Oestrogen-related receptor γ in sepsis-induced cardiomyopathy: role of cardiomyocyte subtype conversion.
Summary
Single-nucleus RNA-seq and cross-species models reveal that sepsis drives contractile cardiomyocytes into an injury-responsive subtype via ERRγ reduction, trading contractility for cytoprotection. ERRγ agonism after the acute phase reconverts cells to the contractile state, improving cardiac function; findings are validated in human hearts.
Key Findings
- Cardiomyocytes in normal hearts comprise contractile, injury-responsive, and transitional subtypes.
- Sepsis induces conversion of contractile to injury-responsive cardiomyocytes via ERRγ reduction, decreasing contractility but limiting ROS and injury.
- ERRγ agonist after the acute phase reconverts injury-responsive cardiomyocytes to contractile phenotype, improving function; validated in human hearts.
Clinical Implications
Supports ERRγ-targeted therapeutics and timing strategies (post-acute-phase agonism) to restore contractility in SICM, informing translational trial design.
Why It Matters
Introduces cardiomyocyte subtype conversion as a core SICM mechanism and positions ERRγ as a druggable node with demonstrated functional rescue in vivo.
Limitations
- Predominantly preclinical with translational validation; clinical trials are needed to confirm efficacy and safety
- Timing and dosing windows for ERRγ agonism require precise delineation in humans
Future Directions
Phase I/II studies of ERRγ agonists in SICM with biomarker-guided timing; mapping reversibility windows and interaction with standard sepsis care.
Study Information
- Study Type
- Cohort
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic experiments with human tissue validation
- Study Design
- OTHER