HCR.20.078 – Time to relax: breaking the vicious circle of autonomic dysregulation, fibrosis and right ventricular maladaptation in pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is a fatal lung disease characterized by abnormal remodeling of the pulmonary vessels, leading to a progressive increase in pulmonary artery pressure. The average life expectancy is currently only 3-5 years, whereas the disease occurs most frequently in females (3:1) at a young age (average 40 years). Ultimately, patients die from right heart failure. Although increased right ventricular (RV) afterload is the initial trigger for PAH-induced RV dysfunction, the fate of the right heart is determined by the response to pressure overload, rather than the degree of pressure overload. We have previously shown overt activation of the neurohormonal system. Although initially beneficial, we hypothesize that chronic neurohormonal activation initiates a vicious circle in which RV fibrosis hampers RV function and adaptation. Recent advances in cell and tissue culture models and imaging modalities provides us now with the possibility to unravel the exact contribution of neurohormonal activation on right heart failure in PAH-patients, opening up new therapeutic opportunities. In this NWA-application, we will combine ex-vivo analyses of cardiomyocytes, fibroblasts and engineered heart tissue of PAH-patients with in-vivo functional analyses of RV filling, flow and fibrosis to reveal the underlying mechanisms and consequence of enhanced neurohormonal activation. The causality between neurohormonal activity and RV maladaptation will be assessed by a single-blinded cross-over trial in which we enhance parasympathetic activity to counteract the neurohormonal disbalance. We ensure clinical translation in this study by: 1. using only patients or patient-derived tissues and 2. Collaborating with translational researchers, pulmonary physicians, (pediatric) cardiologists, molecular cell biologists, engineers and radiologists. Therefore, we are confident that by making the patients a little bit more relaxed, we can break the vicious circle of neurohormonal activation, RV fibrosis and right heart failure.
autonomic regulation, fibrosis, mechanosensing, Pulmonary hypertension, Right heart failure
Eindhoven University of Technology (TU/e), Erasmus Medical Center (EMC), Leiden Universitair Medisch Centrum (LUMC), UMC Utrecht (UMCU)
|Name||Dr. F.S. (Frances) de Man|