AtheroGEN

• Mete CIVELEK, University of Virginia School of Medicine (USA)
• Hester DEN RUIJTER, University Medical Center Utrecht (Netherlands)

Cardiovascular disease causes 51% of deaths in women and 42% of deaths in men in Europe. Women account for a greater proportion of increased hospitalizations for coronary artery disease (CAD) at younger ages. Missed and delayed diagnoses are more common in women than men, likely due to sex differences in CAD pathophysiology. Men often experience atherosclerotic plaque rupture as the underlying mechanism for myocardial infarction, whereas women more often suffer from plaque erosion. Knowledge about the mechanisms that explain the sex differences in CAD and plaque erosion is lacking. This is due, in part, to the underrepresentation of women in clinical trials for CAD and biobank studies.

The AtheroGEN partners have made substantial progress in elucidating sex-specific mechanisms driving atherogenesis. We identified important sex differences in gene regulation of atherosclerosis in humans, mice, and cells, pointing to contributions from both sex chromosomes and hormones in atherosclerosis development. Our data suggest that cell phenotypic switching is dominant in female atherosclerotic plaques. We propose to take the crucial next step in AtheroGEN and unravel how sex itself affects atherosclerosis on a molecular level and predisposes females to symptomatic fibrous plaques. We aim to identify target genes that prevent the development of symptomatic eroded fibrous lesions. This is a challenging but necessary step to close the knowledge gap on atherosclerosis in women and promote health equity between women and men with CAD.

Beyond the scope of this work, the results of AtheroGEN can have a significant impact on the understanding of other pathogenetic mechanisms that have a higher prevalence in women, such as sudden coronary artery dissection, vasospastic angina, and heart failure with preserved ejection fraction. These pathologies are all impacted by the dysfunction of vascular wall cells. Unraveling how sex interacts with these cells in atherosclerosis allows fast translation of sex-biased mechanisms to these other female-prevalent pathologies.