Calcific aortic valve disease, the heart condition that can lead to valve replacement surgery, affects both men and women. But patients actually experience a different version of the same disease with potentially distinct underlying mechanisms, depending on their sex.
“We believe that both men and women are on a similar path to developing disease, but that at some point they diverge,” says Kristyn Masters, a Vilas Distinguished Achievement professor and vice chair of biomedical engineering at the University of Wisconsin-Madison.
An expert in tissue engineering and heart valve disease, Masters has received a four-year, $1.5 million grant from the National Institutes of Health to model and understand differences in disease progression between sexes.
Nearly 10 years ago, her lab was the first to discover a key difference in cellular behavior in heart valve cells: Cells from male pigs more readily calcified than those from females. In recent years, the scientific community has placed greater emphasis on the idea of sex as a biological variable, with the National Institutes of Health in 2015 asking researchers to address the topic in proposals that include studies using vertebrate animals and humans.
A 2016 study from researchers at Universite Laval in Quebec revealed an underlying difference between men and women with similar cases of calcific aortic stenosis: The men exhibited higher levels of calcification in their valves, while the women experienced a greater buildup of collagen fibers, or fibrosis.
Masters plans to model the disease at different stages to determine the point at which men and women diverge. She and her students will build tissue-engineered models, which they’ll treat with common risk factors for the disease, such as high cholesterol.
“What we don’t know about these risk factors and how the disease progresses is whether it’s a case of you have male cells and female cells and when faced with the same risk factor, they respond differently,” she says. “Do they have different magnitudes of response? Or are they actually fundamentally activating different or alternative pathways in the cells based upon whether the cell origin is male or female?”
They’ll check observations from their models against actual valves whose genes they’ll edit to simulate the disease, with the help of colleague Krishanu Saha, an assistant professor of biomedical engineering at UW-Madison.
While no drug treatments currently exist to slow the progression of calcific aortic valve disease, a more nuanced understanding of the condition could lead to differentiating future therapies by sex.
Masters is also collaborating with two faculty members from the UW School of Medicine and Public Health: Bo Liu, a professor of surgery and expert in vascular inflammation, and Amish Raval, an associate professor and UW Health clinician who will assist with identifying the potential clinical relevance of the findings. All are members of the UW Cardiovascular Research Center.
Author: Tom Ziemer