Cellular Basis of HFpEF: Abnormal Lipids and the Emerging Role of Electronegative VLDL (V5)
核心洞察
Heart failure with preserved ejection fraction (HFpEF) (搜索) is a major unmet medical need marked by high morbidity and mortality and a lack of effective targeted therapies.
Abnormal lipid metabolism drives lipotoxicity, endothelial dysfunction, myocardial fibrosis, and inflammation, which are central to HFpEF pathogenesis, especially in the obese/cardiometabolic phenotype.
The review hypothesizes that electronegative VLDL subfraction V5 may be a previously unrecognized, highly pathogenic trigger linking circulating dyslipidemia to intracellular lipid accumulation.
Heart failure with preserved ejection fraction (HFpEF) (搜索) represents one of the largest unmet medical needs in cardiovascular medicine, characterized by high morbidity and mortality and a lack of effective targeted treatments. A comprehensive review published in Frontiers in Cardiovascular Medicine examines the cellular basis of HFpEF, focusing on the contributions of abnormal lipids—particularly lipoproteins—to disease initiation and progression. The authors propose that changes in circulating plasma lipids mediate pathophysiological processes that drive HFpEF through an imbalance among circulating lipid supply, cardiac fat uptake, and fatty acid metabolism, resulting in the myocardial accumulation of harmful lipid intermediates, a process known as lipotoxicity that contributes to diastolic dysfunction.
The Lipotoxic Cascade in HFpEF
The review delineates how abnormal lipid metabolism acts as a central driver of HFpEF pathology. In the healthy adult heart, fatty acid oxidation accounts for approximately 60%–70% of ATP production, with mitochondrial oxidative metabolism generating 95% of the heart's total energy. However, in HFpEF—which frequently occurs in the context of systemic metabolic syndrome and obesity—myocardial lipid uptake exceeds the oxidative capacity of mitochondria. This mismatch forces the diversion of excess fatty acids into non-oxidative pathways, leading to the intracellular accumulation of highly bioactive, toxic lipid intermediates such as ceramides (搜索) and diacylglycerols (DAGs) (搜索).
Proton magnetic resonance spectroscopy of the heart has shown that HFpEF patients have significantly more intramyocardial fat than do HFrEF or control subjects. This myocardial steatosis promotes lipotoxicity and may exacerbate diastolic stiffness and concentric remodeling, correlating with the severity of diastolic dysfunction independent of other risk factors. Rather than simply causing an energy deficit, this lipid accumulation acts as an active signaling trigger that provokes mitochondrial alterations, reduces fatty acid oxidation, exacerbates reactive oxygen species (ROS) production, and impairs myocardial energetics.
Endothelial Dysfunction, Fibrosis, and Inflammation
The impact of dyslipidemia on endothelial dysfunction in HFpEF is multifaceted. Elevated plasma levels of saturated fatty acids induce endothelial dysfunction via toll-like receptor 4-dependent activation of NF-κB, significantly decreasing nitric oxide (NO) availability. Saturated fatty acids also activate the NLRP3 inflammasome within endothelial cells, resulting in expression of IL-1β and an exacerbated inflammatory response.
Lipid derangements also promote cardiac fibrosis. Dysregulation of fatty acid oxidation and accumulation of lipid intermediates such as ceramides (搜索) and DAGs activate pro-fibrotic signaling pathways, including transforming growth factor-β (TGF-β) and connective tissue growth factor, ultimately leading to extracellular matrix deposition and fibrosis. Key signaling pathways implicated include TGF-β, PPAR, PKC, and AMP-activated protein kinase (AMPK), each playing distinct roles in cardiac remodeling and fibrosis.
Abnormal lipid metabolism also triggers a chronic low-grade inflammatory state termed metabolic inflammation or meta-inflammation. The accumulation of toxic lipid intermediates activates inflammatory signaling pathways including the toll-like receptor 4 pathway and induces pro-inflammatory cytokine production, such as interleukin-6, TNF-α, and interleukin-1β.
The Electronegative VLDL (V5) Hypothesis
A central, hypothesis-driven contribution of the review is the proposal that electronegative very low-density lipoprotein (VLDL), specifically the V5 subfraction, may serve as a novel, highly pathogenic systemic trigger bridging the gap between circulating dyslipidemia and intracellular lipid accumulation. V5 is the most electronegative VLDL fraction, and preliminary data from Chen et al. showed that V5 was rich in apoCIII, signaling a possible mechanism for triacylglycerol accumulation in cells.
The authors note that the combined electronegativity of L5 and V5 correlated with coronary heart disease risk in asymptomatic individuals, and that treatment with L5 + V5 induced significantly more senescence-associated β-Gal activity in cultured human aortic endothelial cells than less electronegative fractions. However, the review is careful to acknowledge that direct clinical evidence evaluating V5 specifically in HFpEF cohorts is limited, and that evidence demonstrating the pro-inflammatory, lipotoxic, and profibrotic effects of V5 is predominantly derived from models of atherosclerosis, macrovascular coronary artery disease, and isolated endothelial cell assays. Extrapolating these findings directly to HFpEF pathogenesis therefore requires caution.
Therapeutic Implications
The review emphasizes that therapeutic strategies should target intracellular lipotoxicity and systemic metabolic dysfunction, rather than simply correcting circulating dyslipidemia. Notably, multiple large randomized clinical trials and meta-analyses have consistently failed to demonstrate a reduction in heart failure events or mortality with statin therapy in HFpEF patients, reflecting the fact that intracellular lipid intermediates such as ceramides (搜索) appear to be more critical drivers of the disease than circulating LDL-C.
In contrast, modern agents that broadly modulate systemic metabolism and reduce lipotoxicity have shown significant success. SGLT2 inhibitors such as empagliflozin and dapagliflozin—established as foundational therapy through the EMPEROR-Preserved and DELIVER trials—promote a shift toward ketogenesis, modulate the myocardial sodium-hydrogen exchanger, and reduce epicardial adipose tissue inflammation. GLP-1 receptor agonists, demonstrated in the STEP-HFpEF trial with semaglutide, substantially reduce body weight, improve heart failure-related symptoms, and enhance exercise capacity in obese patients with HFpEF.
Emerging experimental approaches include inhibitors of ceramide synthesis, agents targeting the TGF-β pathway, and gene therapy using adeno-associated viruses to deliver AMPK or PPAR activators directly to the heart. The authors conclude that bridging the gap between molecular lipid research and clinical trial design will be paramount in discovering disease-modifying therapies capable of halting or reversing HFpEF progression.