By studying men and women separately, much remains to be discovered about the development of arterial calcification. Hester den Ruijter, associate professor of Experimental Cardiology at UMC Utrecht received an ERC grant to research the development of arteriosclerosis in women. With this, she hopes to develop a risk test. “In the field of arteriosclerosis and cardiovascular disease, there has been little focus on looking at men and women separately,” she said.
When it comes to cardiovascular disease, the sexes differ substantially: women are on average older than men when they suffer a heart attack. This dichotomy is visible even at the level of atherosclerotic plaques, the arterial calcification that can lead to such an infarction. Men and women seem to develop these plaques differently, says Hester den Ruijter. “Men are more likely to have unstable plaques. These tear open, which causes the vessels to clog up and eventually cause a heart attack. This is in contrast to the stable plaques that are more common in women, especially younger women. Of these, the idea is that the cells on the stable plaques detach, creating clots that can block a blood vessel.”
In scientific research on cardiovascular disease, men and women are not equally represented, Hester says. This is true not only for research on plaques, with “unstable plaques” receiving the most attention in the past, and thus primarily studying male tissue. “There are more knowledge gaps in this area because the findings are based, on average, on 70 percent men and 30 percent women. That distribution does not always match how cardiovascular disease occurs in society.” Along with American colleagues, Hester conducted research on how genes behave in the heart in severe vascular disease based on gender. After selecting women from that group, Hester was able to discern a specific female pattern. “In the analyses so far, you saw mostly how the genes behave in men because the analyses were based on mostly male tissue. The female patterns we discovered have not been discovered before in scientific research.” She was awarded a €2 million grant from the European Research Council (ERC) for her research on this topic.
With this ERC grant, Hester wants to spend the next five years figuring out how genes behave in women. In doing so, she not only looks at heart and blood vessels at the tissue level, but also at the cellular level. The endothelium, the layer of cells on the inside of heart and blood vessels, plays a role in the development of arterial calcification and cardiovascular disease. “We see that the stable plaques nevertheless cause heart attacks, especially in the younger women with heart attacks,” says Hester. “We think this is because in them the endothelial cells on the plaques detach. That assumption seems to fit very well with the picture we see in the clinic.” In that process, gender differences seem to play a role in endothelial cell function. “There are indications that sex chromosomes may also play a role in this.”
In how the DNA behaves, Hester thinks she can distinguish features that are especially important in women given their arterial calcification. After all, endothelial cells contribute to the cell-free DNA floating around in the bloodstream. She and her colleagues want to scrutinize that DNA from endothelium and develop the results into a diagnostic test. “I want to investigate whether we can pick up the processes behind cardiovascular disease in this. If that’s possible, it would allow us to better predict heart attacks in women.” An actual risk test based on cell-free DNA remains to be seen. “We are starting studies in women who have had a heart attack based on a stable plaque,” says Hester. “In such an extreme group, we should be able to pick up a signal in the DNA.” In any case, she thinks there is a need for a test. “It makes sense to distinguish between patients with different risks of cardiovascular disease so you can offer them different treatments. You don’t want to put a 40-year-old woman on all kinds of preventive medication right away, unless a test shows she’s at high risk.”