Stem cell models to unravel the susceptibility and resilience to develop heart failure
The overarching objective of STOP-HF is to generate human induced pluripotent stem cells (hiPSC) derived cardiomyocytes from two specific forms of heart failure (HF) with a clear trigger to unravel common pathophysiological mechanisms involved in the early development of HF.
The project is focused on two specific forms of HF, both with a clear trigger: pregnancy and anthracyclines. Better understanding of early molecular pathways leading to HF and knowledge about inter-individual susceptibility is needed. For detection of early changes on a molecular level cardiac tissue is needed. Generation of patient specific cardiac cells from skin fibroblasts (hiPSC technology) is a novel and innovative approach.
1. Fabrication and maturation of 3D cardiac tissue from hiPSC derived cardiomyocytes.
2. Generate and characterize hiPSC derived cardiomyocytes and endothelial cells from females with pregnancy induced HF and unravel differences on transcriptome level.
3. Generate and characterize hiPSC derived cardiomyocytes from patients with high susceptibility and resilience to develop anthracycline-induced HF and compare them on transcriptome level.
4. Integrate the results for coding and non-coding RNAs from objective 1+2 and identify overlapping pathways.
5. Validate discoveries on transcriptome level in vitro, in vivo and apply for the development of HF in the general population.
WP1: Optimize fabrication and maturation of 3D cardiac tissue from hiPSC derived cardiomyocytes
WP2A: Validate the model and compare hiPSC derived cardiomyocytes and endothelial cells from PPCM and healthy sisters on transcriptome level;
WP2B: Validate the model and compare hiPSC derived cardiomyocytes from both patients with high susceptibility and resilience to develop HF after anthracyclins on transcriptome level;
WP3: Integration of transcriptome data from WP 2A+2B;
WP4: Validation of novel pathways in vitro, in vivo and new onset HF in the general population.
In peripartum cardiomyopathy Plasminogen Activator Inhibitor-1 is a potential new biomarker with controversial roles.
Ricke-Hoch M, Hoes MF, Pfeffer TJ, Schlothauer S, Nonhoff J, Haidari S, Bomer N, Scherr M, Stapel B, Stelling E, Kiyan Y, Falk C, Haghikia A, Binah O, Arany Z, Thum T, Bauersachs J, Meer P van der, Hilfiker-Kleiner D. Cardiovasc Res. 2019view on publisher site
EURObservational Research Programme: A Worldwide Registry on Peripartum Cardiomyopathy (PPCM) in Conjunction With the Heart Failure Association of the European Society of Cardiology Working Group on PPCM
Karen Sliwa, Denise Hilfiker-Kleiner, Alexandre Mebazaa, Mark C Petrie, Aldo P Maggioni, Vera Regitz-Zagrosek, Maria Schaufelberger, Luigi Tavazzi, Dirk J van Veldhuisen, Jolien W Roos-Hesslink, Ajay J Shah, Petar M Seferovic, Uri Elkayam, Karin van Spaendonck-Zwarts, Katrin Bachelier-Walenta, Frederic Mouquet, Elisabeth Kraigher-Krainer, Roger Hall, Piotr Ponikowski, John J V McMurray, Burkert Pieske. Eur J Heart Fail. 2014.view on publisher site
Long‐term prognosis, subsequent pregnancy, contraception and overall management of peripartum cardiomyopathy: practical guidance paper from the Heart Failure Association of the European Society of Cardiology Study Group on Peripartum Cardiomyopathy
Karen Sliwa, Mark C. Petrie, Denise Hilfiker‐Kleiner, Alexandre Mebazaa, Alice Jackson, Mark R. Johnson, Peter van der Meer, Amam Mbakwem, Johann Bauersachs. Eur J Heart Fail. 2018.view on publisher site
Pathophysiology, Diagnosis and Management of Peripartum Cardiomyopathy: A Position Statement From the Heart Failure Association of the European Society of Cardiology Study Group on Peripartum Cardiomyopathy
Johann Bauersachs, Tobias König Peter van der Meer Mark C. Petrie Denise Hilfiker‐Kleiner Amam Mbakwem Righab Hamdan Alice M. Jackson Paul Forsyth Rudolf A. de Boer Christian Mueller Alexander R. Lyon Lars H. Lund Massimo F. Piepoli Stephane Heymans Ovidiu Chioncel Stefan D. Anker Piotr Ponikowski Petar M. Seferovic Mark R. Johnson Alexandre Mebazaa Karen Sliwa. Eur J Heart Fail. 2019.view on publisher site