Key result
Direct glucocorticoid receptor inhibition rescues obesity-induced diastolic dysfunction independently of weight loss in mice.
Why the study?
The molecular events initiating early diastolic dysfunction in HFpEF and the individual contributions of systemic comorbidities remain poorly defined.
Early diastolic dysfunction in HFpEF is driven by comorbidity-specific molecular programs, with obesity-induced glucocorticoid receptor activation identified as a causal and actionable target.
Answers are grounded in this paper and cite their sources.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“no single therapeutic strategy applies to all patients.”
“the results show that obesity and hyperglycemia drive more intense and extensive molecular remodeling than other factors, with changes across multiple cardiac cell types: cardiomyocytes, fibroblasts, endothelial cells, and macrophages.”
Distinct comorbidity routes to early diastolic dysfunction identified in mice; leaves open targeted prevention strategies pending clinical validation.
AIMS: Early diastolic dysfunction precedes the development of HFpEF, but the molecular events that initiate this process remain poorly defined. HFpEF arises in the setting of systemic comorbidities such as obesity (OB), hypertension, hyperglycaemia (HG), and sleep apnoea, which often coexist and make it difficult to distinguish their individual contributions to early cardiac remodelling. Here, we aimed to define the early, comorbidity-specific mechanisms that initiate diastolic dysfunction across major HFpEF-associated conditions. METHODS AND RESULTS: We performed single-nucleus RNA sequencing (snRNA-seq) of left ventricles from mouse models of OB, systemic arterial hypertension (SAH), chronic intermittent hypoxia (CIH), and HG at the time point corresponding to early diastolic impairment. Findings were validated by qRT-PCR, immunohistochemistry, and targeted interventions.OB and HG induced the most extensive transcriptional remodelling, affecting cardiomyocytes, fibroblasts, endothelial cells, and macrophages, while SAH and CIH produced comparatively more modest changes. Cardiomyocytes developed comorbidity-specific stress programmes, with glucocorticoid receptor (GR)-driven activation in OB, combined FoxO and GR signalling in HG, mitochondrial and sarcomeric remodelling in hypertension, and minimal changes in hypoxia. Fibroblasts and endothelial cells in OB and HG mice adopted profibrotic and angiogenesis-impaired profiles, and macrophages polarized towards GR-regulated or immunomodulatory states, depending on the comorbidity. Correction of OB at mid-life improved ventricular relaxation, delayed HFpEF onset, and reduced GR target expression. Direct GR inhibition through overexpression of the lncRNA GAS5 or with mifepristone treatment rescued diastolic function independently of weight loss. In HG mice, CnAβ1 overexpression reduced baseline expression of FoxO target genes, corrected atrophy, but did not prevent FoxO target induction under HG or restore relaxation. CONCLUSION: Early diastolic dysfunction arises through comorbidity-specific molecular programmes. OB-induced GR activation emerges as a causal and actionable driver of diastolic dysfunction. These findings provide mechanistic insight into comorbidity-specific pathways in HFpEF and support the development of stratified therapeutic approaches.
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Ausiello et al. (2026) studied Early diastolic dysfunction and HFpEF. Glucocorticoid receptor inhibition (mifepristone or GAS5 overexpression) and correction of obesity was evaluated on Diastolic function and ventricular relaxation. In mouse models, obesity-induced glucocorticoid receptor activation emerged as a causal driver of early diastolic dysfunction, which was rescued by direct GR inhibition independently of weight loss.
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