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  • Review Article
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Diffuse myocardial fibrosis: mechanisms, diagnosis and therapeutic approaches

Nature Reviews Cardiology volume 18, pages 479–498 (2021)Cite this article

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Abstract

Diffuse myocardial fibrosis resulting from the excessive deposition of collagen fibres through the entire myocardium is encountered in a number of chronic cardiac diseases. This lesion results from alterations in the regulation of fibrillary collagen turnover by fibroblasts, facilitating the excessive deposition of type I and type III collagen fibres within the myocardial interstitium and around intramyocardial vessels. The available evidence suggests that, beyond the extent of fibrous deposits, collagen composition and the physicochemical properties of the fibres are also relevant in the detrimental effects of diffuse myocardial fibrosis on cardiac function and clinical outcomes in patients with heart failure. In this regard, findings from the past 20 years suggest that various clinicopathological phenotypes of diffuse myocardial fibrosis exist in patients with heart failure. In this Review, we summarize the current knowledge on the mechanisms and detrimental consequences of diffuse myocardial fibrosis in heart failure. Furthermore, we discuss the validity and usefulness of available imaging techniques and circulating biomarkers to assess the clinicopathological variation in this lesion and to track its clinical evolution. Finally, we highlight the currently available and potential future therapeutic strategies aimed at personalizing the prevention and reversal of diffuse myocardial fibrosis in patients with heart failure.

Key points

  • Diffuse myocardial fibrosis is characterized by excessive diffuse interstitial and perivascular deposition of highly crosslinked collagen fibres (type I collagen) and other components of the extracellular matrix.

  • Diffuse myocardial fibrosis is present in nearly all chronic cardiac diseases and impairs cardiac function and therefore has a crucial role in the development of heart failure and its outcomes and is an important global health problem.

  • Modification of the biosynthetic properties of cardiac fibroblasts that result in the alteration of fibrillary collagen turnover are the major determinants in the pathogenesis of diffuse myocardial fibrosis.

  • Diffuse myocardial fibrosis is not a single, homogenous entity but a complex entity in which multiple mechanisms lead to variable histomolecular patterns of fibrosis that, in turn, translate into diverse clinical phenotypes.

  • Although imaging and biochemical methods have been developed to assess diffuse myocardial fibrosis non-invasively in patients, none of the currently available biomarkers meets all the criteria to be implemented in clinical practice for accurate quantification of diffuse myocardial fibrosis.

  • Although therapeutic reversal of diffuse myocardial fibrosis is feasible, some challenges need to be taken into account when considering the use of currently available heart failure treatments as cardiac antifibrotic therapies and when developing novel antifibrotic strategies.

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Fig. 1: Pathogenesis and consequences of diffuse myocardial fibrosis.
Fig. 2: Histology of diffuse myocardial fibrosis in heart failure.
Fig. 3: Major signalling pathways involved in the activation of cardiac fibroblasts.
Fig. 4: Diffuse myocardial fibrosis and left ventricular dysfunction.
Fig. 5: Non-invasive diagnosis of cardiac fibrosis.
Fig. 6: Generation and release into the bloodstream of fibrillary collagen-derived peptides.
Fig. 7: Selection of novel antifibrotic targets for drug discovery and development.

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Acknowledgements

The authors are funded by the Spanish Ministry of Science, Innovation and Universities (Instituto de Salud Carlos III: CIBERCV CB16/11/00483, and PI17/01999 and PI18/01469 co-financed by FEDER funds), the ERA-CVD Joint Transnational Call 2016 LYMIT-DIS (AC16/00020) and LIPCAR-HF (AC16/00016), the European Commission H2020 Programme (CRUCIAL project 848109), and the Dirección General de Industria, Energía e Innovación, Gobierno de Navarra, Spain (MINERVA project 0011-1411-2018-000053).

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  1. These authors contributed equally: Begoña López, Susana Ravassa, María U. Moreno.

Authors and Affiliations

  1. Program of Cardiovascular Diseases, CIMA Universidad de Navarra and IdiSNA, Pamplona, Spain

    Begoña López, Susana Ravassa, María U. Moreno, Gorka San José, Javier Beaumont, Arantxa González & Javier Díez

  2. CIBERCV, Instituto de Salud Carlos III, Madrid, Spain

    Begoña López, Susana Ravassa, María U. Moreno, Gorka San José, Javier Beaumont, Arantxa González & Javier Díez

  3. Departments of Nephrology and Cardiology, University of Navarra Clinic, Pamplona, Spain

    Javier Díez

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All the authors researched data for the article, provided substantial contributions to the discussion of content, wrote the manuscript, and reviewed and/or edited the manuscript before submission.

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Glossary

Diffuse myocardial fibrosis

Diffuse and patchy deposition of excess fibrous tissue relative to the mass of cardiomyocytes within the myocardial interstitium and around intramyocardial vessels that alters the architecture and function of the extracellular matrix.

Extracellular matrix

(ECM). Part of the myocardial interstitium in which cardiac cells, fibroblasts and blood vessels are embedded and predominantly made up of structural collagen, with smaller amounts of other structural and non-structural proteins and other compounds.

Collagen crosslinking

Formation of intramolecular and intermolecular covalent bonds (crosslinks) between lysine residues in the collagen molecules that make the deposited collagen fibres stiffer and more resistant to degradation.

Myofibroblasts

Cells originating mainly but not exclusively from the differentiation of fibroblasts that have ultrastructural and phenotypical characteristics of smooth muscle cells and features of synthetically active fibroblasts.

Fibrocytes

Circulating mesenchymal cells that arise from monocyte precursors, are present in injured organs and have both the inflammatory features of macrophages and the tissue remodelling properties of fibroblasts.

Epithelial-to-mesenchymal transition

A cellular reprogramming process in which epithelial cells acquire a mesenchymal phenotype associated with modifications in the expression of genes and proteins, including those related to the extracellular matrix.

Endothelial-to-mesenchymal transition

A cellular reprogramming process in which endothelial cells acquire a mesenchymal phenotype associated with modifications in the expression of genes and proteins, including those related to the extracellular matrix.

Profibrotic secretome

Set of molecules secreted by activated fibroblasts and myofibroblasts that are required to modify the extracellular processing of fibrillary collagen, resulting in quantitative and qualitative alterations of the myocardial collagen network leading to diffuse myocardial fibrosis.

Matrikines

Bioactive fragments released from the degradation of extracellular matrix proteins (including fibrillary collagens), proteoglycans and glycosaminoglycans that regulate a number of processes, including fibrosis, inflammation and angiogenesis.

Extracellular volume fraction

(ECV). Parameter assessed with cardiovascular MRI to quantify the fractional distribution of extracellular volume in the myocardium. This parameter has been proposed as a biomarker for quantifying the diffuse deposition of fibrous tissue.

Collagen-derived peptides

Peptides generated during the extracellular processing of collagen and measurable in blood by immunoassays that have been proposed as biomarkers to quantify and qualify diffuse myocardial collagen deposition and crosslinking.

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López, B., Ravassa, S., Moreno, M.U. et al. Diffuse myocardial fibrosis: mechanisms, diagnosis and therapeutic approaches. Nat Rev Cardiol 18, 479–498 (2021). https://doi.org/10.1038/s41569-020-00504-1

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