Eyeing differences between women and men in cardiovascular disease led to more knowledge and innovations. The mission of Hester den Ruijter, professor of cardiovascular disease in women, is to translate new knowledge in science into clinical practice to improve the diagnosis of cardiovascular disease in women. This will allow doctors to increasingly prevent and treat heart attacks in women in the future. She delivered her oration “From the bottom of her heart” on Oct. 14.
Studying women and men separately in scientific research leads to many new insights. A look back in history shows that this was not a given. “The idea of ‘equality or parity’ was that if you treated women identically to men you provided the best care,” Hester says. “The outcomes of cardiovascular research based on large groups of men were also applied to women through medical guidelines. For a long time we thought in only two groups, patients and controls.”
Historically, the idea prevailed that the female cycle with fluctuations in hormones during the month would negatively affect the study results. Female physiology was seen as complicated. “Little is known about why fewer women were studied, but it seems logical that it had to do with criteria used for studies. For example, women are more likely to have chronic conditions such as heart failure with preserved ejection fraction, whereas most research was done on heart failure with reduced ejection fraction, which is more common in men. Also, most studies were conducted on patients with heart disease who had completely occluded vessels around the heart, while women more often do not. As a result, chronic conditions, which are thus more common in women, have been understudied. In addition to these reasons, the role of women in society may be an explanation. The combination of work and care responsibilities that women have these days, and more limited access to transportation may prevent women from participating.”
In the studies that do study women separately, the data are difficult to interpret. This is because with a small group of women, there is greater uncertainty about whether, for example, the drug works. “Our research shows that women report more and different side effects from medication,” Hester says. “Side effects are often a reason to stop the medication which increases the risk of a second heart problem. In the near future, we are going to conduct nationwide research on how to better screen and retain women for research. We will also study how best to handle data when the group of women is small.”
What are the causes of cardiovascular disease and where do the differences between women and men come from? A big cause is arterial calcification in the vessels that surround the heart, called coronary arteries. If there after, a chronic accumulation of fat and inflammation in the vessel wall the blood no longer flows properly, the heart gets oxygen deficiency. Hester: “Because women score lower than men in almost all prediction models for the diagnosis of cardiovascular disease, the chance that the heart attack is not recognized in women is higher.”
With a grant from the Heart Foundation in 2013, a nationwide study of cardiovascular disease in women was launched from UMC Utrecht: Queen of Hearts. “In women at high risk for heart failure, we saw differences from men in the proteins in the blood. Early heart damage in women seems to go hand in hand with a protein, interferon alpha 5. This protein also plays a role in autoimmune diseases, a disease that affects women much more often than men, and also puts them at high risk for cardiovascular disease.”
In addition to research in large groups of female patients, the focus was also on understanding arterial calcification in women. The team of researchers showed that bleeding in arterial calcification in women contained no information about further prognosis. In men, on the contrary, it was very clear that bleeding was the main predictor of a second stroke, myocardial infarction or other complication. “That bleeding was also intuitively well explained. Bleeding into a the plaque pushes the wall from the inside, causing the plaque to rupture. The inside of the plaque comes into contact with the blood and in response the vessel clogs up.”
But how did the female plaques often cause heart attacks and strokes without bleeding? “conclusively, we found that in women, most of the information in arterial calcification came from the smooth muscle cell. That information told us that in women, that smooth muscle cell was very actively transforming. Smooth muscle cells in arterial calcification can transform to another cell type. Probably those cells do that to repair damage in the vessel wall, they put on a different jacket. Discovering these cell transformations has been pioneered before by groups in America and elsewhere, only the question remained whether these transforming cells in arterial calcification were good or bad. It also never looked at differences between women and men. But by studying the data separately, we find out that the transforming cells that were thought to be good and stabilizing are precisely what put women at risk. We think these cell transformations in women probably contribute to coarsening of the surface of arterial calcification causing blood clots. In the near future we are going to see if this biology of women can be explained by sex chromosomes and sex hormones.”
In the media we also hear a lot about women with symptoms and other heart attacks. “This is due to lack of oxygen in the heart, probably due to malfunctioning small vessels or temporary contraction of the vessels. The reason these problems have not come to light before is that it is technically complicated to properly measure the function of the small vessels. Meanwhile, cardiac catheterization provides the answer. A knowledge gap is that it is unknown exactly who should be referred with persistent complaints. With a grant from the Heart Foundation, we will conduct nationwide research to gain insight into how often and in whom these problems now occur.
“So we have only just begun to unravel these fascinating differences between women and men with cardiovascular disease, and there is still a world to be won for women’s hearts.”
