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. 2019 May 14;73(18):2267-2282.
doi: 10.1016/j.jacc.2019.02.049.

Myofibroblast Phenotype and Reversibility of Fibrosis in Patients With End-Stage Heart Failure

Chandan K Nagaraju  1 , Emma L Robinson  1 , Mouna Abdesselem  1 , Sander Trenson  1 , Eef Dries  1 , Guillaume Gilbert  1 , Stefan Janssens  2 , Johan Van Cleemput  2 , Filip Rega  2 , Bart Meyns  2 , H Llewelyn Roderick  1 , Ronald B Driesen  1 , Karin R Sipido  3
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Free article

Myofibroblast Phenotype and Reversibility of Fibrosis in Patients With End-Stage Heart Failure

Chandan K Nagaraju et al. J Am Coll Cardiol. .
Free article

Abstract

Background: Interstitial fibrosis is an important component of diastolic, and systolic, dysfunction in heart failure (HF) and depends on activation and differentiation of fibroblasts into myofibroblasts (MyoFb). Recent clinical evidence suggests that in late-stage HF, fibrosis is not reversible.

Objectives: The study aims to examine the degree of differentiation of cardiac MyoFb in end-stage HF and the potential for their phenotypic reversibility.

Methods: Fibroblasts were isolated from the left ventricle of the explanted hearts of transplant recipients (ischemic and dilated cardiomyopathy), and from nonused donor hearts. Fibroblasts were maintained in culture without passaging for 4 or 8 days (treatment studies). Phenotyping included functional testing, immunostaining, and expression studies for markers of differentiation. These data were complemented with immunohistology and expression studies in tissue samples.

Results: Interstitial fibrosis with cross-linked collagen is prominent in HF hearts, with presence of activated MyoFbs. Tissue levels of transforming growth factor (TGF)-β1, lysyl oxidase, periostin, and osteopontin are elevated. Fibroblastic cells isolated from HF hearts are predominantly MyoFb, proliferative or nonproliferative, with mature α-smooth muscle actin stress fibers. HF MyoFb express high levels of profibrotic cytokines and the TGF-β1 pathway is activated. Inhibition of TGF-β1 receptor kinase in HF MyoFb promotes dedifferentiation of MyoFb with loss of α-smooth muscle actin and depolymerization of stress fibers, and reduces the expression of profibrotic genes and cytokines levels to non-HF levels.

Conclusion: MyoFb in end-stage HF have a variable degree of differentiation and retain the capacity to return to a less activated state, validating the potential for developing antifibrotic therapy targeting MyoFb.

Keywords: contractile function; extracellular matrix; fibroblasts; inflammation.

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Comment in

  • Can Myocardial Fibrosis Be Reversed?
    Frangogiannis NG. Frangogiannis NG. J Am Coll Cardiol. 2019 May 14;73(18):2283-2285. doi: 10.1016/j.jacc.2018.10.094. J Am Coll Cardiol. 2019. PMID: 31072571 No abstract available.
  • Reversible fibroblast phenotypes in HF.
    Huynh K. Huynh K. Nat Rev Cardiol. 2019 Aug;16(8):456. doi: 10.1038/s41569-019-0217-y. Nat Rev Cardiol. 2019. PMID: 31110264 No abstract available.

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