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 Ca²⁺ reuptake, enhanced diastolic Ca²⁺ leak, reduced sarcolemmal Ca²⁺ extrusion, and disrupted mitochondrial Ca²⁺-energy coupling collectively delay Ca²⁺ clearance and sustain elevated end-diastolic cytosolic Ca²⁺, thereby contributing to impaired diastolic relaxation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors may improve Na⁺-Ca²⁺ 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 Ca²⁺ clearance. More direct approaches, including modulation of Ca²⁺-handling proteins, ryanodine receptor 2 (RyR2) stabilization, sarcoplasmic reticulum Ca²⁺-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 Ca²⁺ defects, and stratification of patients according to the dominant mechanism of Ca²⁺ dysregulation.