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ERC

IndivuHeart Report Summary

Project ID: 340248
Funded under: FP7-IDEAS-ERC
Country: Germany

Mid-Term Report Summary - INDIVUHEART (Individualized early risk assessment for heart diseases)

Heart failure (HF) is the common end-stage of different medical conditions. It is the only growing cardiovascular disease and its prognosis remains worse than that of many malignancies. Inherited cardiomyopathies like dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) can serve as paradigmatic examples of different HF pathogenesis. However, mutations alone do not predict the severity of cardiomyopathies nor therapy, because their impact on cardiac myocyte function is modified by numerous factors, including the genetic context. Today, patient-specific cardiac myocytes can be evaluated by the induced pluripotent stem cell (hiPSC) technology. Yet, unfolding the true potential of this technology requires robust, quantitative, high content assays 3D-engineered heart tissue (EHT) from hiPSC provides an automated, high content analysis of heart muscle function and the response to stressors in the dish. The aim of the project IndivuHeart is to make the technology a clinically applicable test. During the first funding period, a total of 58 probands were recruited into the study, 22 heart diseased patents and (10 patients with HCM and 12 patients with DCM) and 36 healthy volunteers. While the recruiting process for HCM, DCM and healthy volunteers was successful, no patients with heart failure with preserved ejection fraction (HFpEF) met the inclusion and exclusion criteria, and therefore HFpEF was excluded from the study. An in depth clinical study entry phenotyping was conducted with all probands, the followup of the clinical course and the genotyping will follow in the second funding period. Skin biopsies were taken from all probands and reprogramming into human induced pluripotent stem cells was completed for 48 of the 57 probands. Culture conditions, cardiac differentiation protocols and quantitative assessment of hiPSC function in EHTs were the focus of the experimental work in the first period. Robust standard operation procedures (SOPs) could be established. To assess the technical and biological variability of our processes, we unblinded us for three control cell lines. While SOPs were established for modalities of disease modeling and drug testing in hiPSC EHTs, other assays like the afterload enhancement did not yet result in the expected responses in hiPSC EHTs. To improve hiPSC culture and expansion, we tested a variety of quality controls and protocols, and established a Master Cell Bank based approach tackling the problem of genomic instability and variable cardiac differentiation potential. In the second period of the project IndivuHeart we will be able to utilize our SOP-based assay to produce standard values for hiPSC-EHT function/stress responses from healthy volunteers and patients with DCM and HCM.

Reported by

UNIVERSITAETSKLINIKUM HAMBURG-EPPENDORF
Germany
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