serum microRNA 483-5p levels may predict patients at risk of post-operative atrial fibrillation. Eur. J. Cardiothorac. Surg. 2017; 51 (1): 73–78. DOI: 10.1093/ejcts/ezw245.Harling L., Lambert J., Ashrafian H., Darzi A., Gooderham N.J., Athanasiou T. Elevated serum microRNA 483-5p levels may predict patients at risk of post-operative atrial fibrillation. Eur. J. Cardiothorac. Surg. 2017; 51 (1): 73–78. DOI: 10.1093/ejcts/ezw245.Rao M., Hu J., Zhang Y., Gao F., Zhang F., Yang Z., Zhang X., Hou Y. Time-dependent cervical vagus nerve stimulation and frequency-dependent right atrial pacing mediates induction of atrial fibrillation. Anatol. J. Cardiol. 2018; 20 (4): 206–212. DOI: 10.14744/AnatolJCardiol.2018.73558.Rao M., Hu J., Zhang Y., Gao F., Zhang F., Yang Z., Zhang X., Hou Y. Time-dependent cervical vagus nerve stimulation and frequency-dependent right atrial pacing mediates induction of atrial fibrillation. Anatol. J. Cardiol. 2018; 20 (4): 206–212. DOI: 10.14744/AnatolJCardiol.2018.73558.Shen M.J., Choi E.K., Tan A.Y., Lin S.F., Fishbein M.C., Chen L.S., Chen P.S. Neural mechanisms of atrial arrhythmias. Nat. Rev. Cardiol. 2011; 9 (1): 30–39. DOI: 10.1038/nrcardio.2011.139.Shen M.J., Choi E.K., Tan A.Y., Lin S.F., Fishbein M.C., Chen L.S., Chen P.S. Neural mechanisms of atrial arrhythmias. Nat. Rev. Cardiol. 2011; 9 (1): 30–39. DOI: 10.1038/nrcardio.2011.139.Morishima M., Iwata E., Nakada C., Tsukamoto Y., Takanari H., Miyamoto S., Moriyama M., Ono K. Atrial fibrillation-mediated upregulation of miR-30d regulates myocardial electrical remodeling of the g-protein-gated K(+) channel, IK.ACh. Circ. J. 2016; 80 (6): 1346–1355. DOI: 10.1253/circj.CJ-15-1276.Morishima M., Iwata E., Nakada C., Tsukamoto Y., Takanari H., Miyamoto S., Moriyama M., Ono K. Atrial fibrillation-mediated upregulation of miR-30d regulates myocardial electrical remodeling of the g-protein-gated K(+) channel, IK.ACh. Circ. J. 2016; 80 (6): 1346–1355. DOI: 10.1253/circj.CJ-15-1276.Zhang Y., Zheng S., Geng Y., Xue J., Wang Z., Xie X., Wang J., Zhang S., Hou Y. MicroRNA profiling of atrial fibrillation in canines: miR-206 modulates intrinsic cardiac autonomic nerve remodeling by regulating SOD1. PLoS One. 2015; 10 (3): e0122674. DOI: 10.1371/journal.pone.0122674.Zhang Y., Zheng S., Geng Y., Xue J., Wang Z., Xie X., Wang J., Zhang S., Hou Y. MicroRNA profiling of atrial fibrillation in canines: miR-206 modulates intrinsic cardiac autonomic nerve remodeling by regulating SOD1. PLoS One. 2015; 10 (3): e0122674. DOI: 10.1371/journal.pone.0122674.Wei J., Zhang Y., Li Z., Wang X., Chen L., Du J., Liu J., Liu J., Hou Y. GCH1 attenuates cardiac autonomic nervous remodeling in canines with atrial-tachypacing via tetrahydrobiopterin pathway regulated by microRNA-206. Pacing Clin. Electrophysiol. 2018; 41 (5): 459–471. DOI: 10.1111/pace.13289.Wei J., Zhang Y., Li Z., Wang X., Chen L., Du J., Liu J., Liu J., Hou Y. GCH1 attenuates cardiac autonomic nervous remodeling in canines with atrial-tachypacing via tetrahydrobiopterin pathway regulated by microRNA-206. Pacing Clin. Electrophysiol. 2018; 41 (5): 459–471. DOI: 10.1111/pace.13289.Harada M., Luo X., Murohara T., Yang B., Dobrev D., Nattel S. MicroRNA regulation and cardiac calcium signaling: role in cardiac disease and therapeutic potential. Circ. Res. 2014; 114 (4): 689–705. DOI: 10.1161/CIRCRESAHA.114.301798.Harada M., Luo X., Murohara T., Yang B., Dobrev D., Nattel S. MicroRNA regulation and cardiac calcium signaling: role in cardiac disease and therapeutic potential. Circ. Res. 2014; 114 (4): 689–705. DOI: 10.1161/CIRCRESAHA.114.301798.Denham N.C., Pearman C.M., Caldwell J.L., Madders G.W.P., Eisner D.A., Trafford A.W., Dibb K.M. Calcium in the pathophysiology of atrial fibrillation and heart failure. Front. Physiol. 2018; 9: 1380. DOI: 10.3389/fphys.2018.01380.Denham N.C., Pearman C.M., Caldwell J.L., Madders G.W.P., Eisner D.A., Trafford A.W., Dibb K.M. Calcium in the pathophysiology of atrial fibrillation and heart failure. Front. Physiol. 2018; 9: 1380. DOI: 10.3389/fphys.2018.01380.Chiang D.Y., Kongchan N., Beavers D.L., Alsina K.M., Voigt N., Neilson J.R., Jakob H., Martin J.F., Dobrev D., Wehrens X.H., Li N. Loss of microRNA-106b-25 cluster promotes atrial fibrillation by enhancing ryanodine receptor type-2 expression and calcium release. Circ. Arrhythm. Electrophysiol. 2014; 7(6): 1214–1222. DOI: 10.1161/CIRCEP.114.001973.Chiang D.Y., Kongchan N., Beavers D.L., Alsina K.M., Voigt N., Neilson J.R., Jakob H., Martin J.F., Dobrev D., Wehrens X.H., Li N. Loss of microRNA-106b-25 cluster promotes atrial fibrillation by enhancing ryanodine receptor type-2 expression and calcium release. Circ. Arrhythm. Electrophysiol. 2014; 7(6): 1214–1222. DOI: 10.1161/CIRCEP.114.001973.Canon S., Caballero R., Herraiz-Martínez A., Perez-Hernández M., Lopez B., Atienza F., Jalife J., Hove-Madsen L., Delpón E., Bernad A. miR-208b upregulation interferes with calcium handling in HL-1 atrial myocytes: Implications in human chronic atrial fibrillation. J. Mol. Cell Cardiol. 2016; 99: 162–173. DOI: 10.1016/j.yjmcc.2016.08.012.Canon S., Caballero R., Herraiz-Martínez A., Perez-Hernández M., Lopez B., Atienza F., Jalife J., Hove-Madsen L., Delpón E., Bernad A. miR-208b upregulation interferes with calcium handling in HL-1 atrial myocytes: Implications in human chronic atrial fibrillation. J. Mol. Cell Cardiol. 2016; 99: 162–173. DOI: 10.1016/j.yjmcc.2016.08.012.D’Alessandra Y., Devanna P., Limana F., Straino S., Di Carlo A., Brambilla P.G., Rubino M., Carena M.C., Spazzafumo L., De Simone M., Micheli B., Biglioli P., Achilli F., Martelli F., Maggiolini S., Marenzi G., Pompilio G., Capogrossi M.C. Circulating microRNAs are new and sensitive biomarkers of myocardial infarction. Eur. Heart J. 2010; 31 (22): 2765–2773. DOI: 10.1093/eurheartj/ehq167.D’Alessandra Y., Devanna P., Limana F., Straino S., Di Carlo A., Brambilla P.G., Rubino M., Carena M.C., Spazzafumo L., De Simone M., Micheli B., Biglioli P., Achilli F., Martelli F., Maggiolini S., Marenzi G., Pompilio G., Capogrossi M.C. Circulating microRNAs are new and sensitive biomarkers of myocardial infarction. Eur. Heart J. 2010; 31 (22): 2765–2773. DOI: 10.1093/eurheartj/ehq167.Widera C., Gupta S.K., Lorenzen J.M., Bang C., Bauersachs J., Bethmann K., Kempf T., Wollert K.C., Thum T. Diagnostic and prognostic impact of six circulating microRNAs in acute coronary syndrome. J. Mol. Cell Cardiol. 2011; 51 (5): 872–875. DOI: 10.1016/j.yjmcc.2011.07.011.Widera C., Gupta S.K., Lorenzen J.M., Bang C., Bauersachs J., Bethmann K., Kempf T., Wollert K.C., Thum T. Diagnostic and prognostic impact of six circulating microRNAs in acute coronary syndrome. J. Mol. Cell Cardiol. 2011; 51 (5): 872–875. DOI: 10.1016/j.yjmcc.2011.07.011.Zampetaki A., Willeit P., Drozdov I., Kiechl S., Mayr M. Profiling of circulating microRNAs: from single biomarkers to re-wired networks. Cardiovasc. Res. 2012; 93 (4): 555–562. DOI: 10.1093/cvr/cvr266.Zampetaki A., Willeit P., Drozdov I., Kiechl S., Mayr M. Profiling of circulating microRNAs: from single biomarkers to re-wired networks. Cardiovasc. Res. 2012; 93 (4): 555–562. DOI: 10.1093/cvr/cvr266.Natsume Y., Oaku K., Takahashi K., Nakamura W., Oono A., Hamada S., Yamazoe M., Ihara K., Sasaki T., Goya M., Hirao K., Furukawa T., Sasano T. Combined analysis of human and experimental murine samples identified novel circulating microRNAs as biomarkers for atrial fibrillation. Circ. J. 2018; 82 (4): 965–973. DOI: 10.1253/circj.CJ-17-1194.Natsume Y., Oaku K., Takahashi K., Nakamura W., Oono A., Hamada S., Yamazoe M., Ihara K., Sasaki T., Goya M., Hirao K., Furukawa T., Sasano T. Combined analysis of human and experimental murine samples identified novel circulating microRNAs as biomarkers for atrial fibrillation. Circ. J. 2018; 82 (4): 965–973. DOI: 10.1253/circj.CJ-17-1194.

The authors declare that there are no conflicts of interest present.