Journal Article

Disconnect between Fibrotic Response and Right Ventricular Dysfunction

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

2019

Overview

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 PDGFRα (platelet-derived growth factor receptor-α), but generally lacked αSMA (α-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 PDGFRα/vimentin-expressing cardiac fibroblasts. However, interventions effectively targeting fibrosis lack significant beneficial effects on RV function.

• Publisher: Oxford University Press,American Thoracic Society
• Subject: Animals / Austria / Baltimore / Cardiology / Consent / Critical care / Disease Models, Animal / Extracellular matrix / Fibroblasts / Fibrosis - complications / Fibrosis - physiopathology / Galectin 3 - immunology / Growth factors / Heart failure / Humans / Hypertrophy, Right Ventricular - etiology / Hypertrophy, Right Ventricular - physiopathology / Hypoxia / Laboratories / Male / Mice / Original / Pulmonary arteries / Pulmonary hypertension / Rats / Thoracic surgery / Veins & arteries / Ventricular Dysfunction, Right - etiology / Ventricular Dysfunction, Right - physiopathology / Ventricular Function, Right - drug effects