Editorial Comment Cardiology 2015;131:55–57 DOI: 10.1159/000381282
Received: February 26, 2015 Accepted: February 26, 2015 Published online: April 8, 2015
A New Insight into the Molecular Mechanism of Atrial Fibrillation: The Role of MicroRNAs Shimon Rosenheck Hadassah Hebrew University Medical Center, Jerusalem, Israel
© 2015 S. Karger AG, Basel 0008–6312/15/1311–0055$39.50/0 E-Mail [email protected] www.karger.com/crd
has been associated with decreased Sprouty1 expression in the left atrium of patients with atrial fibrillation [2]. Cytokine connective tissue growth factor, Rho GTPase Rac1 and lysyl oxidase are all upregulated and contribute to increased fibrosis. The intracellular lysyl oxidase upregulates miR-21 through Drosha and Dicer and decreases Sprouty1, an inhibitor of ERK-MAP kinase. The final result is the fibroblast survival and fibrotic remodeling of the atrium [2, 3]. In a very recent study, miR-21 and miR150 were significantly lower in the blood of patients with atrial fibrillation than in patients with normal sinus rhythm [4]. In another study, miR-21 had an inverse correlation with the mRNA of the α1c subunit of the calcium channel expression and caused a significant decrease in the density of ICaL. This finding suggests that there is more than one site of action of miR-21. miR-150 prevents fibrosis, and its expression is significantly reduced in patients with chronic atrial fibrillation [5, 6]. MiR-29 expression was found to be decreased in dogs with pacing-induced congestive heart failure. This particular microRNA targets the genes of collagen 1A1 and 3A1 and fibrillin, contributing to the fibrotic remodeling of the atrium and increasing the propensity for atrial fibrillation [7].
Shimon Rosenheck, MD Hadassah Hebrew University Medical Center, Heart Institute Kiryat Hadassah, PO Box 12000 Jerusalem 91120 (Israel) E-Mail shimonr @ ekmd.huji.ac.il
Downloaded by: NYU Medical Center Library 128.122.253.212 - 4/15/2015 2:36:20 PM
Atrial fibrillation is the most frequent arrhythmia and its incidence is increasing parallel to the aging of the population. As with all arrhythmias, a trigger delivered onto a susceptible substrate initiates the fibrillation. Facilitators adopt the substrate, allowing both the initiation and perpetuation of arrhythmia. An enlarged left atrium constitutes the substrate, and an electrical discharge, mainly from the pulmonary veins adjacent to the insertion into the left atrium, is the trigger. However, the mechanism that adjusts the trigger to the substrate has not been completely elucidated. The personal predilection to this arrhythmia is also not yet understood. Recently, disturbances in the intra-atrial and blood concentrations of microRNAs that coincide with the presence of atrial fibrillation was suggested and strongly supported by experimental data. The available data are complex and even occasionally contradictory. In this issue of Cardiology, Poudel et al. [1] review the basic mechanism of atrial fibrillation and the information on the contribution of microRNAs. In response to a decrease in left ventricular compliance, the left atrium enlarges and the atrial tissue becomes infiltrated by fibrous tissue. The molecular mechanism of the profibrotic activity has been extensively studied and important information has been accumulated. Increased miR-21 expression
Table 1. Summary of the design of the studies recently published on the correlation of the extent of microRNAs and atrial fibrillation
Study population
Tests
Tissue
microRNA
Reference
Human with CHF
qRT-PCR, platelet array
serum, platelets
miR-150
5
Human
qRT-PCR
plasma, atrial tissue
miR-21, miR-150
41
Rats after myocardial infarction
qRT-PCR, immunoblot
atrial tissue
miR-21
3
Human
qRt-PCR, Western blot
myocardial cells
miR-21
6
Human, dog model of CHF
qRT-PCR
atrial tissue, fibroblasts
miR-29
7 11
Dog AF model, human AF and rheumatic heart disease, mice
qER-PCR, microarray, Northern blot
atrial tissue
miR-3282
Human (Framingham)
qRT-PCR
whole blood
miR-328, miR-150-5p
12
Human during surgery
qRT-PCR array
right atrial appendage3
miR-106b, miR-144, miR-451, miR-208a4
14
Canine AF model, human
qRT-PCR, Western blot
atrial tissue
miR-26
8
Human, mouse HL-1 cells
microarray qRT-PCR, Western blot
atrial tissue
miR-499
9
Patients with valvular heart disease
microarray qRT-PCR
right and left atrial appendage
multiple5
13
Mouse model of myocardial infarction, human during mitral valve surgery
qRT-PCR, Western blot
atrial tissue
miR-21
8
Human mitral stenosis
microarray qRT-PCR
right atrial appendage
multiple
15
Human
immunoblot, qRT-PCR
atrial tissue
miR-1
10
Other microRNAs affect repolarization. Shortening the repolarization is crucial in the fibrillation process, favoring the rapid recovery of the myocardial cells from previous stimulation. miR-26 correlates inversely with the density of the inward-rectifier potassium current [8]. MiR-499 is significantly upregulated in atrial fibrillation and causes the downregulation of SK3 channels [9]. Increased expression of miR-1 is associated with an increase in the density of Kir2.1 (Ik1) [10]. In patients with rheumatic heart disease, it was found that several microRNAs were upregulated and others were downregulated. The most prominent upregulated microRNA was miR-328, with potential targets being CACA1C and CACNB1 which encode the cardiac L-type calcium channel [11, 12]. 56
Cardiology 2015;131:55–57 DOI: 10.1159/000381282
Other studies have shown significant differences between the expression of microRNAs in the right and left atria [13, 14]. In one study, 136 different expressions of microRNAs were found in patients with atrial fibrillation and mitral stenosis compared to healthy controls [15]. However, patients with mitral stenosis in sinus rhythm and healthy controls had 96 differently expressed microRNAs. There were also 28 differently expressed microRNAs in patients with mitral stenosis with and without atrial fibrillation. As several different levels of microRNAs can be detected in the peripheral blood, serum or platelets, microRNAs could, in the future, be considered as biomarkers for a propensity for atrial fibrillation and even as indicators of successful atrial fibrillation ablation. Rosenheck
Downloaded by: NYU Medical Center Library 128.122.253.212 - 4/15/2015 2:36:20 PM
AF = Atrial fibrillation; CHF = congestive heart failure. 1 Effect of radiofrequency ablation. 2 Also upregulated miR-223, miR-664 and miR-517 and downregulated miR-101, miR-133, miR-145, miR-320, miR-373 and miR-499. 3 In 1 patient, left atrial appendage. 4 Also miR-15, miR-106, miR-18a, miR-18b, miR-19a, miR-19b, miR-23a, miR-25, miR-30a, miR-486-5p and miR-93. 5 Including miR-21.
MicroRNAs or the antagonists, called antagomirs, offer possibilities for future atrial fibrillation therapy. Table 1 presents a summary of studies. The widely varying results and the multiplicity of the microRNAs with the same final result can be explained by the tissue evaluated, the different models used and the different
methods of testing, even though qRT-PCR was unanimously used in all the studies. This subject is complex and further information is needed for the complete picture. The review by Poudel et al. [1] in this issue of Cardiology makes a small step in this direction.
References
A New Insight into the Molecular Mechanism of Atrial Fibrillation
6 Barana A, Matamoros M, Dolz-Gaiton P, Perez-Hernandez M, Amoros I, Nunez M, Sacristan S, Pedraz A, Pinto A, Fernandez-Aviles F, Tamargo J, Delpon E, Caballero R: Chronic atrial fibrillation increases microRNA-21 in human atrial myocytes decreasing L-type calcium current. Circ Arrhythm Electrophysiol 2014;7:861–868. 7 Dawson K, Wakili R, Ordog B, Caluss S, Chen Y, Iwasaki Y, Voigt N, Qi XY, Sinner MF, Dobrev D, Kaab S, Nattel: MicroRNA29. A mechanistic contributor and potential biomarker in atrial fibrillation. Circulation 2013; 127:1466–1475. 8 Lou X, Pan Z, Shan H, Xiao J, Sun X, Wang N, Lin H, Xiao L, Maguy A, Qi XY, Li Y, Dong D, Zhang Y, Bai Y, Ai J, Sun L, Lu H, Lou XY, Wang Z, Lu Y, Yang B, Nattel S: MicroRNA -26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation. J Clin Invest 2013;123:1939–1951. 9 Ling TY, Wang XL, Chai Q, Lau TW, Koestler CM, Park SJ, Daly RC, Greason KL, Jen J, Wu LQ, Shen WF, Shen WK, Cha YM, Lee HC: Regulation of SK3 channel by microRNA-499 – potential role in atrial fibrillation. Heart Rhythm 2013:10:1001–1009. 10 Girmatsion Z, Biliczki P, Bonauer A, Wimmwe-Greinecker G, Scherer M, Moritz A, Bukowska A, Goette A, Nattel S, Hohnloser SH, Ehrlich JR: Changes in microRNA-1 expression and IK1 up-regulation in human atrial fibrillation. Heart Rhythm 2009; 6: 1802–1809.
11 Lu Y, Zhang Y, Wang N, Pan Z, Gao X, Zhang F, Zhang Y, Shan H, Lou 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: 2378–2387. 12 McMaus DD, Lin H, Tanriverdi K, Quercio M, Yin X, Larson MG, Ellinor PT, Levy D, Freedman JE, Benjamin EJ: Relation between circulating microRNAs and atrial fibrillation: data from the Framingham Offspring Study. Heart Rhythm 2014;11:663–669. 13 Cooley N, Cowley MJ, Lin RCY, Marasco S, Wong C, Kaye DM, Dart AM, Woodcock EA: Influence of atrial fibrillation on microRNA expression in left and right atria from patients with valvular heart disease. Physiol Genomics 2012;44:211–219. 14 Slagsvold KH, Johnsen AB, Rognmo O, Hoydal MA, Wisloff U, Wahba A: Mitochondrial respiration and microRNA expression in right and left atrium of patients with atrial fibrillation. Physiol Genomics 2014; 46: 505– 511. 15 Xiao J, Liang D, Zhang Y, Liu Y, Zhang H, Liu Yi, Li L, Liang X, Sun Y, Chen YH: MicroRNA expression signature in atrial fibrillation with mitral stenosis. Physiol Genomics 2011; 43: 655–664.
Cardiology 2015;131:55–57 DOI: 10.1159/000381282
57
Downloaded by: NYU Medical Center Library 128.122.253.212 - 4/15/2015 2:36:20 PM
1 Poudel P, Xu Y, Cui Z, Sharma D, Tian B, Paudel S: Atrial fibrillation: recent advances in understanding the role of microRNAs in atrial remodeling with an electrophysiological overview. Cardiology 2015; 131: 58–67. 2 Adam O, Lohfelm B, Thum T, Gupta SK, Puhl SL, Schafers HJ, Bohm M, Laufs U: Role of miR-21 in the pathogenesis of atrial fibrosis. Basic Res Cardiol 2012;107:278. 3 Cardin S, Guasch E, Lou X, Naud P, Quang KL, Shi Y, Tardif JC, Comtois P, Nattel S: Role for microRNA-21 in atrial profibrillatory fibrotic remodeling associated with experimental postinfarction heart failure. Circ Arrhythm Electrophysiol 2012;5:1027–1035. 4 McManus D, Tanriverdi K, Lin H, Esa N, Kinno M, Mandapati D, Tam S, Okike ON, Ellinor PT, Keaney JF, Donahue JK, Benjamin EJ, Freedman JE: Plasma microRNA are associated with atrial fibrillation and changes after catheter ablation (miRhythm study). Heart Rhythm 2015;12:3–10. 5 Goren Y, Meiri E, Hogan C, Mitchell H, Lebanony D, Salman N, Schliamser JE, 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;113:976–981.
Received: February 26, 2015 Accepted: February 26, 2015 Published online: April 8, 2015
A New Insight into the Molecular Mechanism of Atrial Fibrillation: The Role of MicroRNAs Shimon Rosenheck Hadassah Hebrew University Medical Center, Jerusalem, Israel
© 2015 S. Karger AG, Basel 0008–6312/15/1311–0055$39.50/0 E-Mail [email protected] www.karger.com/crd
has been associated with decreased Sprouty1 expression in the left atrium of patients with atrial fibrillation [2]. Cytokine connective tissue growth factor, Rho GTPase Rac1 and lysyl oxidase are all upregulated and contribute to increased fibrosis. The intracellular lysyl oxidase upregulates miR-21 through Drosha and Dicer and decreases Sprouty1, an inhibitor of ERK-MAP kinase. The final result is the fibroblast survival and fibrotic remodeling of the atrium [2, 3]. In a very recent study, miR-21 and miR150 were significantly lower in the blood of patients with atrial fibrillation than in patients with normal sinus rhythm [4]. In another study, miR-21 had an inverse correlation with the mRNA of the α1c subunit of the calcium channel expression and caused a significant decrease in the density of ICaL. This finding suggests that there is more than one site of action of miR-21. miR-150 prevents fibrosis, and its expression is significantly reduced in patients with chronic atrial fibrillation [5, 6]. MiR-29 expression was found to be decreased in dogs with pacing-induced congestive heart failure. This particular microRNA targets the genes of collagen 1A1 and 3A1 and fibrillin, contributing to the fibrotic remodeling of the atrium and increasing the propensity for atrial fibrillation [7].
Shimon Rosenheck, MD Hadassah Hebrew University Medical Center, Heart Institute Kiryat Hadassah, PO Box 12000 Jerusalem 91120 (Israel) E-Mail shimonr @ ekmd.huji.ac.il
Downloaded by: NYU Medical Center Library 128.122.253.212 - 4/15/2015 2:36:20 PM
Atrial fibrillation is the most frequent arrhythmia and its incidence is increasing parallel to the aging of the population. As with all arrhythmias, a trigger delivered onto a susceptible substrate initiates the fibrillation. Facilitators adopt the substrate, allowing both the initiation and perpetuation of arrhythmia. An enlarged left atrium constitutes the substrate, and an electrical discharge, mainly from the pulmonary veins adjacent to the insertion into the left atrium, is the trigger. However, the mechanism that adjusts the trigger to the substrate has not been completely elucidated. The personal predilection to this arrhythmia is also not yet understood. Recently, disturbances in the intra-atrial and blood concentrations of microRNAs that coincide with the presence of atrial fibrillation was suggested and strongly supported by experimental data. The available data are complex and even occasionally contradictory. In this issue of Cardiology, Poudel et al. [1] review the basic mechanism of atrial fibrillation and the information on the contribution of microRNAs. In response to a decrease in left ventricular compliance, the left atrium enlarges and the atrial tissue becomes infiltrated by fibrous tissue. The molecular mechanism of the profibrotic activity has been extensively studied and important information has been accumulated. Increased miR-21 expression
Table 1. Summary of the design of the studies recently published on the correlation of the extent of microRNAs and atrial fibrillation
Study population
Tests
Tissue
microRNA
Reference
Human with CHF
qRT-PCR, platelet array
serum, platelets
miR-150
5
Human
qRT-PCR
plasma, atrial tissue
miR-21, miR-150
41
Rats after myocardial infarction
qRT-PCR, immunoblot
atrial tissue
miR-21
3
Human
qRt-PCR, Western blot
myocardial cells
miR-21
6
Human, dog model of CHF
qRT-PCR
atrial tissue, fibroblasts
miR-29
7 11
Dog AF model, human AF and rheumatic heart disease, mice
qER-PCR, microarray, Northern blot
atrial tissue
miR-3282
Human (Framingham)
qRT-PCR
whole blood
miR-328, miR-150-5p
12
Human during surgery
qRT-PCR array
right atrial appendage3
miR-106b, miR-144, miR-451, miR-208a4
14
Canine AF model, human
qRT-PCR, Western blot
atrial tissue
miR-26
8
Human, mouse HL-1 cells
microarray qRT-PCR, Western blot
atrial tissue
miR-499
9
Patients with valvular heart disease
microarray qRT-PCR
right and left atrial appendage
multiple5
13
Mouse model of myocardial infarction, human during mitral valve surgery
qRT-PCR, Western blot
atrial tissue
miR-21
8
Human mitral stenosis
microarray qRT-PCR
right atrial appendage
multiple
15
Human
immunoblot, qRT-PCR
atrial tissue
miR-1
10
Other microRNAs affect repolarization. Shortening the repolarization is crucial in the fibrillation process, favoring the rapid recovery of the myocardial cells from previous stimulation. miR-26 correlates inversely with the density of the inward-rectifier potassium current [8]. MiR-499 is significantly upregulated in atrial fibrillation and causes the downregulation of SK3 channels [9]. Increased expression of miR-1 is associated with an increase in the density of Kir2.1 (Ik1) [10]. In patients with rheumatic heart disease, it was found that several microRNAs were upregulated and others were downregulated. The most prominent upregulated microRNA was miR-328, with potential targets being CACA1C and CACNB1 which encode the cardiac L-type calcium channel [11, 12]. 56
Cardiology 2015;131:55–57 DOI: 10.1159/000381282
Other studies have shown significant differences between the expression of microRNAs in the right and left atria [13, 14]. In one study, 136 different expressions of microRNAs were found in patients with atrial fibrillation and mitral stenosis compared to healthy controls [15]. However, patients with mitral stenosis in sinus rhythm and healthy controls had 96 differently expressed microRNAs. There were also 28 differently expressed microRNAs in patients with mitral stenosis with and without atrial fibrillation. As several different levels of microRNAs can be detected in the peripheral blood, serum or platelets, microRNAs could, in the future, be considered as biomarkers for a propensity for atrial fibrillation and even as indicators of successful atrial fibrillation ablation. Rosenheck
Downloaded by: NYU Medical Center Library 128.122.253.212 - 4/15/2015 2:36:20 PM
AF = Atrial fibrillation; CHF = congestive heart failure. 1 Effect of radiofrequency ablation. 2 Also upregulated miR-223, miR-664 and miR-517 and downregulated miR-101, miR-133, miR-145, miR-320, miR-373 and miR-499. 3 In 1 patient, left atrial appendage. 4 Also miR-15, miR-106, miR-18a, miR-18b, miR-19a, miR-19b, miR-23a, miR-25, miR-30a, miR-486-5p and miR-93. 5 Including miR-21.
MicroRNAs or the antagonists, called antagomirs, offer possibilities for future atrial fibrillation therapy. Table 1 presents a summary of studies. The widely varying results and the multiplicity of the microRNAs with the same final result can be explained by the tissue evaluated, the different models used and the different
methods of testing, even though qRT-PCR was unanimously used in all the studies. This subject is complex and further information is needed for the complete picture. The review by Poudel et al. [1] in this issue of Cardiology makes a small step in this direction.
References
A New Insight into the Molecular Mechanism of Atrial Fibrillation
6 Barana A, Matamoros M, Dolz-Gaiton P, Perez-Hernandez M, Amoros I, Nunez M, Sacristan S, Pedraz A, Pinto A, Fernandez-Aviles F, Tamargo J, Delpon E, Caballero R: Chronic atrial fibrillation increases microRNA-21 in human atrial myocytes decreasing L-type calcium current. Circ Arrhythm Electrophysiol 2014;7:861–868. 7 Dawson K, Wakili R, Ordog B, Caluss S, Chen Y, Iwasaki Y, Voigt N, Qi XY, Sinner MF, Dobrev D, Kaab S, Nattel: MicroRNA29. A mechanistic contributor and potential biomarker in atrial fibrillation. Circulation 2013; 127:1466–1475. 8 Lou X, Pan Z, Shan H, Xiao J, Sun X, Wang N, Lin H, Xiao L, Maguy A, Qi XY, Li Y, Dong D, Zhang Y, Bai Y, Ai J, Sun L, Lu H, Lou XY, Wang Z, Lu Y, Yang B, Nattel S: MicroRNA -26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation. J Clin Invest 2013;123:1939–1951. 9 Ling TY, Wang XL, Chai Q, Lau TW, Koestler CM, Park SJ, Daly RC, Greason KL, Jen J, Wu LQ, Shen WF, Shen WK, Cha YM, Lee HC: Regulation of SK3 channel by microRNA-499 – potential role in atrial fibrillation. Heart Rhythm 2013:10:1001–1009. 10 Girmatsion Z, Biliczki P, Bonauer A, Wimmwe-Greinecker G, Scherer M, Moritz A, Bukowska A, Goette A, Nattel S, Hohnloser SH, Ehrlich JR: Changes in microRNA-1 expression and IK1 up-regulation in human atrial fibrillation. Heart Rhythm 2009; 6: 1802–1809.
11 Lu Y, Zhang Y, Wang N, Pan Z, Gao X, Zhang F, Zhang Y, Shan H, Lou 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: 2378–2387. 12 McMaus DD, Lin H, Tanriverdi K, Quercio M, Yin X, Larson MG, Ellinor PT, Levy D, Freedman JE, Benjamin EJ: Relation between circulating microRNAs and atrial fibrillation: data from the Framingham Offspring Study. Heart Rhythm 2014;11:663–669. 13 Cooley N, Cowley MJ, Lin RCY, Marasco S, Wong C, Kaye DM, Dart AM, Woodcock EA: Influence of atrial fibrillation on microRNA expression in left and right atria from patients with valvular heart disease. Physiol Genomics 2012;44:211–219. 14 Slagsvold KH, Johnsen AB, Rognmo O, Hoydal MA, Wisloff U, Wahba A: Mitochondrial respiration and microRNA expression in right and left atrium of patients with atrial fibrillation. Physiol Genomics 2014; 46: 505– 511. 15 Xiao J, Liang D, Zhang Y, Liu Y, Zhang H, Liu Yi, Li L, Liang X, Sun Y, Chen YH: MicroRNA expression signature in atrial fibrillation with mitral stenosis. Physiol Genomics 2011; 43: 655–664.
Cardiology 2015;131:55–57 DOI: 10.1159/000381282
57
Downloaded by: NYU Medical Center Library 128.122.253.212 - 4/15/2015 2:36:20 PM
1 Poudel P, Xu Y, Cui Z, Sharma D, Tian B, Paudel S: Atrial fibrillation: recent advances in understanding the role of microRNAs in atrial remodeling with an electrophysiological overview. Cardiology 2015; 131: 58–67. 2 Adam O, Lohfelm B, Thum T, Gupta SK, Puhl SL, Schafers HJ, Bohm M, Laufs U: Role of miR-21 in the pathogenesis of atrial fibrosis. Basic Res Cardiol 2012;107:278. 3 Cardin S, Guasch E, Lou X, Naud P, Quang KL, Shi Y, Tardif JC, Comtois P, Nattel S: Role for microRNA-21 in atrial profibrillatory fibrotic remodeling associated with experimental postinfarction heart failure. Circ Arrhythm Electrophysiol 2012;5:1027–1035. 4 McManus D, Tanriverdi K, Lin H, Esa N, Kinno M, Mandapati D, Tam S, Okike ON, Ellinor PT, Keaney JF, Donahue JK, Benjamin EJ, Freedman JE: Plasma microRNA are associated with atrial fibrillation and changes after catheter ablation (miRhythm study). Heart Rhythm 2015;12:3–10. 5 Goren Y, Meiri E, Hogan C, Mitchell H, Lebanony D, Salman N, Schliamser JE, 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;113:976–981.
