The Texas Heart Institute

Cellular Basis of HFpEF: Abnormal Lipids and the Emerging Role of Electronegative VLDL (V5)

- Heart failure with preserved ejection fraction (HFpEF) 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. - Modern agents such as SGLT2 inhibitors and GLP-1 receptor agonists show benefit by reducing lipotoxicity and systemic metabolic dysfunction, whereas statins have not demonstrated targeted HFpEF benefit.