Abstract 12371: Genetic Deletion of Cystathionine Gamma Lyase in Endothelial Cells Exacerbates Cardiovascular Dysfunction in Heart Failure With Preserved Ejection Fraction

Abstract

Background: Endothelial dysfunction has been suggested as a central pathophysiological mechanism in heart failure with preserved ejection fraction (HFpEF). We reported that Cystathionine Gamma Lyase (CSE), one of the 3 hydrogen sulfide producing enzymes, expressed in endothelial cells is critical for maintaining normal endothelial function and protecting against myocardial ischemia/reperfusion injury. However, the role of endothelial CSE in HFpEF remains unknown. Method: Endothelial specific CSE knockout mice (EC-CSE KO, n=15) and CSE flox/flox control animals (n=6) were fed a high-fat diet (60% kcal from fat) and administered L-NAME (0.5 g/L in drinking water) for 18 weeks to induce HFpEF. Body weight and cardiac function (echocardiography and doppler imaging) were monitored every 4 weeks. Invasive left ventricular hemodynamic procedures were performed and vascular reactivity was measured in isolated thoracic aorta at 18 weeks. Results: Baseline body weight, ejection fraction (EF), the ratios of E/A and E/E’ were not different between EC-CSE KO and controls. At 12 & 16 weeks following HFD and L-NAME, E/E’ ratios were significantly higher in EC-CSE KO compared to controls (p < 0.05), with normal EF in both groups. At 18 weeks of HFpEF, a 33.3% of mortality was observed in the EC-CSE KO group while no mortality was shown in control. In addition, left ventricular end-diastolic pressure (LVEDP) was higher (p < 0.01) and aortic vasorelaxation maximal response to acetylcholine was lower (p < 0.01) in EC-CSE KO compared to controls. Conclusion: Genetic deletion of CSE in vascular endothelial cells exacerbates cardiac diastolic dysfunction, promotes vascular dysfunction, and increases mortality in HFpEF. Studies are currently underway to define the protective role of endothelial CSE in HFpEF.