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Myocardial fibrosis: a defense mechanism or main cause of adverse outcomes?

Authors: Troshin D.S., Averina I.I., Aleksandrova S.A., Marchenko D.S., Donakanyan S.A.

Company: Bakoulev National Medical Research Center for Cardiovascular Surgery, Moscow, Russian Federation

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Type:  Reviews


DOI: https://doi.org/10.24022/1997-3187-2023-17-4-464-473

For citation: Troshin D.S., Averina I.I., Aleksandrova S.A., Marchenko D.S., Donakanyan S.A. Myocardial fibrosis: a defense mechanism or main cause of adverse outcomes? Creative Cardiology. 2023; 17 (4): 464–73 (in Russ.). DOI: 10.24022/1997-3187-2023-17-4-464-473

Received / Accepted:  29.08.2023 / 07.11.2023

Keywords: myocardial fibrosis cardiac fibrosis extracellular matrix diagnosis of myocardial fibrosis treatment of myocardial fibrosis fibrosis biomarkers



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Abstract

Myocardial fibrosis is associated with the most cardiovascular diseases. Based on the pathological process, the excessive accumulation of extracellular matrix components may not only serve as a defense mechanism, but also lead to the worsening disease course and heart failure progression, indicating poor prognosis. The basics of physiology and biochemistry of the extracellular matrix, both normally and in various pathological conditions are discussed in this article. Diagnostic issues including non-invasive methods for quantification both focal and diffuse fibrosis as well as potential biomarkers of myocardial fibrosis are described in detail. The use of myocardial fibrosis assessment in early risk stratification in patients with various cardiovascular diseases and a review of meta-analyses on this topic is presented. Thus, therapeutic options aimed to affect extracellular matrix as as well as personalised management strategies, described in the article, appear to be essencial to improve clinical state and outcomes of cardiovascular diseases.

References

  1. Frangogiannis N.G. Cardiac fibrosis: Cell biological mechanisms, molecular pathways and therapeutic opportunities. Mol. Aspects Med. 2019; 65: 70–99. DOI: 10.1016/j.mam.2018.07.001
  2. Karetnikova V.N., Kashtalap V.V., Kosareva S.N., Barbarash O.L. Myocardial fibrosis: current aspects of the problem. Therapeutic Archive. 2017; 89 (1): 88–93 (in Russ.). DOI: 10.17116/terarkh201789188-93
  3. Berk B.C., Fujiwara K., Lehoux S. ECM remodeling in hypertensive heart disease. J. Clin. Invest. 2007; 117 (3): 568– 75. DOI: 10.1172/JCI31044
  4. AlQudah M., Hale T.M., Czubryt M.P. Targeting the reninangiotensin-aldosterone system in fibrosis. Matrix Biol. 2020; 91–92: 92–108. DOI: 10.1016/j.matbio.2020.04.005
  5. Sadoshima J., Izumo S. Molecular characterization of angiotensin II--induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. Circ. Res. 1993; 73 (3): 413–23. DOI: 10.1161/01.res.73.3.413
  6. Nuamnaichati N., Sato V.H., Moongkarndi P., ParichatikanondW., Mangmool S. Sustained β-AR stimulation induces synthesis and secretion of growth factors in cardiac myocytes that affect on cardiac fibroblast activation. Life Sci. 2018; 193: 257–69. DOI: 10.1016/j.lfs.2017.10.034
  7. Hinz B., Phan S.H., Thannickal V.J., Galli A., BochatonPiallat M.L., Gabbiani G. The myofibroblast: one function, multiple origins. Am. J. Pathol. 2007; 170 (6): 1807–16. DOI: 10.2353/ajpath.2007.070112
  8. Nguyen M.N., Kiriazis H., Gao X.M., Du X.J. Cardiac fibrosis and arrhythmogenesis. Compr. Physiol. 2017; 7 (3): 1009–49. DOI: 10.1002/cphy.c160046
  9. Frangogiannis N.G. Cardiac fibrosis. Cardiovasc. Res. 2021; 117 (6): 1450–88. DOI: 10.1093/cvr/cvaa324
  10. Rathod R.H., Powell A.J., Geva T. Myocardial fibrosis in congenital heart disease. Circ. J. 2016; 80 (6): 1300–07. DOI: 10.1253/circj.CJ-16-0353
  11. Thomas T.P., Grisanti L.A. The dynamic interplay between cardiac inflammation and fibrosis. Front. Physiol. 2020; 11: 529075. DOI: 10.3389/fphys.2020.529075
  12. Averina I.I., Bockeria O.L., Mironenko M.Yu., Aleksandrova S.A. Development of diastolic dysfunction in patients with acquired heart diseases in the postoperative period. Kardiologiia. 2019; 59 (5): 26–35 (in Russ.). DOI: 10.18087/cardio.2019.5.10256
  13. Assadi H., Jones R., Swift A.J., Al-Mohammad A., Garg P. Cardiac MRI for the prognostication of heart failure with preserved ejection fraction: A systematic review and metaanalysis. Magn. Reson. Imaging. 2021; 76: 116–22. DOI: 10.1016/j.mri.2020.11.011
  14. Golukhova E., Bulaeva N., Alexandrova S., Gromova O., Berdibekov B. Prognostic value of characterizing myocardial tissue by cardiac MRI with T1 mapping in HFpEF patients: a systematic review and meta-analysis. J. Clin. Med. 2022; 11 (9): 2531. DOI: 10.3390/jcm11092531
  15. Disertori M., Rigoni M., Pace N., Casolo G., Masè M., Gonzini L. et al. Myocardial fibrosis assessment by LGE is a powerful predictor of ventricular tachyarrhythmias in ischemic and nonischemic LV dysfunction: a meta-analysis. JACC Cardiovasc. Imaging. 2016; 9 (9): 1046–55. DOI: 10.1016/j.jcmg.2016.01.033
  16. Zhuang B., Sirajuddin A., Wang S., Arai A., Zhao S., Lu M. Prognostic value of T1 mapping and extracellular volume fraction in cardiovascular disease: a systematic review and metaanalysis. Heart Fail. Rev. 2018; 23 (5): 723–31. DOI: 10.1007/s10741-018-9718-8
  17. Chen H., Zeng J., Liu D., Yang Q. Prognostic value of late gadolinium enhancement on CMR in patients with severe aortic valve disease: a systematic review and meta-analysis. Clin. Radiol. 2018; 73 (11): 983.e7–14. DOI: 10.1016/j.crad.2018.07.095
  18. Balciunaite G., Skorniakov V., Rimkus A., Zaremba T., Palionis D., Valeviciene N. et al. Prevalence and prognostic value of late gadolinium enhancement on CMR in aortic stenosis: meta-analysis. Eur. Radiol. 2020; 30 (1): 640–51. DOI:10.1007/s00330-019-06386-3
  19. Kong P., Christia P., Frangogiannis N.G. The pathogenesis of cardiac fibrosis. Cell Mol. Life Sci. 2014; 71 (4): 549–74. DOI: 10.1007/s00018-013-1349-6
  20. Haaf P., Garg P., Messroghli D.R., Broadbent D.A., Greenwood J.P., Plein S. Cardiac T1 Mapping and Extracellular Volume (ECV) in clinical practice: a comprehensive review. J. Cardiovasc. Magn. Reson. 2016; 18 (1): 89. DOI: 10.1186/s12968-016-0308-4
  21. Hayashi H., Oda S., Emoto T., Kidoh M., Nagayama Y., Nakaura T. et al. Myocardial extracellular volume quantification by cardiac CT in pulmonary hypertension: comparison with cardiac MRI. Eur. J. Radiol. 2022; 153: 110386. DOI: 10.1016/j.ejrad.2022.110386
  22. Li L., Zhao Q., Kong W. Extracellular matrix remodeling and cardiac fibrosis. Matrix Biol. 2018; 68–69: 490–506. DOI: 10.1016/j.matbio.2018.01.013
  23. Briasoulis A., Mallikethi-Reddy S., Palla M., Alesh I., Afonso L. Myocardial fibrosis on cardiac magnetic resonance and cardiac outcomes in hypertrophic cardiomyopathy: a meta-analysis. Heart. 2015; 101 (17): 1406–11. DOI: 10.1136/heartjnl-2015-307682
  24. Weng Z., Yao J., Chan R.H., He J., Yang X., Zhou Y., He Y. Prognostic value of LGE-CMR in HCM: a meta-analysis. JACC Cardiovasc. Imaging. 2016; 9 (12): 1392–402. DOI: 10.1016/j.jcmg.2016.02.031
  25. Bittencourt M.I., Cader S.A., Araújo D.V., Salles A.L.F., Albuquerque F.N., Spineti P.P.M. et al. Role of myocardial fibrosis in hypertrophic cardiomyopathy: a systematic review and updated meta-analysis of risk markers for sudden death. Arq. Bras. Cardiol. 2019; 112 (3): 281–89. DOI: 10.5935/abc.20190045
  26. Green J.J., Berger J.S., Kramer C.M., Salerno M. Prognostic value of late gadolinium enhancement in clinical outcomes for hypertrophic cardiomyopathy. JACC Cardiovasc. Imaging. 2012; 5 (4): 370–77. DOI: 10.1016/j.jcmg.2011.11.021
  27. He D., Ye M., Zhang L., Jiang B. Prognostic significance of late gadolinium enhancement on cardiac magnetic resonance in patients with hypertrophic cardiomyopathy. Heart Lung. 2018; 47 (2): 122–6. DOI: 10.1016/j.hrtlng.2017.10.008
  28. Grigoratos C., Barison A., Ivanov A., Andreini D., AmzulescuM.S., Mazurkiewicz L. et al. Meta-analysis of the prognostic role of late gadolinium enhancement and global systolic impairment in left ventricular noncompaction. JACC Cardiovasc. Imaging. 2019; 12 (11 Pt 1): 2141–51. DOI: 10.1016/j.jcmg.2018.12.029
  29. Papanastasiou C.A., Kokkinidis D.G., Kampaktsis P.N., Bikakis I., Cunha D.K., Oikonomou E.K. et al. The prognostic role of late gadolinium enhancement in aortic stenosis: a systematic review and meta-analysis. JACC Cardiovasc. Imaging. 2020; 13 (2 Pt 1): 385–92. DOI: 10.1016/j.jcmg.2019.03.029
  30. Zhang C., Liu J., Qin S. Prognostic value of cardiac magnetic resonance in patients with aortic stenosis: a systematic review and meta-analysis. PLoS One. 2022; 17 (2): e0263378. DOI: 10.1371/journal.pone.0263378
  31. Golukhova E.Z., Bulaeva N.I., Alexandrova S.A., Mrikaev D.V., Gromova O.I., Ruzina E.V., Berdibekov B.S. The extent of late gadolinium enhancement predicts mortality, sudden death and major adverse cardiovascular events in patients with nonischaemic cardiomyopathy: a systematic review and metaanalysis. Clin. Radiol. 2023; 78 (4): e342–9. DOI: 10.1016/j.crad.2022.12.015
  32. Yang Z., Xu R., Wang J.R., Xu H.Y., Fu H., Xie L.J. et al. Association of myocardial fibrosis detected by late gadoliniumenhanced MRI with clinical outcomes in patients with diabetes: a systematic review and meta-analysis. BMJ Open. 2022; 12 (1): e055374. DOI: 10.1136/bmjopen-2021-055374
  33. Coleman G.C., Shaw P.W., Balfour P.C., Jr., Gonzalez J.A., Kramer C.M., Patel A.R., Salerno M. Prognostic value of myocardial scarring on CMR in patients with cardiac sarcoidosis. JACC Cardiovasc. Imaging. 2017; 10 (4): 411–20. DOI: 10.1016/j.jcmg.2016.05.009
  34. Gyöngyösi M., Winkler J., Ramos I., Do Q.T., Firat H., McDonald K. et al. Myocardial fibrosis: biomedical research from bench to bedside. Eur. J. Heart Fail. 2017; 19 (2): 177–91. DOI: 10.1002/ejhf.696
  35. Weidemann F., Herrmann S., Störk S., Niemann M., Frantz S., Lange V. et al. Impact of myocardial fibrosis in patients with symptomatic severe aortic stenosis. Circulation. 2009; 120 (7): 577–84. DOI: 10.1161/CIRCULATIONAHA.108.847772
  36. Wang J., Gong X., Chen H., Qin S., Zhou N., Su Y., Ge J. Effect of cardiac resynchronization therapy on myocardial fibrosis and relevant cytokines in a canine model with experimental heart failure. J. Cardiovasc. Electrophysiol. 2017; 28 (4): 438–45. DOI: 10.1111/jce.13171
  37. Lok S.I., Nous F.M., van Kuik J., van der Weide P., Winkens B., Kemperman H. et al. Myocardial fibrosis and pro-fibrotic markers in end-stage heart failure patients during continuousflow left ventricular assist device support. Eur. J. Cardiothorac. Surg. 2015; 48 (3): 407–15. DOI: 10.1093/ejcts/ezu539
  38. Wang H., Ding L., Tian L., Tian Y., Liao L., Zhao J. Empagliflozin reduces diffuse myocardial fibrosis by extracellular volume mapping: a meta-analysis of clinical studies. Front. Endocrinol. 2022; 13: 917761. DOI: 10.3389/fendo.2022.917761
  39. Brilla C.G., Funck R.C., Rupp H. Lisinopril-mediated regression of myocardial fibrosis in patients with hypertensive heart disease. Circulation. 2000; 102 (12): 1388–93. DOI: 10.1161/01. cir.102.12.1388
  40. Shimada Y.J., Passeri J.J., Baggish A.L., O’Callaghan C., Lowry P.A., Yannekis G. et al. Effects of losartan on left ventricular hypertrophy and fibrosis in patients with nonobstructive hypertrophic cardiomyopathy. JACC Heart Fail. 2013; 1 (6): 480–87. DOI: 10.1016/j.jchf.2013.09.001
  41. Díez J., Querejeta R., López B., González A., Larman M., Martínez Ubago J.L. Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation. 2002; 105 (21): 2512–17. DOI: 10.1161/01.cir.0000017264.66561.3d
  42. López B., Querejeta R., Varo N., González A., Larman M., Martínez Ubago J.L. et al. Usefulness of serum carboxyterminal propeptide of procollagen type I in assessment of the cardioreparative ability of antihypertensive treatment in hypertensive patients. Circulation. 2001; 104 (3): 286–91. DOI: 10.1161/01.cir.104.3.286
  43. Kawamura M., Ito H., Onuki T., Miyoshi F., Watanabe N., Asano T. et al. Candesartan decreases type III procollagenN-peptide levels and inflammatory marker levels and maintains sinus rhythm in patients with atrial fibrillation. J. Cardiovasc. Pharmacol. 2010; 55 (5): 511–17. DOI: 10.1097/FJC.0b013e3181d70690
  44. Kosmala W., Przewlocka-Kosmala M., Szczepanik-Osadnik H., Mysiak A., O’Moore-Sullivan T., Marwick T.H. A randomized study of the beneficial effects of aldosterone antagonism on LV function, structure, and fibrosis markers in metabolic syndrome. JACC Cardiovasc. Imaging. 2011; 4 (12): 1239–49. DOI: 10.1016/j.jcmg.2011.08.014
  45. Kosmala W., Przewlocka-Kosmala M., Szczepanik-Osadnik H., Mysiak A., Marwick T.H. Fibrosis and cardiac function in obesity: a randomised controlled trial of aldosterone blockade. Heart. 2013; 99 (5): 320–26. DOI: 10.1136/heartjnl-2012-303329
  46. Zannad F., Alla F., Dousset B., Perez A., Pitt B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation. 2000; 102 (22): 2700–06. DOI: 10.1161/01.cir.102.22.2700
  47. Ravassa S., Trippel T., Bach D., Bachran D., González A., López B. et al. Biomarker-based phenotyping of myocardial fibrosis identifies patients with heart failure with preserved ejection fraction resistant to the beneficial effects of spironolactone: results from the Aldo-DHF trial. Eur. J. Heart Fail. 2018; 20 (9): 1290–99. DOI: 10.1002/ejhf.1194
  48. Deswal A., Richardson P., Bozkurt B., Mann D.L. Results of the Randomized Aldosterone Antagonism in Heart Failure with Preserved Ejection Fraction trial (RAAM-PEF). J. Card. Fail. 2011; 17 (8): 634–42. DOI: 10.1016/j.cardfail.2011.04.007
  49. Iraqi W., Rossignol P., Angioi M., Fay R., Nuée J., Ketelslegers J.M. et al. Extracellular cardiac matrix biomarkers in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure: insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) study. Circulation. 2009; 119 (18): 2471–79. DOI: 10.1161/CIRCULATIONAHA.108.809194
  50. Abulhul E., McDonald K., Martos R., Phelan D., Spiers J.P., Hennessy M. et al. Long-term statin therapy in patients with systolic heart failure and normal cholesterol: effects on elevated serum markers of collagen turnover, inflammation, and B-type natriuretic peptide. Clin. Ther. 2012; 34 (1): 91–100. DOI: 10.1016/j.clinthera.2011.11.002
  51. Chang Y.Y., Wu Y.W., Lee J.K., Lin Y.M., Lin Y.T., Kao H.L. et al. Effects of 12 weeks of atorvastatin therapy on myocardial fibrosis and circulating fibrosis biomarkers in statin-naïve patients with hypertension with atherosclerosis. J. Investig. Med. 2016; 64 (7): 1194–99. DOI: 10.1136/jim-2016-000092
  52. López B., Querejeta R., González A., Sánchez E., Larman M., Díez J. Effects of loop diuretics on myocardial fibrosis and collagen type I turnover in chronic heart failure. J. Am. Coll. Cardiol. 2004; 43 (11): 2028–35. DOI: 10.1016/j.jacc.2003.12.052
  53. López B., González A., Beaumont J., Querejeta R., Larman M., Díez J. Identification of a potential cardiac antifibrotic mechanism of torasemide in patients with chronic heart failure. J. Am. Coll. Cardiol. 2007; 50 (9): 859–67. DOI: 10.1016/j.jacc.2007.04.080
  54. Giannetta E., Isidori A.M., Galea N., Carbone I., Mandosi E., Vizza C.D. et al. Chronic Inhibition of cGMP phosphodiesterase 5A improves diabetic cardiomyopathy: a randomized, controlled clinical trial using magnetic resonance imaging with myocardial tagging. Circulation. 2012; 125 (19): 2323–33. DOI: 10.1161/CIRCULATIONAHA.111.063412
  55. Cunningham J.W., Claggett B.L., O’Meara E., Prescott M.F., Pfeffer M.A., Shah S.J. et al. Effect of sacubitril/valsartan on biomarkers of extracellular matrix regulation in patients with HFpEF. J. Am. Coll. Cardiol. 2020; 76 (5): 503–14. DOI: 10.1016/j.jacc.2020.05.072
  56. Ashton E., Windebank E., Skiba M., Reid C., Schneider H., Rosenfeldt F. et al. Why did high-dose rosuvastatin not improve cardiac remodeling in chronic heart failure? Mechanistic insights from the UNIVERSE study. Int. J. Cardiol. 2011; 146 (3): 404–07. DOI: 10.1016/j.ijcard.2009.12.028

About Authors

  • Dmitriy S. Troshin, Postgraduate, Cardiologist; ORCID
  • Irina I. Averina, Dr. Med. Sci., Professor, Senior Researcher, Cardiologist; ORCID
  • Svetlana A. Aleksandrova, Cand. Med. Sci., Senior Researcher, Radiologist; ORCID
  • Darya S. Marchenko, Postgraduate, Radiologist; ORCID
  • Sergey A. Donakanyan, Dr. Med. Sci., Professor, Cardiovascular Surgeon; ORCID

Chief Editor

Leo A. Bockeria, MD, PhD, DSc, Professor, Academician of Russian Academy of Sciences, President of Bakoulev National Medical Research Center for Cardiovascular Surgery


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