Lab-grown human heart tissue links relaxation failure to inflammation

When Hidenori Tani’s team adjusted glucose and fatty-acid concentrations in a dish at Fujita Health University, one detail changed the direction of the experiment: too much fatty acid made the engineered heart tissue less able to dilate. Led by Professor Shugo Tohyama and Tani, the Japanese researchers have turned that observation into a human model of heart failure with preserved ejection fraction, or HFpEF—a disease in which the heart contracts normally but fails to relax properly.

HFpEF affects more than 30 million people globally, yet has few effective treatment options and poor outcomes. The model begins with hiPSCs, or human induced pluripotent stem cells reprogrammed from human cells, which the team converted into cardiomyocytes, the cells that make up heart muscle. The researchers then formed 3D tissue using collagen derived from porcine hearts and added epicardial cells, endothelial cells and macrophages as supporting components.

The tissue was cultured with high levels of fatty acids and L-NAME, an inhibitor of nitric oxide synthase. It developed the structural and functional signature the researchers were seeking: impaired diastolic relaxation alongside normal systolic contraction. The model also showed increased fibrosis-related genes, a stiffer form of collagen and TITIN, altered genes involved in calcium transport, and higher levels of inflammation.

The team used the model to test six drugs being used or explored for HFpEF. Empagliflozin, a sodium-glucose cotransporter 2 inhibitor and antidiabetic medicine, was the only one that partially prevented the development of diastolic dysfunction. The other tested agents had no effect on relaxation time, while a hyperpolarization-activated cyclic nucleotide-gated channel inhibitor worsened the disease. The researchers linked empagliflozin’s partial benefit to endothelial cells, reduced inflammatory molecules such as IL-1β and IL-6, and improved removal of sodium and calcium ions from the cells through their exchanger channels.

Concretely, the immediate gain is for laboratories: a human-derived, 3D system for studying why the heart becomes stiff and for comparing candidate drugs before clinical research. Tohyama’s team says it could also support research on aging and personalized medicine. The boundary is just as clear: these findings come from engineered tissue in vitro, and the study reports no patient treatment result. Empagliflozin’s effect was partial in this model, so the platform narrows the search for mechanisms and therapies without settling their clinical value.