A Sex-specific View on Atherosclerosis: From molecular plaque insights to innovative diagnostics

Abstract

Coronary artery disease (CAD) is the leading cause of death in women worldwide. Yet, women are often diagnosed too late or even misdiagnosed. A major reason is the long-standing perception of CAD as a predominantly male disease, which has contributed to the underrepresentation of women in cardiovascular research and shaped a diagnostic framework that does not account for sex-specific disease presentation and underlying biology. CAD is predominantly caused by atherosclerosis, a chronic, progressive disease characterized by the accumulation of fat, immune cells, and fibrous tissue within the arterial walls. Over time, this leads to plaque formation, causing the arteries to narrow and stiffen, which reduces blood flow to the heart. This thesis reveals molecular and cellular differences in atherosclerotic plaque biology between men and women that help explain these diagnostic gaps. These findings provide a mechanistic basis for the well-known sex differences in CAD pathology and show why current diagnostic tools may be less effective in women. They also highlight the need for approaches that can capture these biological disparities directly. One such approach is targeting circulating cell-free DNA (cfDNA) in blood, which carries tissue-specific markers, including those originating from atherosclerotic plaques. This offers a promising non-invasive way to detect vascular pathology and capture differences between men and women. A deeper understanding of these sex-specific pathways will enable further refinement of cfDNA targets and strengthen its potential as a precision diagnostic tool.