Disconnect between fibrotic response and right ventricular dysfunction

Slaven Crnkovic, Bakytbek Egemnazarov, Rachel Damico, Leigh M. Marsh, Bence M. Nagy, Philipp Douschan, Kwame Atsina, Todd M. Kolb, Stephen C. Mathai, Jody E. Hooper, Bahil Ghanim, Walter Klepetko, Friedrich Fruhwald, Dirk Lassner, Andrea Olschewski, Horst Olschewski, Paul M. Hassoun, Grazyna Kwapiszewska

Research output: Contribution to journalArticle

Abstract

Rationale: Remodeling and fibrosis of the right ventricle (RV) may cause RV dysfunction and poor survival in patients with pulmonary hypertension. Objectives: To investigate the consequences of RV fibrosis modulation and the accompanying cellular changes on RV function. Methods: Expression of fibrotic markers was assessed in the RV of patients with pulmonary hypertension, the murine pulmonary artery banding, and rat monocrotaline and Sugen5416/hypoxia models. Invasive hemodynamic and echocardiographic assessment was performed on galectin-3 knockout or inhibitor-treated mice. Measurements and Main Results: Established fibrosis was characterized by marked expression of galectin-3 and an enhanced number of proliferating RV fibroblasts. Galectin-3 genetic and pharmacologic inhibition or antifibrotic treatment with pirfenidone significantly diminished RV fibrosis progression in the pulmonary artery banding model, without improving RV functional parameters. RV fibrotic regions were populated with mesenchymal cells coexpressing vimentin and PDGFRa (platelet-derived growth factor receptor-a), but generally lacked aSMA (a-smooth muscle actin) positivity. Serum levels of galectin-3 were increased in patients with idiopathic pulmonary arterial hypertension but did not correlate with cardiac function. No changes of galectin-3 expression were observed in the lungs. Conclusions: We identified extrapulmonary galectin-3 as an important mediator that drives RV fibrosis in pulmonary hypertension through the expansion of PDGFRa/vimentin-expressing cardiac fibroblasts. However, interventions effectively targeting fibrosis lack significant beneficial effects on RV function.

Original languageEnglish (US)
Pages (from-to)1550-1560
Number of pages11
JournalAmerican journal of respiratory and critical care medicine
Volume199
Issue number12
DOIs
StatePublished - Jun 15 2019

Keywords

  • Galectin-3
  • PDGFRa
  • Right ventricle fibrosis
  • Right ventricular function

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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  • Cite this

    Crnkovic, S., Egemnazarov, B., Damico, R., Marsh, L. M., Nagy, B. M., Douschan, P., Atsina, K., Kolb, T. M., Mathai, S. C., Hooper, J. E., Ghanim, B., Klepetko, W., Fruhwald, F., Lassner, D., Olschewski, A., Olschewski, H., Hassoun, P. M., & Kwapiszewska, G. (2019). Disconnect between fibrotic response and right ventricular dysfunction. American journal of respiratory and critical care medicine, 199(12), 1550-1560. https://doi.org/10.1164/rccm.201809-1737OC