Severe hyperchylomicronemia sensitizes the heart to pathological remodeling: evidence from GPIHBP1-deficient mice

Aim Circulating triglyceride and triglyceride-rich lipoprotein (TRL) accumulation is increasingly recognized as a residual atherosclerotic risk, but their specific effects on cardiac remodeling and heart failure (HF) remain largely unexplored. Here, this issue was investigated in Gpihbp1 knockout (KO) mice, which develop severe hyperchylomicronemia due to disruption of intravascular TRL hydrolysis. Methods Cardiac lipid metabolism and remodeling were evaluated in 10-month-old Gpihbp1 KO mice and their wild-type littermates under physiological conditions. Mice were also subjected to transverse aortic constriction (TAC) to evaluate the effects of severe hyperchylomicronemia on pressure overload-induced remodeling and HF. Furthermore, Gpihbp1 KO mice were crossed into an low-density lipoprotein receptor ( Ldlr) KO background to study the effects of severe hyperchylomicronemia on hemorheology and high-fat diet (HFD)-induced cardiac pathology. Results Untargeted cardiac lipidomics revealed 214 differentially regulated lipid species that were specifically enriched in glycerophospholipid, fatty acid (FA) and diacylglycerol subclasses. Quantitative real-time PCR (qPCR) confirmed that FA oxidation-related genes were downregulated and that glucose utilization-related genes were upregulated. Electron microscopy revealed swollen mitochondria with fragmented cristae, and RNA-seq revealed reduced respiratory chain gene expression. These abnormalities resulted in impaired cardiac contractile performance in 10-month-old G pihbp1 KO mice without the induction of hypertrophy or fibrosis. After TAC, Gpihbp1 KO hearts exhibited exaggerated diastolic dysfunction and more severe myocyte hypertrophy and fibrosis. In Gpihbp1/Ldlr double-knockout (dKO) mice, reduced erythrocyte deformability and increased whole blood viscosity were observed and worsened post-HFD. Additionally, HFD consumption resulted in significant diastolic impairment, cardiac hypertrophy and fibrosis in dKO mice. Conclusion Severe hyperchylomicronemia due to Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) deficiency sensitizes the heart to pathological remodeling and HF. These findings indicate a potential pathogenic contribution of hypertriglyceridemia and TRL accumulation to cardiac disease.