Uncovering the epigenetic signature of female-specifiC biological networks and key driver genes of coronary ArteRy diseasE

Project Information

UCARE

Grant agreement ID: 866478

DOI

10.3030/866478

Project closed

EC signature date 16 March 2020

Start date 1 September 2020

End date 31 August 2025

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 999 979,00

EU contribution

€ 1 999 979,00

Coordinated by

UNIVERSITAIR MEDISCH CENTRUM UTRECHT
Netherlands

Periodic Reporting for period 3 - UCARE (Uncovering the epigenetic signature of female-specifiC biological networks and key driver genes of coronary ArteRy diseasE)

Reporting period: 2023-09-01 to 2025-02-28

Summary of the context and overall objectives of the project

Cardiovascular disease in women is understudied due to underrepresentation in clinical studies. This underrepresentation has led to serious questions around diagnosis and treatment of cardiovascular disease in women as pathophysiology of the disease has different characteristics compared to men.
In this project, we aim to unravel these sex differences and translate female-specific biology to blood diagnostics to improve the diagnoses of heart diseases in women.

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

Cardiovascular disease causes 51% of deaths in women and 42% of deaths in men in Europe. Women are contributing mostly to the worrying trend of increases in hospitalizations for coronary artery disease (CAD) at younger ages. Missed and delayed diagnoses in women are more common than in men, as the pathophysiology of CAD in women is different than in men. Men often have atherosclerotic plaque rupture as underlying mechanism for CAD whereas women more often suffer from plaque erosion. Knowledge on mechanisms that explain the sex differences in CAD and plaque erosion is lagging behind. This is due to the underrepresentation of women in clinical trials for CAD and biobank studies.
In the last year, my team has made substantial progress in the elucidation of sex-specific mechanisms driving atherosclerotic disease. We identified important sex differences in gene regulation of atherosclerosis in humans pointing to crucial involvement of smooth muscle cells in atherosclerosis development. Our data suggest that cell phenotypic switching is a dominant feature in female atherosclerosis (Hartman et al. Circulation 2021). Next steps are to understand how these sex differences arise, whether these are driven by sex hormones and their receptors, or sex chromosomes. In addition, we will further identify biomarker profiles that relate to plaque erosion in women.

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)

While this project focusses on atherosclerosis, mulitple other heart disease have sex-specific characteristics as well. Heart failure with preserved ejection fraction, coronary microvascular dysfunction, coronary dissections are all more prevalent in women as compared to men. During this project, we aim to understand if the mechanisms underlying sex differences found in atherosclerosis may also play a role in the other pathologies.

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