1349363 - Cardiovascular Magnetic Resonance Assessment of Targeted Right Ventricular Therapy With GP-130 antagonist in Large Animal Model of RV Dysfunction

Right ventricular (RV) failure is the leading cause of death in pulmonary arterial hypertension (PAH). Although RV dysfunction is the main predictor of negative outcomes in this population, there is no therapy directedly targeting the RV.

A promising approach to target RV dysfunction is inflammatory modulation as clinical studies demonstrate elevations in the inflammatory cytokine interleukin-6 (IL6) predicts right ventricular dysfunction and mortality in PAH.



Methods:

We examined the effects of GP130 antagonism, the membrane receptor for the IL6 superfamily of cytokines, in a large animal model of RV dysfunction. We included 12 Yorkshire cross piglets (7-12 kg) divided in three experimental groups: control, pulmonary artery banded (PAB) treated with placebo and PAB treated with SC144 a GP-130 antagonist. Three weeks after PAB, treatment was initiated in daily doses for three weeks, and then comprehensive invasive hemodynamic and non-invasive assessment by Cardiovascular Magnetic Resonance (CMR) at six weeks post surgery.

RV free wall sections were stained with Picrosirius Red to quantify fibrosis, and these values were correlated with MRI derived extra cellular volume (ECV).



Results:

A total of 12 piglets were included in the analysis. The primary endpoint of the study was met with significant improvement in RV function in the animals treated with SC144 (RVEF 38%) compared to placebo (RVEF 19%) p=0.011 (Figure 1).

Pulmonary artery (PA) banding ratio (area proximal PA/area at the site of banding) was not statistically significant between the PAB-SC144 and placebo groups p=0.275.  RV mass was significantly increased in the PAB-placebo treated animals (37 grams) compared to control (17 grams) p=0.04, but not in the PAB-SC144 group.

Myocardial fibrosis (Figure 2) measured by ECV was significantly increased in the PAB-Placebo compared to PAB-SC144 p=0.03, and there was strong correlation between CMR derived ECV and histological quantification.



Conclusion:

Targeted RV therapy with GP130 antagonist leads to significant improvement in RV function and prevents myocardial fibrosis in a large animal model of RV failure assessed by CMR. Inflammatory modulation with SC144 may be a translatable approach for RV dysfunction, a currently untreatable consequence of PAH.