Disconnect between Fibrotic Response and Right Ventricular Dysfunction

Rationale: Remodeling and fibrosis of the right ventricle (RV) may cause RV dysfunction and poor survival in patients with pulmonary hypertension (PH). 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 PH patients, the murine pulmonary artery banding (PAB)-, and rat monocrotaline-, and Sugen5416/hypoxia models. Invasive hemodynamic and echocardiographic assessment was performed on galectin-3 knock-out 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 pharmacological inhibition or anti-fibrotic treatment with pirfenidone significantly diminished RV fibrosis progression in the PAB model, without improving RV functional parameters. RV fibrotic regions were populated with mesenchymal cells co-expressing vimentin and PDGFR?, but generally lacked ?SMA positivity. Serum levels of galectin-3 were increased in idiopathic pulmonary arterial hypertension patients, 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 PH through the expansion of PDGFR?/vimentin-expressing cardiac fibroblasts. However, interventions effectively targeting fibrosis lack significant beneficial effects on RV function.