Heart disease is the leading cause of death among people with obesity, a condition affecting one in eight people worldwide. Studies show that fat around the heart can fuel inflammation, damage heart muscle cells, disrupt heart rhythm and increase the risk of heart failure, but the precise mechanisms remain unclear.
To better understand how obesity affects the heart, Pinar Zorlutuna, the Roth-Gibson Professor of Bioengineering at the University of Notre Dame, and her lab have developed a 3D-printed model that integrates heart and fat cells to mimic obesity’s effects and test potential therapies.
Their results were published in Advanced Science. Lara Çelebi, doctoral student in bioengineering at the University of Notre Dame, is the paper’s first author.
“The fat cells that surround the heart are different from those that surround the body’s other organs in that they share blood vessels,” said Zorlutuna. “Substances released by the fat—such as hormones or inflammatory chemicals—can move directly into the heart muscle. This close connection enables fat around the heart to affect heart health more than fat stored elsewhere.”
While some fat around the heart is necessary since it supplies energy, supports blood vessels and aids metabolism, fat cells in obese people behave differently. When these cells are overloaded with too much fat, they enlarge and malfunction chemically.
Using mice and rats to study this relationship is not effective because rodent fat does not touch the heart. To replicate how heart tissue behaves in obese patients, Zorlutuna’s team needed a 3D structure where heart and fat cells could interact.
First, her team reprogrammed stem cells so that they developed into fat and heart cells, specifically from the atria, the heart’s upper chamber, since obesity increases the risk of atrial fibrillation by about 50%. Then, with the aid of a 3D bioprinter, the team layered the heart and fat cells into a gelatin and collagen scaffold that mimicked human tissue.
Preserving the enlarged nature of the fat cells was key, but it also made them too fragile to print. To resolve this, the team 3D printed “baby” fat cells, growing them to their problematic size within the 3D engineered tissue.
Ultimately, the team’s 3D printed model, not only accurately demonstrated the dysfunctional relationship that can develop between heart and fat cells, but the efficacy of metformin (a common diabetes medication) in reversing some of the harmful effects of enlarged fat cells. The drug improves both how strongly heart cells contract and how efficiently heart cells use energy.
“For the first time, we’ve built human heart tissue that includes real fat, giving us a lifelike model to study how obesity drives heart disease,” said Zorlutuna. “This platform allows us to identify and prioritize the most effective treatments before they ever reach animal or clinical trials.”
This research was supported by the National Institutes of Health and the National Science Foundation.
—Karla Cruise, Notre Dame Engineering; Photos by Wes Evard, Notre Dame Engineering