Mitochondrial-inflammatory coupling in HFpEF: an emerging mechanistic framework for understanding the cardioprotective effects of SGLT2 inhibitors

Figures

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  Figure 1. Multilayered immunometabolic framework underlying HFpEF pathogenesis. The condition of heart failure with preserved ejection fraction (HFpEF) results from the combination of multiple systemic cardiometabolic conditions, which include obesity, diabetes, aging, and chronic kidney disease. The cardiovascular tissues experience a continuous metabolic battle because of these conditions. The central disease pathway develops through two main processes, which include mitochondrial dysfunction and ongoing mild body inflammation. The body uses its metabolic pathways to create energy while producing harmful mitochondrial byproducts, which enable the immune system to respond and activate inflammatory pathways. The two systems work together to create a unique HFpEF condition, which shows diastolic heart failure, microvascular damage, heart muscle rigidity, and decreased ability to exercise. The hierarchical structure demonstrates that HFpEF functions as an entire body immunometabolic condition, which results from the combined effects of mitochondrial dysfunction and inflammatory system disturbances, instead of just heart functions that are not working properly.

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  Figure 2. Proposed mechanistic framework for mitochondrial-inflammatory interactions in HFpEF and potential modulation by SGLT2 inhibitors. Schematic illustration of the proposed interactions between metabolic stress, mitochondrial dysfunction, and chronic inflammatory signaling in HFpEF. The left panel demonstrates how cardiometabolic risk factors, including obesity, diabetes, aging, and chronic kidney disease, may contribute to impaired mitochondrial energetics, altered substrate utilization, disrupted mitochondrial quality control, increased reactive oxygen species (ROS) production, and activation of inflammatory pathways, including the NLRP3 inflammasome. These interconnected processes are proposed to contribute to sustained immunometabolic dysregulation in HFpEF. The right panel illustrates the proposed mechanisms through which SGLT2 inhibitors may improve mitochondrial function, enhance substrate utilization and mitochondrial quality control, reduce oxidative stress, and attenuate inflamamtory signaling. These mechanisms may contribute to improvd myocardial energetic efficiency and clinical outcomes in HFpEF, although the relative myocardial energetic efficiency and clinical outcomes…

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  Figure 3. Comparative immunometabolic and structural features of HFpEF and HFrEF and their potential therapeutic implications. The schematic comparison of the predominant biological characteristics of heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). HFpEF is characterized by relatively preserved myocardial structure with prominent metabolic dysfunction, mitochondrial impairment, chronic low-grade inflammation, and microvascular dysfunction, whereas HFrEF is generally associated with more extensive cardiomyocyte loss, adverse ventricular remodeling, and replacement fibrosis. Mitochondrial dysfunction, inflammatory activation, and oxidative stress contribute to both syndromes, although their relative contributions may differ. The figure illustrates the proposed concept that the therapies targeting immunometabolic and mitochondrial pathways, including SGLT2 inhibitors, may be particularly relevant in cardiometabolic HFpEF phenotypes while acknowledging that multiple mechanisms likely contribute to therapeutic responses in both HFpEF and HFrEF (88, 89).