Dynamic engIneered heart tiSsue to Study intEr-individual susCeptibily and improve Treatment of Heart Failure

The objective of DISSECT-HF is to generate engineered heart tissue (EHT) with the use of human induced pluripotent stem cells (hiPSC) from specific forms of heart failure (HF).

It focusses on three etiologies of HF with a clear trigger and a large inter-individual susceptibility (pregnancy induced HF, anthracycline cardiotoxicity and PLN cardiomyopathy) to unravel common pathophysiological mechanisms involved in the development of HF.

The rationale is: - Better understanding of molecular pathways leading to HF and knowledge about inter-individual susceptibility is needed to improve treatment. - For detection of changes on a molecular level cardiac tissue is needed. - Using innovative experimental approaches, such as dynamic loaded EHT (dyn-EHT), patient specific cells, unbiased target finding and deep phenotyping, I will dissect common disease pathways in the development of HF.

SPECIFIC OBJECTIVES: 1. Construction of dyn-EHT from patient specific hiPSC derived cardiomyocytes, endothelial cells and fibroblasts. 2.

Generation and deep-phenotyping of dyn-EHT from: A) Females with pregnancy induced HF (susceptible) and siblings with a normal pregnancy (resilience) B) Cancer patients with severe HF after anthracyclines (susceptibility) and patients who could resist high dose anthracyclines (resilience) C) Patients with an early PLN cardiomyopathy phenotype (susceptible) versus elderly asymptomatic PLN mutation carriers (resilience) 3.

Identify overlapping and diverse factors. 4. Validate discoveries and apply in unique human cohorts with data on incident HF. WORKPACKAGES: WP1: Optimize construction of dyn-EHT from patient specific hiPSC. WP2: Phenotyping of dyn-EHT from the three HF etiologies focussing on susceptibility and resilience.

WP3: Explore the transcriptome and proteome and apply a systems biology approach. WP4: Validate results and explore human relevance in a large cohort with unique phenotyping.