Calcium dysregulation in diabetic cardiomyopathy & heart failure with preserved ejection fraction

Figures

• 

  Figure 1. EC coupling in healthy cardiomyocytes and its dysregulation in diabetic cardiomyopathy. In healthy cardiomyocytes, action potential-triggered Ca2⁺ entry via L-type Ca2⁺ channels initiates calcium-induced calcium release from the SR through RyR2, driving contraction. The insulin–PKB–SPEG axis maintains RyR2 and SERCA2a phosphorylation, while cAMP–PKA–CaMKII signalling regulates key Ca2⁺ handling proteins and the cGMP pathway governs titin-mediated myofilament compliance. In diabetic cardiomyopathy, reduced L-type channel conductance, leaky RyR2, and impaired SR Ca2⁺ reuptake disrupt Ca2⁺ homeostasis. Insulin dysfunction suppresses PKB–SPEG signalling, mitochondria-derived ROS impairs intermediate Ca2⁺-regulating proteins, and titin hypophosphorylation increases myocardial stiffness which is a hallmark of DbCM. Created in BioRender. Sharma, V. (2026) https://BioRender.com/zgorvb3.

• 

  Figure 2. Structural and molecular hallmarks of HFrEF and HFpEF. HFrEF is characterized by LV dilation, weakened myocardium, and LVEF ≤ 40%, driven by aggressive RyR2 hyperphosphorylation, SR Ca2⁺ depletion, and quantitative loss of SERCA2a expression. HFpEF presents with concentric hypertrophy, thick ventricular walls, and LVEF ≥ 50%, underpinned by titin hypophosphorylation-induced passive stiffness, RyR2 hypersensitivity, and localized SERCA2a regulatory dysfunction. Both phenotypes share fibrosis, arrhythmias, Ca2⁺ dysregulation, CaMKII activation, and chronic inflammation and oxidative stress as common drivers. Created in BioRender. Sharma, V. (2026) https://BioRender.com/2cg1t0f.

• 

  Figure 3. AAV-mediated gene therapy strategies for cardiac Ca2+ restoration in HF. The top panels illustrate the two target HF phenotypes (HFrEF and HFpEF) and delivery modalities, including viral vectors such as AAV1 and AAV9, and non-viral small molecules such as SGLT2 inhibitors. The lower panel depicts AAV-mediated cardiomyocyte transduction, in which the vector enters via receptor-mediated endocytosis, undergoes endosomal uncoating, and enables nuclear transcription of the therapeutic transgene. Key intracellular targets such as SERCA2a, RyR2, S100A1, andcBIN1, are highlighted within the Ca2+ handling machinery of the sarcoplasmic reticulum and t-tubule system. Created in BioRender. Sharma, V. (2026) https://BioRender.com/4g1me2g.