Delta Plan Heart Failure

Pulmonary Hypertension (PH), particularly Pulmonary Arterial Hypertension (PAH), presents a fatal complication in chronic diseases, affecting 1 in 50,000 individuals, predominantly at a young age and more often in females. The underlying genetic link involves mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene, disrupting BMP signaling. The PHAEDRA-IMPACT consortium aims to understand PH and PAH. The Research The research focuses on understanding PAH through the transforming growth factor-β (TGFβ) signaling pathway, particularly influenced by mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene, prevalent in heritable and some non-hereditary PAH cases. The PHAEDRA initiative identified compounds that modulate the TGFβ/BMP balance, showing efficacy in restoring endothelial function and reversing pulmonary vascular remodeling in preclinical models, though not curing PAH, making early detection crucial. PHAEDRA has identified biomarkers for timely diagnosis and personalized treatment. PHAEDRA-IMPACT will enhance early detection using non-invasive risk assessments, imaging, and biomarker profiling to detect pre-capillary PH. Precision medicine will guide tailored therapies based on advanced imaging and biomarker analyses, addressing disease progression variability among predisposed individuals. Additionally, patient-derived induced pluripotent stem (iPS) cells will be used in 3D culture models of lung and heart tissues to uncover PAH mechanisms and identify therapeutic targets. This comprehensive approach aims to advance our understanding of PAH pathogenesis, accelerate drug development, and enable personalized treatment and preventive strategies for individuals at risk or affected by PH. Origin This consortium was funded through the Impulse Grant program by the Dutch Heart Foundation.

Familial Hypercholesterolemia (‘FH’) is the most prevalent genetic cause of premature atherosclerotic cardiovascular disease (ASCVD). FH has an estimated prevalence of 1:300 in the general population in the Netherlands. FH is characterized by lifelong elevation of LDL cholesterol, resulting in a profoundly increased risk of coronary heart disease (CHD) and premature death. Early identification of FH and intensive LDL cholesterol management are essential to minimize the lifetime cumulative cholesterol burden and associated risks. FH is inherited. Typically, parents with one pathogenic mutation have a 50% chance of passing down the condition to each child. Therefore, it is essential to screen first degree relatives (children, parents, brothers & sisters) of an individual diagnosed with FH, to detect other family members who may have inherited FH. LEEFH network In the Netherlands we have long track record with FH index identification, cascade screening of first degree relatives and associated research activities. Stichting LEEFH support healthcare professionals pro-actively to pursue cascade screening, aiming to identify FH-patients as early as possible. LEEFH works in a voluntary network with 39 hospitals (LEEFH centres) to optimize FH care and cascade screening. Over the years, an active database has been built up with approximately 7,000 family pedigrees and more than 37,000 FH positive tested patients. Annually, we detect ~ 300 FH+ indexes (new FH families) and 500 FH+ family members by cascade screening. A unique example of early prevention. The Research LEEFH supports research activities in the field of FH detection and treatment with its acquired knowledge, database and network. Recent examples of this include FH identification via central laboratory data, electronic health records and general practitioners. We also participate in research projects with other genetic disorders in order to further improve cascade screening through knowledge sharing (for example in the consortium ‘eCG Family Clinic’ (e-Cardiovascular Genetics Family Clinic). The Orgin The LEEFH network is a voluntary partnership since 2013. 39 hospitals are now affiliated. Each hospital (LEEFH center) has a number of healthcare professionals with a great deal of knowledge and affinity with FH. The LEEFH network aims to prevent (unnecessary) cardiovascular diseases by a) detecting FH family members through cascade screening and b) creating more awareness about FH. We do a lot of knowledge sharing about FH, both among ourselves and also through regional meetings with families and general practitioners. We have signed network agreements with ‘who’ does ‘what’ and ‘when’ in the cascade screening . The aim is to inform and support each family in the right way in the cascade screening. The DNA diagnostics are carried out by the Amsterdam UMC. Application forms and test packages are available via Stichting LEEFH.