A cell in a crucial heart valve leaflet feels a disruptive stretch, so it produces more of the structural protein collagen—and in extreme cases even produces calcium—to ease its physical stress.
It’s a little remodeling job with broader consequences: If enough cells join in, the overall structure of the aortic valve leaflet thickens and hardens, impairing its ability to open and close as blood pumps. As the valve narrows due to this disease-induced feedback loop, it can have dire consequences for the heart, including congestive heart failure and sudden cardiac death. However, calcific valve disease has no viable treatment options—apart from surgically replacing the valve with a prosthetic.
“The problem in this pathologic situation is that what’s good for the cell is not good for the organ,” says Colleen Witzenburg, the Jane R. and John G. Mandula Assistant Professor of biomedical engineering at the University of Wisconsin-Madison.
Witzenburg is using a National Science Foundation CAREER Award to illuminate the unknown but important mechanisms behind the structural changes that accompany and drive calcific aortic valve disease.
By employing complex mechanical testing in combination with advanced imaging of lab-cultured aortic valve leaflets, the five-year, roughly $650,000 project will lay the groundwork to identify potential therapeutic targets to disrupt this feedback and slow, or even halt, disease progression.
Calcific aortic valve disease, the most common heart valve ailment, involves progressive thickening and stiffening—with fat, collagen and, eventually, calcium deposits—of the three leaflets that make up the aortic valve. These one-to-two-millimeter-thick leaflets open and close to pump blood from the heart out to the rest of the body, doing so billions of times over an average lifespan. That combination of fine physical structure and robust mechanical function is difficult to replicate in synthetic prosthetics, which require invasive surgeries and generally only last 10-15 years.
“We’re able to diagnose and treat end-stage disease, but there are no options for early-stage disease except wait and watch,” says Witzenburg. “Furthermore, drugs and less invasive solutions for other heart problems have not been successful in calcific aortic valve disease.”
When calcification occurs, it does so in a patchwork manner, rather than uniformly across the tissue. The mechanical forces at play influence that spatial variability—making it difficult to study. Enter Witzenburg’s lab, which uses a mechanical system to test leaflet cells in multiple directions and then culture them under mechanical loads with components typically featured in surgical robots. In this latest work, she and her students will also use an imaging technique called quantitative polarized light imaging to examine the alignment of collagen fibers in which the cells live. That work will help the researchers narrow down tissue sections to look at in greater detail; on that, they’ll collaborate with Peter Tong Department Chair and Professor Paul Campagnola, whose second harmonic generation imaging offers unparalleled resolution.
“A lot of studies have shown that if you put these cells in different mechanical conditions, they behave in very different ways,” says Witzenburg. “So mechanics plays a critical role in modulating their behavior. Therefore, our culture system will involve cyclic stretching in physiologic ranges.”
In the outreach component of the project, Witzenburg’s research group will develop heart-and mechanics-related science activities for kids to share with Camp Odayin, a Minnesota-based organization that offers programming for kids with heart disease and their families in Minnesota and Wisconsin.
“Science outreach rarely goes to kids,” she says. “We usually ask them to come to us.”
Photo: Joel Hallberg