Researchers have developed a human iPS-cell-derived heart tissue model of HFpEF that has helped identify a mechanism behind the effects of SGLT2 inhibitors.

Human heart tissue model reproduces HFpEF features

A research team led by Fujita Health University and Keio University has developed an engineered heart tissue model that reproduces key features of heart failure with preserved ejection fraction (HFpEF), including impaired relaxation despite preserved contraction.

The model was created using human induced pluripotent stem (iPS) cells and three-dimensional engineered heart tissue. Researchers exposed the tissue to high fatty acid levels and an inhibitor of nitric oxide production to reproduce features associated with HFpEF. The resulting tissue showed reduced relaxation while maintaining contractile function, alongside increased levels of the heart failure marker BNP and abnormalities in calcium handling.

The researchers also identified structural and functional changes associated with heart failure, including fibrosis and abnormalities affecting mitochondria, the structures responsible for producing energy within cells.

HFpEF is a form of heart failure in which the heart retains its ability to contract but has difficulty relaxing and filling with blood. The condition is increasingly common with ageing and is associated with conditions including hypertension, diabetes and obesity.

The new model could provide a human-cell-based system for investigating HFpEF mechanisms and evaluating potential treatments.

SGLT2 inhibition improves diastolic function

The researchers used the engineered heart tissue to compare the effects of several existing heart failure treatments.

An SGLT2 inhibitor improved the reduced relaxation function observed in the HFpEF model and lowered the increase in NPPB, a gene associated with heart failure. The researchers then investigated the biological mechanisms behind the response.

The analysis identified vascular endothelial cells as an important component of the response to SGLT2 inhibition.

In the HFpEF model, activity in the eNOS-NO-cGMP-PKG signalling pathway was reduced. This pathway has a role in regulating vascular and cardiac function. Treatment with an SGLT2 inhibitor restored activity in the pathway and was associated with an anti-inflammatory effect.

The researchers also found that AMPK, a protein involved in regulating cellular energy and metabolism, was activated following SGLT2 inhibition.

When the researchers removed eNOS function from the model, the SGLT2 inhibitor no longer improved the relaxation defect, heart failure markers or inflammation. The findings therefore indicate that restoration of eNOS signalling is an important part of the observed response in the engineered tissue.

Model could support HFpEF drug discovery

The study also investigated the role of sodium and calcium handling in the engineered heart tissue.

The HFpEF model showed excessive accumulation of sodium and calcium within cells. SGLT2 inhibition reduced this accumulation, while experiments with sodium-hydrogen exchanger inhibitors produced similar improvements in the model.

The researchers found that vascular endothelial cells had an important role in maintaining normal sodium and calcium levels, suggesting that changes in endothelial signalling may contribute to cellular stress and inflammation in HFpEF.

The findings provide a potential explanation for some of the effects of SGLT2 inhibitors beyond their established use in diabetes and heart failure. However, the study was conducted using engineered human heart tissue rather than patients, so the findings do not establish a new clinical effect of SGLT2 inhibitors.

The research was published in Cell Stem Cell in August 2026, following online publication in July.

The researchers said the human iPS-cell-derived model could be used to investigate HFpEF disease mechanisms and support the development and testing of future heart failure treatments.

The study was conducted by researchers from Fujita Health University, Keio University, Kyoto University and collaborating institutions. The work included contributions from the Center for iPS Cell Research and Application at Kyoto University and the Keio University Regenerative Medicine Research Center.