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PhD student Alana Stempien
June 6, 2022

Cell mechanics offers new clue in genetic heart disease

Written By: Tom Ziemer

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Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a mouthful of a heart disease that’s essentially an invisible ticking time bomb for the estimated 1 in 10,000 people who have it. Often, the rare genetic disease goes undetected; those who carry it have hearts that appear structurally and functionally normal under typical circumstances.

But physical or emotional stress can trigger a life-threatening irregular heart rhythm, leading to a diagnosis that can arrive tragically late.

“If you don’t have a known family history of the disease, the first appearance of the disease could be a sudden-death event,” says Alana Stempien, a 2022 PhD graduate in biomedical engineering from the University of Wisconsin-Madison.

Wendy Crone
Wendy Crone

Stempien and Wendy Crone, her PhD advisor and a professor of engineering physics, have worked with collaborators across the UW-Madison campus to uncover new details about the mechanical characteristics of heart cells in CPVT—basic science research that they hope might someday inform treatment strategies. They published their findings in the journal Frontiers in Bioengineering and Biotechnology.

Stempien and Crone used an engineered, two-dimensional cell culture platform and image tracking technique to compare cardiomyocytes (the cells responsible for heart contraction) derived from a patient with CPVT with those from his mother, who didn’t carry a CPVT mutation. To do so, they leveraged stem cell lines developed by collaborators in the UW-Madison School of Medicine and Public Health.

In analyzing the pulsing cardiomyocytes, the researchers found statistically significant differences in two mechanical measures: maximum contractile strain (deformation per contraction) and intrinsic contraction rate (speed of contraction). The patient-derived cells showed a higher strain and a slower rate. While the rate results meshed with previously reported research—validating their approach—the difference in mechanical strain was a new discovery. The mechanical attributes of cardiomyocytes in CPVT as a whole have rarely been explored in human cell cultures; most research has concentrated on the electrophysiology.

“Finding this difference in mechanical function in itself is interesting, but I think it further implies that the mechanical function is something worth understanding more in this disease,” says Stempien, who’s planning to pursue a career in research and development in the biotechnology industry after completing the UW Cardiovascular Research Center Training Program in Translational Cardiovascular Science. “We always look at it from the electrical function, because it’s an arrhythmia disease; that’s how it presents. But there are other aspects of function that are important, that could tell us more about the disease, and maybe give us more insight in the longer term in understanding and developing treatments.”

Crone says other researchers could now investigate the biological underpinnings of those mechanical differences using this cell culture platform.

“This is very early basic science work that could enable future clinically relevant treatments,” says Crone, whose research focuses on biomechanics at the cellular level. “It’s very early and you don’t know what’s necessarily going to pay off, but this has some potential. It’s identified something very clear in terms of a measurable quantity that we can test under different conditions.”

Stempien and Crone have also worked with coauthor J. Carter Ralphe, a pediatric cardiologist, to examine mechanical cell function in hypertrophic cardiomyopathy, another genetic heart condition in which the heart muscle becomes too thick, impairing the heart’s ability to pump blood.

Wendy Crone is the Karen Thompson Medhi Professor in the Department of Nuclear Engineering and Engineering Physics and a Discovery Fellow at the Wisconsin Institute for Discovery. Other UW-Madison authors on the paper include biomedical engineering graduate student Mitchell Josvai (BSBME ’22); Willem De Lange, an associate scientist in the Department of Pediatrics; physiology PhD alumnus Jonathan Hernandez, now chief research and development officer at Signature Biologics; Jacob Notbohm, the Harvey D. Spangler Assistant Professor of engineering physics; Timothy Kamp, a professor in the Department of Medicine and director of the Stem Cell and Regenerative Medicine Center; Hector Valdivia, a professor in the Department of Medicine; Lee Eckhardt, an associate professor in the Department of Medicine; Kathleen Maginot, an associate professor in the Department of Pediatrics; and J. Carter Ralphe, a professor in the Department of Pediatrics.

Funding for this research came from: UW-Madison (through the Karen Thompson Medhi Professorship); the UW-Madison Graduate School; the UW-Madison Office of the Vice Chancellor for Research and Graduate Education; the UW School of Medicine and Public Health’s Wisconsin Partnership Program; the National Institutes of Health under awards T32 HL 007936, RO1 HL 139738-01, R01 HL055438, U01HL134764 and R01 EB007534; and the National Science Foundation Engineering Research Center for Cell Manufacturing Technologies and grant CBET-1066311.