Mitochondrial dysfunction as a contributor to decreased perfusion in heart failure with preserved ejection franction(HFpEF) in a swine model of kidney disease and diabetes

Abstract Background Diabetes, hypercholesterolemia, and chronic kidney disease (CKD) are known to promote oxidative stress—a critical component in the development of heart failure with preserved ejection fraction (HFpEF)(1). In our previous work, we showed that increased left ventricular diastolic stiffness was secondary to oxidative stress(2). Proteomic data revealed that mitochondrial proteins were among the most differentially expressed, along with extracellular remodeling proteins. Purpose To investigate the role of mitochondrial dysfunction post-chronic kidney disease and with or without diabetes, and its correlation to cardiac perfusion. Methods Chronic kidney disease (CKD) was induced by renal micro embolization in both wild-type (WT) and diabetic (DM) swine. 6 months, in vivo coronary flow measurements were performed using a coronary flow probe. 8-hydroxy-2'-deoxyguanosine staining (8-OHdG) was performed in paraffin embed tissue and GPX3 mRNA expression was measured by RT PCR. In isolated mitochondria, we examined mitochondrial respiration using high-resolution respirometry (Oroboros Oxygraph-2k), calcium retention capacity using Calcium-Green. These findings higlight the intertwines effects of CKD and DM in mitochondrial function, oxidative stress, and HFpEF. Results Swine with CKD and/or DM displayed increased baseline coronary blood flow but reduced coronary flow reserve (CFR), indicating impaired ability to meet heightened metabolic demands. Additionally, levels of glutathione peroxidase 3 (GPX3), an antioxidant enzyme, were significantly reduced, suggesting increased oxidative stress, which was further confirmed by (8-OHdG) staining showing oxidative damage in left ventricular tissues. Mitochondrial experiment showed that WT-control swine exhibited the highest oxygen consumption, indicating the most efficient mitochondrial respiration in response to ADP. In WT-CKD vs. WT swine, respiratory capacity with pyruvate-malate-glutamate (PMG) as the substrate for complex I of the respiratory chain was reduced with incremental concentrations of ADP. Mitochondrial respiration was significantly reduced in DM, while the combination of DM and CKD did not have an additional effect Furthermore, mitochondrial calcium retention capacity was diminished in the DMs and the CKD, which was rescued by cyclosporine A, indicating premature opening of the permeability transition pore. Conclusions Impaired mitochondrial function following chronic kidney disease (CKD) and diabetes is a crucial signaling mechanism that contributes to the pathogenesis of HFpEF. Understanding this dysfunction and its relation to cardiac perfusion is essential for unraveling the complexities of heart failure in patients with these comorbid conditions. By investigating how therapeutic agents improve cardiac perfusion, we aim to identify novel therapeutic targets to enhance treatment strategies for HFpEF.