Background: Type 2 diabetes mellitus (T2DM) is a major driver of cardiovascular disease and the most prevalent comorbidity in heart failure with preserved ejection fraction (HFpEF), a condition characterized by impaired diastolic function, especially in elderly individuals and women. The mechanisms by which diabetes exacerbates HFpEF remain incompletely understood, but emerging evidence points to integrated dysregulation of β-adrenergic signaling, inflammation, oxidative stress, and protein quality control (PQC) pathways.
Objective: This study aimed to unravel the myocardial mechanisms underlying diastolic dysfunction in diabetic HFpEF, with a focus on β-adrenergic receptor signaling, kinase-mediated phosphorylation, oxidative stress, inflammation, and PQC pathways, including autophagy and chaperone function.
Methods: Endomyocardial biopsies were collected from 30 HFpEF patients (LVEF >50%, no coronary artery disease), including 16 with T2DM. Isolated cardiomyocytes were assessed for passive stiffness, calcium sensitivity, and maximal force generation. Functional assays were combined with biochemical and molecular analyses of signaling components (β1/β2-adrenergic receptors, G proteins, GRKs, PKA, PI3K/AKT/mTOR, AMPK, PKG), oxidative stress markers (ROS, GSH/GSSG ratio), and inflammatory mediators (NF-κB, IL-6, NLRP3). PQC pathways were evaluated via expression of heat shock proteins (HSP27, HSP70) and markers of autophagy.
Results: Diabetic HFpEF patients displayed markedly increased cardiomyocyte passive stiffness and calcium sensitivity, with impaired force generation, phenotypes that were reversible upon exogenous PKA stimulation. This corresponded to reduced endogenous PKA activity and lower expression of β1-/β2-adrenergic receptors, GRK2/5, and Gs proteins, with concurrent elevation of Gi protein expression. These molecular alterations resulted in diminished phosphorylation of key contractile and calcium-handling proteins, including troponin I, myosin-binding protein C, phospholamban, and SERCA2a.
Moreover, diabetic hearts exhibited profound inflammation (↑NF-κB, IL-6, NLRP3) and oxidative stress, with impaired NO-sGC-cGMP-PKG signaling and reduced phosphorylation of AKT and mTOR, indicating dysregulated insulin signaling. PQC impairment was confirmed by reduced HSP27 and HSP70 expression, correlating with increased cardiomyocyte stiffness. Targeted interventions of IL-6 inhibition, mitochondrial antioxidant (Mito-TEMPO), and HSP supplementation significantly improved cardiomyocyte biomechanics by reducing passive stiffness of the cardiomyocyte and restoring kinase activity.
Conclusion: Diabetic HFpEF is marked by a synergistic disruption of β-adrenergic signaling, inflammatory and oxidative stress responses, and PQC machinery, collectively promoting cardiomyocyte stiffness and diastolic dysfunction. These findings highlight novel therapeutic targets, such as kinase modulation, anti-inflammatory strategies, mitochondrial antioxidants, and chaperone-based therapies that could reverse cardiomyocyte dysfunction and improve outcomes in this high-risk HFpEF population.
