Modeling Diastolic Dysfunction in HFpEF Using Human iPSC-Derived Engineered Heart Tissues

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Summary of  Cell Stem Cell https://doi.org/10.1016/j.stem.2026.06.007
Dr. Hidenori Tani et al.

Points

Fujita Health University researchers engineered a three-dimensional human heart tissue model using induced pluripotent stem cells to study heart failure with preserved ejection fraction mechanisms.
Supplementing culture medium with excess fatty acids and nitric oxide synthase inhibitors successfully induced characteristic diastolic relaxation impairment while preserving systolic contraction capacity.
Molecular profiling of disease models confirmed elevated natriuretic peptide secretion, abnormal calcium handling gene expression, pro-fibrotic tissue remodeling, and heightened inflammatory cytokine pathways.
Pharmacological screening across six cardiovascular drug classes identified empagliflozin as the sole agent capable of significantly improving tissue relaxation and mitigating diastolic dysfunction.
Mechanistic analyses revealed that sodium-glucose cotransporter 2 inhibitors act through endothelial cells to reduce inflammation and restore the protective eNOS-NO-cGMP-PKG signaling axis.

Summary

This study evaluated the development and therapeutic responsiveness of a human engineered heart tissue (hEHT) model of heart failure with preserved ejection fraction (HFpEF), a condition affecting over 30 million individuals worldwide. Led by Shugo Tohyama and Hidenori Tani at Fujita Health University in Japan and published in Cell Stem Cell, the investigation utilized human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with epicardial cells, endothelial cells (ECs), and macrophages in porcine heart-derived collagen scaffolds. The research sought to establish a physiologically relevant in vitro 3D cardiac platform mimicking diastolic dysfunction under high fatty acid and L-NG-nitroarginine methyl ester (L-NAME) culture supplementation.

Functional and molecular evaluations demonstrated that the HFpEF-hEHT model successfully recapitulated impaired relaxation function while preserving systolic contractile capacity. The engineered tissues exhibited elevated secretion of N-terminal pro-B-type natriuretic peptide (NT-proBNP), increased NPPB mRNA levels, abnormal calcium transients, and downregulated expression of essential calcium-handling genes, including RYR2, SERCA2A, and PLN. Structural remodeling was evidenced by upregulation of pro-fibrotic genes and isoform transitions toward stiffer collagen and TITIN variants. Inflammatory signaling cascades were also pathologically upregulated, mimicking human disease phenotypes.

Comparative pharmacotherapeutic testing across six clinical HFpEF drug classes revealed that only empagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), partially prevented relaxation impairment and attenuated diastolic dysfunction. Transcriptomic profiling indicated that SGLT2i exerted anti-inflammatory effects by suppressing interleukin-1β (IL-1β) and interleukin-6 (IL-6) expression. This therapeutic benefit required the presence of endothelial cells and operated via partial restoration of the endothelial nitric oxide synthase (eNOS)–NO–cGMP–PKG signaling axis alongside improved intracellular Na+ and Ca2+ clearance. The authors conclude that this hiPSC-derived hEHT platform provides a robust foundation for modeling HFpEF pathogenesis and developing targeted therapies.

Link to the article: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(26)00234-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1934590926002341%3Fshowall%3Dtrue

References

Tani, H., Haga, K., Moriwaki, T., Bang, U., Fujii, S., Sekiguchi, D., Yamamoto, Y., Momoi, K., Ohno, M., Nakamura, M., Umei, T. C., Morita-Umei, Y., Soma, Y., Kishino, Y., Sano, M., Fukuda, K., Hotta, A., Ieda, M., & Tohyama, S. (2026). Human iPSC-derived engineered heart tissue model of diastolic dysfunction in heart failure with preserved ejection fraction. Cell Stem Cell, 33(8), 1339-1353.e7. https://doi.org/10.1016/j.stem.2026.06.007