Cardiomyocyte calcium homeostasis remodeling in diabetes-related HFpEF: mechanisms and therapeutic perspectives

Heart failure with preserved ejection fraction (HFpEF) is a major heart failure phenotype in type 2 diabetes mellitus, yet therapies directed at its underlying cardiomyocyte mechanisms remain limited. This review focuses on how diabetic metabolic, inflammatory, and structural stress remodel cardiomyocyte Ca 2+ handling. Impaired sarcoplasmic reticulum Ca 2+ reuptake, enhanced diastolic Ca 2+ leak, reduced sarcolemmal Ca 2+ extrusion, and disrupted mitochondrial Ca 2+ –energy coupling collectively delay Ca 2+ clearance and sustain elevated end-diastolic cytosolic Ca 2+ , thereby contributing to impaired diastolic relaxation. Sodium–glucose cotransporter 2 (SGLT2) inhibitors may improve Na + –Ca 2+ coupling by reducing sodium–hydrogen exchanger 1 (NHE1)- and late Na + current-mediated Na + overload, whereas metabolic interventions such as ketone supplementation and glucagon-like peptide-1 receptor agonists may support mitochondrial energetics and Ca 2+ clearance. More direct approaches, including modulation of Ca 2+ -handling proteins, ryanodine receptor 2 (RyR2) stabilization, sarcoplasmic reticulum Ca 2+ -ATPase 2a (SERCA2a) restoration, and repair of T-tubule-associated microdomains, remain largely preclinical or early translational. Advancing this field will require human myocardial validation, biomarkers linked to specific Ca 2+ defects, and stratification of patients according to the dominant mechanism of Ca 2+ dysregulation.