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

Informacje na temat projektu

DISSECT-HF

Identyfikator umowy o grant: 101045236

DOI

10.3030/101045236

Data podpisania przez KE 30 Sierpnia 2022

Data rozpoczęcia 1 Listopada 2022

Data zakończenia 31 Października 2027

Finansowanie w ramach

• European Research Council (ERC)

Koszt całkowity

€ 1 998 775,00

Wkład UE

€ 1 998 775,00

Koordynowany przez

ACADEMISCH ZIEKENHUIS GRONINGEN
Netherlands

Periodic Reporting for period 1 - DISSECT-HF (Dynamic engIneered heart tiSsue to Study intEr-individual susCeptibily and improve Treatment of Heart Failure)

Okres sprawozdawczy: 2022-11-01 do 2025-04-30

Podsumowanie kontekstu i ogólnych celów projektu

Heart failure is a disease when the heart cannot pump sufficient blood through the body. The prognosis of patients with heart failure is very poor with a 5-years survival rate of less than 50%. Heart Failure is a chronic disease and most patients show progression over time and it is rarely cured due to irreversible damage. Therefore it is very important to prevent heart failure from progression. The problem is that little is known about the early changes in the human heart cells. Therefore we will study human heart cells (cardiomyocytes, fibroblasts and endothelial cells) from patients with heart failure. We focus on three etiologies: Heart Failure due chemotherapy, Heart Failure induced by pregnancy and Heart failure due to a genetic mutation. With the use of reprogramming we can make from patient skin cells, stem cells and differentiate them into cardiac cells. With these cells we make 3D tissues and characterize them on a single cell level. By comparing the 3 different etiologies we can find overlapping mechanisms, but also disease specific mechanisms. The novel findings will be validated and applied in unique human cohorts with data on incident heart failure.

Prace wykonane od początku projektu do końca okresu sprawozdawczego oraz najważniejsze dotychczasowe rezultaty

It is important to mature the cardiac 3D tissues, since stem cell derived cells are immature after differentiation. There we first embarked on maturing the cardiac tissue and make them dependent on fatty acid as fuel (compared to glucose in more immature cells). By maturing the tissues we found that the cardiac tissues indeed were able to use fatty acids, showed better contractile force, lower resting membrane potential and faster conduction; all hallmarks of maturity. Regarding the chemotherapy induced heart failure, we were able to identify 6 patients who had been exposed to the cardiotoxic anti-cancer drug anthracycline. Three patients received a very high dose >20years ago, but had a completely normal cardiac function and we compared these patients with three patients who received a relatively low dose, but experienced severe cardiac dysfunction requiring a heart transplantation or cardiac support device. First we developed a clinically meaning protocol of anthracyclines exposure. We identified the optimal dose and repeated this in four cycles, comparable to the clinical treatment scheme. By applying this protocol to cardiac tissues derived from patients with cardiotoxicity and without cardiotoxicity we were able recapitulate the clincal phenotype of cardiotoxicity, characterized by tissue dilatation, reduced contractile force and increased wall stress. We performed RNAseq to identify disease pathways different between the two groups and found several differentially expressed genes and pathways. We are currently exploring these pathways in our models to validate them.

Innowacyjność oraz oczekiwany potencjalny wpływ (w tym dotychczasowe znaczenie społeczno-gospodarcze i szersze implikacje społeczne projektu)

The finding that 3D generated cardiac tissue from patients resilient to cardiotoxicity compared to patients who are susceptible is a novel finding and goes beyond state of the art and opens new avenues to understand mechanisms behind toxicity, but these may also be applicable to cardiac diseases beyond cancer treatment related cardiotoxicity. This will be further explored first in the two other “example” diseases i.e. genetic cardiomyopathy and pregnancy induced cardiac dysfunction.