STEM CELL MODELS TO UNRAVEL THE SUSCEPTIBILITY AND RESILIENCE TO DEVELOP HEART FAILURE

Project Information

STOP-HF

Grant agreement ID: 715732

DOI

10.3030/715732

Project closed

EC signature date 17 February 2017

Start date 1 March 2017

End date 28 February 2022

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 496 875,00

EU contribution

€ 1 496 875,00

Coordinated by

ACADEMISCH ZIEKENHUIS GRONINGEN
Netherlands

Periodic Reporting for period 4 - STOP-HF (STEM CELL MODELS TO UNRAVEL THE SUSCEPTIBILITY AND RESILIENCE TO DEVELOP HEART FAILURE)

Reporting period: 2021-09-01 to 2022-02-28

Summary of the context and overall objectives of the project

STOP-HF focuses on molecular mechanisms that contribute to the development of HF. It is aimed at elucidating the current knowledge gap in molecular mechanisms related to the early pathogenesis of HF before irreversible damage occurs. In this project we use an innovative and multidisciplinary approach. By using human induced pluripotent cells (hiPSC) technology we generated patient-specific heart cells from patients with heart failure (circumventing the need for cardiac biopsies) and used next generation sequencing to identify novel pathways/targets in the pathophysiology of HF.

Importance for society:
- Heart Failure (HF) is a syndrome that occurs when the heart is unable to pump sufficient blood through the body. This inability of the heart to maintain sufficient blood flow is due to an abnormality in cardiac structure and/or function.
- HF is frequently diagnosed; its prevalence is estimated at 1-2% in the general population and the Framingham study demonstrated that the lifetime risk for developing HF is 1 in 5 for both men and women. With aging of the population, the risk to develop the syndrome increases.
- The prognosis of patients with HF is very poor. Patients with HF have a five-year survival rate of less than 50%. HF is very costly to the society; 2% of the annual health care budget is spent on HF.
- HF is a chronic disease and despite advances in medical therapy, the majority of the patients show progression of the disease.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The work we performed was divide in several workpackages (WPs). Below I will described the achieved results so far regarding the different WPs.

WP1: we achieved the generation of 3D cardiac tissue with the use of induced pluripotent stem cells. With this model we are able to put load on the tissues which stretches the tissue. In healthy cells this resulted in better contractility, but in diseased cells (i.e. cell with mutations in the desmosome) this resulted in a strong phenotype.

WP2a/WP3: this WP is related to unraveling peripartum cardiomyopathy, as an example disease. PPCM is a a form of heart failure which occurs late during pregnancy or in the first months after delivery. We generated hiPSC derived cardiomyocytes from 2 patients with PPCM and their used their healthy relatives as a control. With the use of RNAsequencing (WP3), we found that cardiomyocytes from PPCM patients showed a dysregulated metabolic activity. Key factor involved here will be further investigated.

WP2b: this WP is related to why certain chemotherapeutics lead to cardiotoxicity in some patients, while others are resistant to develop this toxicity. We generated hiPSC derived cardiomyocytes from 3 patients with severe toxicity and will compare them to 3 patients without toxicity. These studies are now ongoing.

FINAL PERIOD

STOP-HF focused on molecular mechanisms that contribute to the development of HF. It is aimed at elucidating the current knowledge gap in molecular mechanisms related to the early pathogenesis of HF before irreversible damage occurs. In this project we used an innovative and multidisciplinary approach. By using human induced pluripotent cells (hiPSC) technology we generated patient-specific heart cells from patients with heart failure (circumventing the need for cardiac biopsies) and used next generation sequencing to identify novel pathways/targets in the pathophysiology of HF.
We achieved 3 major goals:
1) Construction of 3D dynamic engineered heart tissue
2) Uncovering of a novel disease pathway in peripartum cardiomyopathy with the use of human induced pluripotent stem cells
3) Identification of a disease mechanism in patients with a cardio-cutaneous syndrome caused by a KLHL24-gain of function mutation

The work we performed was divide in several workpackages (WPs). Below I will described the achieved results so far regarding the different WPs.
WP1: we achieved the generation of 3D cardiac tissue with the use of induced pluripotent stem cells. With this model we are able to put load on the tissues which stretches the tissue. In healthy cells this resulted in better contractility, but in diseased cells (i.e. cell with mutations in the desmosome) this resulted in a strong phenotype.
WP2a/WP3: this WP is related to unraveling peripartum cardiomyopathy, as an example disease. PPCM is a a form of heart failure which occurs late during pregnancy or in the first months after delivery. We generated hiPSC derived cardiomyocytes from 2 patients with PPCM and their used their healthy relatives as a control. With the use of RNAsequencing (WP3), we found that cardiomyocytes from PPCM patients showed a dysregulated metabolic activity. Key factor involved here will be further investigated. WP2b: this WP is related to why certain chemotherapeutics lead to cardiotoxicity in some patients, while others are resistant to develop this toxicity. We generated hiPSC derived cardiomyocytes from 3 patients with severe toxicity and compared them to 3 patients without toxicity. Several targets were identified and we are exploring the pathophysiology behind these mechanisms. One striking difference was observed in genes involved in the uptake of drugs. We are exploring with the Technology Transfer Officer whether these targets can be patented.


REF:
J Clin Invest . 2021 Jul 22;131(17):e140615. doi: 10.1172/JCI140615
Nat Rev Cardiol. 2022 Jan 11. doi: 10.1038/s41569-021-00664-8
Circulation. 2020 Dec 8;142(23):2288-2291. doi: 10.1161/CIRCULATIONAHA.119.044962.
Sci Transl Med . 2021 Jul 21;13(603):eabd1817. doi: 10.1126/scitranslmed.abd1817.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Generation of a 3D dynamic engineered heart tissue platform from patients specific cardiomyocytes is a major breakthrough. This model allowed us to load the tissue leading to a phenotype similar to failing hearts: tissue dilation and reduced contratile force. This finding resulted subsequently in the identification of a new disease mechanism in a family with a cardio-cutaneous syndrome (characterized by skin blistering and heart failure). Without the 3D platform the phenotype would not have been revealed and the discovery could not have been met. The same is true for the identification of a new disease mechanism in pregnancy associated heart failure (PPCM). Our results showed for the first time the impact of cardiac metabolism. This now resulted in further exploration of how metabolism during and after pregnancy impact cardiac function.

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