Cellular basis of HFpEF: contributions of abnormal lipids

Heart failure with preserved ejection fraction (HFpEF), one of the largest unmet medical needs, is characterized by high morbidity and mortality and a lack of effective treatments. Numerous studies suggest that the potential contribution of dysfunctional metabolism to HFpEF, emphasizing the possible role of lipids, especially lipoproteins, in the disease's initiation and progression. Changes in circulating plasma lipids appear to play a role in mediating the pathophysiological processes that may contribute to the development of HFpEF through an imbalance in the circulating lipid supply, cardiac fat uptake, and fatty acid metabolism. This metabolic mismatch results in the accumulation of harmful lipid intermediates within the myocardium. This process, known as lipotoxicity, contributes to diastolic dysfunction. Furthermore, altered plasma lipid levels can potentiate systemic inflammatory responses, endothelial dysfunction, and myocardial fibrosis. Understanding the impact of lipid metabolism on these underlying mechanisms is emerging as a novel avenue for preventing and treating HFpEF. The intricate relationship between HFpEF and lipid metabolism may involve multifaceted factors, including insulin sensitivity and adipose tissue inflammation. Here, we have comprehensively analysed the evidence-based pathophysiological impact of broader lipid abnormalities [including very low-density lipoprotein (VLDL) and low-density lipoprotein] on HFpEF development. Furthermore, drawing on foundational studies in related metabolic disorders, we propose a novel hypothesis regarding the potential, yet underexplored role of electronegative VLDL (V5), a particularly harmful subfraction of VLDL, as a future therapeutic target in HFpEF.