Researchers at the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) have identified the activation of the glucocorticoid receptor as a specific causal mechanism behind early diastolic dysfunction linked to obesity. Published in the journal Cardiovascular Research, the findings indicate that this pathway drives heart damage differently than other metabolic conditions, providing a precise molecular target for future heart failure treatments.
Affecting roughly 23 million people globally, heart failure with preserved ejection fraction (HFpEF) accounts for more than half of all heart failure cases. While the heart maintains its pumping strength in this condition, it struggles to relax and fill with blood properly. The disorder typically develops alongside high blood pressure, high blood sugar, sleep apnea, and obesity, which has historically complicated efforts to isolate individual triggers.
Single-Nucleus Sequencing Reveals Distinct Cellular Remodeling
To untangle how different conditions affect cardiac tissue, the CNIC team used mouse models that simulate disease progression tied to aging. Investigators examined heart tissue during the early stages of impaired ventricular relaxation before full-blown heart failure developed. Using single-nucleus RNA sequencing, the researchers analyzed nearly 50,000 nuclei from the left ventricle to measure gene activity across specific cell types.
First author Antonella Ausiello explained that obesity and hyperglycemia trigger the most intense and widespread molecular remodeling, altering cardiomyocytes, fibroblasts, endothelial cells, and macrophages. By contrast, hypertension and chronic intermittent hypoxia—used to model sleep apnea—produced much more moderate changes in the tissue.
Contasting Effects of Obesity and Hyperglycemia on Cardiac Tissue
Although obesity and high blood sugar share certain overlapping effects, they injure the heart through distinct biological pathways. In obesity models, scientists determined that glucocorticoid receptor activation serves as a primary driver of cardiac injury. The research team confirmed this causal relationship through multiple interventions: reversing obesity via diet changes, directly inhibiting the receptor with the drug mifepristone, and overexpressing the GAS5 molecule all successfully restored cardiac function.
However, blocking this same receptor pathway in hyperglycemia models failed to restore heart function. Enrique Lara-Pezzi, who leads the Molecular Regulation of Heart Failure group at CNIC, noted that these divergent outcomes prove each comorbidity damages the heart through separate molecular mechanisms, meaning a single therapeutic strategy will not work for every patient.
The study authors suggest the data strongly support moving toward stratified medicine approaches tailored to the dominant molecular driver in individual patients. At the same time, the researchers emphasize that these insights stem from experimental models and must be validated in human tissue samples and clinical trials before doctors can apply them in clinical settings.
In addition to CNIC, researchers from the Gregorio Marañón Health Research Institute (IiSGM), CIBER of Cardiovascular Diseases (CIBERCV), Puerta de Hierro Majadahonda University Hospital and its IDIPHIM research institute, the Murcian Institute of Biomedical Research Virgen de la Arrixaca (IMIB-Arrixaca), and the University of Murcia contributed to the work.
Frequently Asked Questions About Obesity and Diastolic Dysfunction
What is diastolic dysfunction in heart failure?
Diastolic dysfunction occurs when the main pumping chamber of the heart struggles to relax and fill adequately with blood between contractions. This condition characterizes heart failure with preserved ejection fraction (HFpEF), which impacts approximately 23 million people worldwide.
How did researchers test the role of the glucocorticoid receptor?
Scientists confirmed the receptor’s causal role in obesity-related heart damage using three separate strategies in animal models: reversing obesity through dietary modifications, inhibiting the receptor with the medication mifepristone, and overexpressing the GAS5 molecule.
Are these treatments currently available for patients?
Investigators stress that clinical trials and human tissue validation are necessary before these targeted therapies can be tested or prescribed for patients.
More than 23 million people worldwide are affected by heart failure with preserved ejection fraction, a condition whose underlying molecular drivers are only now being mapped by researchers.