[en] Introduction: Myocardial remodeling due to large atrial septum defect (ASD) is macroscopically characterized by dilation of the right-sided cardiac cavities secondary to volume overload, the cellular mechanisms of which are not yet understood. We postulated that inflammation, fibrosis, and cell death are actors of right atrial remodeling secondary to ASD. Patients and Methods: In 12 children with large ASD (median age: 63 months), expression of genes coding for proteins involved in the response to cell stress and -protection, inflammation, growth and angiogenesis, fibrosis, and apoptosis was assessed by RT-PCR in right atrial myocardial biopsies taken during cardiac surgery. The presence of cytokines in myocardial cells was confirmed by immunohistochemistry and effective apoptosis by TUNEL assay. Results: In all patients investigated, a cellular response to early mechanical stress with the initiation of early protective mechanisms, of inflammation (and its control), -growth, and -angiogenesis, of fibrosis and apoptosis was present. The apoptotic index assessed by TUNEL assay averaged 0.3%. Conclusions: In children with large ASD, macroscopic right atrial remodeling relates to cellular mechanisms involving the expression of numerous genes that either still act to protect cells and tissues but that also harm as they initiate and/or sustain inflammation, fibrosis, and cell death by apoptosis. This may contribute to long term morbidity in patients with ASD.
Disciplines :
Cardiovascular & respiratory systems Pediatrics
Author, co-author :
Rouatbi, Hatem
FARHAT, Nesrine ; Centre Hospitalier Universitaire de Liège - CHU > Département de Pédiatrie > Service de pédiatrie
Heying, Ruth
GERARD, Arlette ; Centre Hospitalier Universitaire de Liège - CHU > Département de Pédiatrie > Service de pédiatrie
Vazquez-Jimenez, Jaime F.
SEGHAYE, Marie-Christine ; Centre Hospitalier Universitaire de Liège - CHU > Département de Pédiatrie > Service de pédiatrie
Language :
English
Title :
Right Atrial Myocardial Remodeling in Children With Atrial Septal Defect Involves Inflammation, Growth, Fibrosis, and Apoptosis.
Publication date :
February 2020
Journal title :
Frontiers in Pediatrics
eISSN :
2296-2360
Publisher :
Frontiers Media, Lausanne, Switzerland
Volume :
8
Pages :
40
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Copyright (c) 2020 Rouatbi, Farhat, Heying, Gerard, Vazquez-Jimenez and Seghaye.
Humeres C, Frangogiannis NG. Fibroblasts in the infarcted, remodeling, and failing heart. JACC Basic Transl Sci. (2019) 4:449–67. 10.1016/j.jacbts.2019.02.00631312768
Qing M, Schumacher K, Heise R, Wöltje M, Vazquez-Jimenez JF, Richter T, et al. Intramyocardial synthesis of pro- and anti-inflammatory cytokines in infants with congenital cardiac defects. JACC. (2003) 41:2266–74. 10.1016/S0735-1097(03)00477-712821258
Eerola A, Jokinen E, Boldt T, Mattila IP, Pihkala JI. Serum levels of natriuretic peptides in children before and after treatment for an atrial septal defect, a patent ductus arteriosus, and a coarctation of the aorta—a prospective study. Int J Ped. (2010) 2010:674575. 10.1155/2010/67457520445736
Wang D, Gladysheva IP, Fan TM, Sullivan R, Houng AK, Reed GL. Atrial natriuretic peptide affects cardiac remodeling, function, heart failure, and survival in a mouse model of dilated cardiomyopathy. Hypertension. (2014) 63:514–9. 10.1161/HYPERTENSIONAHA.113.0216424379183
Zhou H, Gao J, Lu ZY, Lu L, Dai W, Xu M. Role of c-Fos/JunD in protecting stress-induced cell death. Cell Prolif. (2007) 40:431–44. 10.1111/j.1365-2184.2007.00444.x17531086
Ranek MJ, Stachowski MJ, Kirk JA, Willis MS. The role of heat shock proteins and co-chaperones in heart failure. Philos Trans R Soc Lond B Biol Sci. (2018) 373:20160530. 10.1098/rstb.2016.053029203715
Hall M, Young DA, Waters JG, Rowan AD, Chantry A, Edwards DR, et al. The comparative role of activator protein 1 and smad factors in the regulation oftimp-1and MMP-1 gene expression by transforming growth factor-β1. J Biol Chem. (2003) 278:10304–13. 10.1074/jbc.M212334200
Lee KH, Jang Y, Chung JH. Heat shock protein 90 regulates IκB kinase complex and NF-κB activation in angiotensin II-induced cardiac cell hypertrophy. Exp Mol Med. (2010) 42:703–11. 10.3858/emm.2010.42.10.06920980790
Ueha S, Shand FH, Matsushima K. Cellular and molecular mechanisms of chronic inflammation-associated organ fibrosis. Front Immunol. (2012) 3:71. 10.3389/fimmu.2012.0007122566952
Li J, Brooks G. Differential protein expression and subcellular distribution of TGFβ1, β2 and β3 in cardiomyocytes during pressure overload-induced hypertrophy. J Mol Cell Cardiol. (1997) 29:2213–24. 10.1006/jmcc.1997.04579281452
Sugimoto M, Masutani S, Seki M, Kajino H, Fujieda K, Senzaki H. High serum levels of procollagen type III N-terminal amino peptide in patients with congenital heart disease. Heart. (2009) 95:2023–8. 10.1136/hrt.2009.17024119666460
Mack M. Inflammation and fibrosis. Matrix Biol. (2018) 68:106–21. 10.1016/j.matbio.2017.11.01029196207
Sivasubramanian N, Coker ML, Kurrelmeyer KM, Maclellan WR, Demayo FJ, Spinale FG, et al. Left ventricular remodeling in transgenic mice with cardiac restricted overexpression of tumor necrosis factor. Circulation. (2001) 104:826–31. 10.1161/hc3401.09315411502710
Nian M, Lee P, Khaper N, Liu P. Inflammatory cytokines and postmyocardial infarction remodeling. Circ Res. (2004) 94:1543–53. 10.1161/01.RES.0000130526.20854.fa15217919
Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. (2011) 76:50–83. 10.1128/MMBR.00031-10
Bozkurt B, Kribbs SB, Clubb FJ, Michael LH, Didenko VV, Hornsby PJ, et al. Pathophysiologically relevant concentrations of tumor necrosis factor-α promote progressive left ventricular dysfunction and remodeling in rats. Circulation. (1998) 97:1382–91. 10.1161/01.CIR.97.14.13829577950
Turner N, Mughal R, Warburton P, Oregan D, Ball S, Porter K. Mechanism of TNFα-induced IL-1α, IL-1β and IL-6 expression in human cardiac fibroblasts: effects of statins and thiazolidinediones. Cardiovasc Res. (2007) 6:81–90. 10.1016/j.cardiores.2007.06.003
Lindner D, Zietsch C, Tank J, Sossalla S, Fluschnik N, Hinrichs S, et al. Cardiac fibroblasts support cardiac inflammation in heart failure. Basic Res Cardiol. (2014) 109:5. 10.1007/s00395-014-0428-725086637
Honsho S, Nishikawa S, Amano K, Zen K, Adachi Y, Kishita E, et al. Pressure-mediated hypertrophy and mechanical stretch induces IL-1 release and subsequent IGF-1 generation to maintain compensative hypertrophy by affecting Akt and JNK pathways. Circ Res. (2009) 105:1149–58. 10.1161/CIRCRESAHA.109.20819919834007
Turner NA, Warburton P, Oregan DJ, Ball SG, Porter KE. Modulatory effect of interleukin-1α on expression of structural matrix proteins, MMPs and TIMPs in human cardiac myofibroblasts: role of p38 MAP kinase. Matrix Biol. (2010) 29:613–20. 10.1016/j.matbio.2010.06.00720619343
Siwik DA, Chang DL, Colucci WS. Interleukin-1β and tumor necrosis factor-α decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro. Circ Res. (2000) 86:1259–65. 10.1161/01.RES.86.12.125910864917
Frangogiannis NG. Interleukin-1 in cardiac injury, repair, and remodeling: pathophysiologic and translational concepts. Discoveries. (2015) 3:1. 10.15190/d.2015.3326273700
Sziksz E, Pap D, Lippai R, Béres NJ, Fekete A, Szabó AJ, Vannay Á. Fibrosis related inflammatory mediators: role of the IL-10 cytokine family. Mediat Inflamm. (2015) 1:15. 10.1155/2015/764641
Verma SK, Krishnamurthy P, Barefield D, Singh N, Gupta R, Lambers E, et al. Interleukin-10 treatment attenuates pressure overload–induced hypertrophic remodeling and improves heart function via signal transducers and activators of transcription 3–dependent inhibition of nuclear factor-κB. Circulation. (2012) 126:418–29. 10.1161/CIRCULATIONAHA.112.11218522705886
Fontes JA, Rose NR, Ciháková D. The varying faces of IL-6: From cardiac protection to cardiac failure. Cytokine. (2015) 74:62–8. 10.1016/j.cyto.2014.12.02425649043
Bageghni SA, Hemmings KE, Zava N, Denton CP, Porter KE, Ainscough JF. Cardiac fibroblast-specific p38α MAP kinase promotes cardiac hypertrophy via a putative paracrine interleukin-6 signaling mechanism. FASEB J. (2018) 32:4941–54. 10.1096/fj.201701455RR29601781
Akira S, Hirano T, Taga T, Kishimoto T. Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). FASEB J. (1990) 11:2860–7. 10.1096/fasebj.4.11.2199284
Bortolotti F, Ruozi G, Falcione A, Doimo S, Ferro MD, Lesizza P, et al. In vivo functional selection identifies cardiotrophin-1 as a cardiac engraftment factor for mesenchymal stromal cells. Circulation. (2017) 136:1509–24. 10.1161/CIRCULATIONAHA.117.02900328754835
Abdul-Ghani M, Suen C, Jiang B, Deng Y, Weldrick JJ, Putinski C, et al. Cardiotrophin 1 stimulates beneficial myogenic and vascular remodeling of the heart. Cell Res. (2017) 27:1195–215. 10.1038/cr.2017.8728785017
Serini G, Gabbiani G. Mechanisms of myofibroblast activity and phenotypic modulation. Exp Cell Res. (1999) 250:273–83. 10.1006/excr.1999.454310413583
Bouzegrhane F. Is angiotensin II a proliferative factor of cardiac fibroblasts? Cardiovasc Res. (2002) 53:304–12. 10.1016/S0008-6363(01)00448-511827680
Heying R, Qing M, Schumacher K, Sokalska-Duhme M, Vazquez-Jimenez JF, Seghaye MC. Myocardial cardiotrophin-1 is differentially induced in congenital cardiac defects depending on hypoxemia. Fut Cardiol. (2014) 10:53–62. 10.2217/fca.13.9924344663
Railson J, Lawrence K, Stephanou A, Brar B, Pennica D, Latchman D. Cardiotrophin-1 reduces stress-induced heat shock protein production in cardiac myocytes. Cytokine. (2000) 12:1741–4. 10.1006/cyto.2000.077811052830
González-Guerra JL, Castilla-Cortazar I, Aguirre GA, Muñoz Ú, Martín-Estal I, Ávila-Gallego E, et al. Partial IGF-1 deficiency is sufficient to reduce heart contractibility, angiotensin II sensibility, and alter gene expression of structural and functional cardiac proteins. PLoS ONE. (2017) 12:8. 10.1371/journal.pone.018176028806738
Kim C, Cho Y, Chun Y, Park J, Kim M. Early expression of myocardial HIF-1α in response to mechanical stresses. Circ Res. (2002) 90:E25–33. 10.1161/hh0202.10492311834720
Palojoki E, Saraste A, Eriksson A, Pulkki K, Kallajoki M, Voipio-Pulkki L, et al. Cardiomyocyte apoptosis and ventricular remodeling after myocardial infarction in rats. Am J Physiol Heart Circ Physiol. (2001) 6:H2726-2731. 10.1152/ajpheart.2001.280.6.H2726
Gong J, Qian L, Kong X, Yang R, Zhou L, Sheng Y, et al. Cardiomyocyte apoptosis in the right auricle of patients with ostium secundum atrial septal defect diseases. Life Sci. (2007) 80:1143–51. 10.1016/j.lfs.2006.12.01217275858
Torres AJ. Hemodynamic assessment of atrial septal defects. J Thorac Dis. (2018) 10:S2882–9. 10.21037/jtd.2018.02.1730305948
Seghaye MC, Duchateau J, Bruniaux J, Demontoux S, Bosson C, Serraf A, et al. Interleukin-10 release related to cardiopulmonary bypass in infants undergoing cardiac operations. J Thorac Cardiovasc Surg. (1996) 110:545–53. 10.1016/S0022-5223(96)70306-9
Hövels-Gürich HH, Schumacher K, Vazquez-Jimenez JF, Qing M, Hüffmeier U, Buding B, et al. Cytokine balance in infants undergoing cardiac operation. Ann Thorac Surg. (2002) 73:601–8. 10.1016/S0003-4975(01)03391-411845881
