Cellular basis of HFpEF: contributions of abnormal lipids

Figure 1. Established metabolic shifts in the heart. Cardiac metabolism in a healthy adult heart, a healthy heart during exercise, an adult heart with HFpEF, and an adult heart with HFrEF. A healthy adult heart relies primarily on fatty acid oxidation (FAO) for energy but maintains metabolic flexibility. For example, during exercise and increased demand, the heart seamlessly shifts to utilize more glucose and lactate. In HFpEF, cardiac hypertrophy along with mitochondrial inefficiency causes a decrease in FAO and a shift in substrate use. In contrast, the heart with HFrEF shows marked increase in the use of ketone bodies; the energy-deficient heart has the heaviest reliance on alternative fuels. All arrows are relative to metabolism in a healthy adult heart. Parentheses indicate a slight or variable change.

Figure 2. Proposed mechanism of atherogenic lipoprotein toxicity in HFpEF. This hypothetical model illustrates how highly modified atherogenic lipoproteins (such as electronegative VLDL) may contribute to HFpEF through coordinated effects as extrapolated from other cardiovascular disease models. (A) The proposed hypothesis is that atherogenic lipoproteins may directly impair cardiomyocyte metabolism and survival. The subsequent build-up of toxic lipid metabolites, such as triacylglycerols (TAGs), diacylglycerols (DAGs), and ceramides, impairs ATP production and energy metabolism. (B) In the proposed mechanism, endocardial dysfunction caused by atherogenic lipoproteins may alter cardiomyocyte signaling, oxygen delivery, and metabolic regulation. (C) With these cellular changes, blood flow may decrease in the capillary network surrounding the myocardium, thus impairing myocardial perfusion.

Figure 3. Established pathophysiology of general lipid-induced myocardial remodeling in HFpEF. Systemic metabolic stress and dyslipidemia promote the myocardial accumulation of saturated fatty acids and toxic lipid intermediates, including ceramides and diacylglycerols (DAGs). This lipotoxicity triggers an interconnected, recognized cascade of endothelial dysfunction, mitochondrial impairment, and meta-inflammation. In the endothelium, saturated fatty acids activate TLR4/NF-κB and NLRP3 inflammasomes, reducing nitric oxide (NO) bioavailability and promoting microvascular dysfunction. Concurrently, mitochondrial NAD+ depletion inactivates SIRT3, leading to protein hyperacetylation, impaired fatty acid oxidation, and excessive reactive oxygen species (ROS) generation. These metabolic and oxidative stressors drive immune cell recruitment and pro-inflammatory cytokine release [interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α]. This inflammatory and lipotoxic milieu disrupts critical cellular signaling pathways, characterized by AMPK and PPAR downregulation alongside TGF-β/Smad2/3 and PKC-β activation, which collectively promote fibroblast-to-myofibroblast trans-differentiation. The…

Figure 4. Mitochondrial hyperacetylation cycle as an established mechanism of metabolic failure in HFpEF. A comorbidity-driven reduction in myocardial NAD+ levels leads to widespread inactivation of NAD+-dependent deacetylase sirtuin 3 (SIRT3). The loss of SIRT3 activity prevents the removal of pathological lysine acetylation (AcK) tags from multiple mitochondrial proteins (indicated on enzymes in the TCA cycle and electron transport chain). This persistent “AcK” clog inhibits metabolic flux through these pathways, creating an energy shortage (ATP deficiency). This inhibition further depletes NAD+, perpetuating the hyperacetylation state and redirecting cellular lipids into the formation of toxic intermediates (DAGs/ceramides) that exacerbate cardiomyocyte dysfunction. BDH1: beta-hydroxybutyrate dehydrogenase 1; β-HAD: beta-hydroxyacyl-CoA dehydrogenase; CPT1: carnitine palmitoyltransferase 1; ETC: electron transport chain; FAO: fatty acid oxidation; LCAD: long-chain acyl-CoA dehydrogenase; LCFAs: long-chain fatty acids; MPC: mitochondrial pyruvate carrier; PDH: pyruvate dehydrogenase.