Abstract 11856: Characterization of Endothelial Adipose Triglyceride Lipase in a Preclinical Model of Heart Failure With Preserved Ejection Fraction

Abstract

Background: Metabolic syndrome and endothelial dysfunction are identified as key drivers of Heart Failure with preserved Ejection Fraction. Endothelial cells have an important barrier function including the control of lipid transport from the coronary circulation to the myocardium. In order to determine the role of EC lipid metabolism in HFpEF, we generated mice with an EC-specific deletion of adipose triglyceride lipase and subjected these mice to a hypertensive-obese two-hit HFpEF model. Methods and Results: Cell culture experiments were performed in HUVECS with a pharmacological ATGL inhibitor NG-497. In vitro experiments showed significant reduction of lipolysis by NG-497 and marked endothelial lipid droplet accumulation. Inducible endothelial cell-specific ATGL knockout mice were generated by crossbreeding Atgl fl/fl mice with Cdh5(PAC)-CreERT2 mice. Animals were randomized in a HFpEF or control group. HFpEF mice received a high fat diet and L-NAME for 15 weeks, while animals in the control group were put on a low fat diet and water. To analyse cardiac function, conventional and speckle-tracking echocardiography were performed. After 15 weeks, cre - littermates (wt) with HFpEF developed obesity and hypertension (body weight: wt-Ctrl: 33.8±2.5g vs. wt-HFpEF: 45.1±4.4g, p=0.0001; systolic blood pressure: wt-Ctrl: 99.9±3.7mmHg vs. wt-HFpEF: 135.5±5.6mmHg, p=0.0001), which did not significantly differ in ecATGL-KO mice. In parallel, wt-HFpEF mice developed echocardiographic signs of HFpEF including diastolic dysfunction: E/é: (wt-Ctrl: -22.1±1.4 vs. wt-HFpEF: -45.5±3.8; p<0.0001), IVRT: (wt-Ctrl: 17.8±0.7ms vs. wt-HFpEF: 19.5±0.8ms; p= p<0.0001), and an impaired global longitudinal strain (GLS) (wt-Ctrl: -20.7±1.1% vs. wt-HFpEF 12.9±0.7%; p<0.0001). Parameters of diastolic dysfunction were significantly improved in ecATGLKO mice after 15weeks of HFD/ L-NAME: E/é:-29.3±2.8; p<0.0001 vs. wt-HFpEF; IVRT: 18.3±0.5; p<0.05 vs. wt-HFpEF; GLS: -19.1±1.7; p<0.0001 vs. wt-HFpEF). Conclusion: This study demonstrates that loss of ATGL in ECs may protect from HFpEF. We hypothesize that lipid droplet accumulation in coronary ATGL-deficient ECs may save the myocardium from lipid overload and lipotoxicity, as shown in Cre- HFpEF mice.