Phaedra-Impact: Pulmonary Hypertension and AssociatED Right heart fAilure: IMproved outcomes through Precision medicine, Advanced modelling and early deteCTion
A high pressure in the pulmonary circulation (pulmonary hypertension, PH) complicates several highly prevalent chronic diseases, including left heart failure and chronic thrombo-embolic disease. Pulmonary arterial hypertension (PAH) is a fatally progressive form of PH with characteristic changes in small lung arteries, affecting 1/50.000 humans. PAH occurs most frequently at a young age and females are more likely to develop PAH; why is poorly understood.
PAH is mainly linked to disturbances within the transforming growth factor-β (TGFβ) signaling pathway. In 80% of the heritable PAH cases and 20% of the non-hereditary forms of PAH, the bone morphogenetic protein (BMP)R2 gene is affected by loss of function mutations and deregulation of BMP signaling also occurs in other forms of IPAH. To date, there are no known effective treatments or interventions to reverse pulmonary vascular remodeling or to prevent right heart failure, let alone to cure PAH. The average life expectancy is still only 3-5 years and lung transplantation offers the only outlook on a better survival, although the right heart may still fail. During PHAEDRA we have identified compounds which, through modulation of the TGFβ/BMP balance, could restore endothelial function in vitro and reverse pulmonary vascular remodeling in vivo, they do not cure PAH.
It is currently recognized that early treatment of PAH with a combination of drugs significantly improves outcomes. Recognizing the need for early detection of PAH, in most patients the disease is still detected very late. Within PHAEDRA, biomarkers were identified to facilitate early and accurate diagnosis and precision medicine treatment.
PHAEDRA-IMPACT will continue the pursuit of improved outcomes in PH. We will contribute to the early detection of treatable PH using non-invasive risk scores in combination with imaging and simple blood tests that can detect pre-capillary PH. We will use a precision medicine strategy to identify the right drug for the right patients, based on advanced imaging and biomarker collection, and will help understand why disease development and progression is so variable between subjects who are similarly predisposed to developing PH, such as survivors of acute pulmonary embolism and BMPR2 mutation carriers. A better understanding of predisposing factors and second hits, will aid in developing new drugs and preventive strategies, as well as in early recognition of disease development. Finally, we will use patient derived iPS cells in innovative 3D culture models of lung and heart tissue to unravel mechanisms of disease in PAH and to identify new possible ways of treatment.
Julia de Boer – Theirlynck, Managementassistent CCB, LUMC