Cardiomyocyte Calcium Homeostasis Remodeling in Diabetes-Related HFpEF: Mechanisms and Therapeutic Perspectives.
TL;DR
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.
Abstract
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 Ca2+ 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.