Abstract 16760: HDL Modulates Cardiac Glucose Metabolism And Inflammation And Improves Cardiac Function After Myocardial Ischemia Reperfusion Injury
Objective: High-density lipoprotein (HDL) has multiple actions which may benefit post-ischemic heart function. We examined the effects of reconstituted HDL (rHDL, CSL-111), delivered immediately following myocardial ischemia, on myocardial glucose uptake and leukocyte recruitment in control (chow) and insulin resistant (high fat diet-HFD) mice.
Methods: A single intravenous bolus of rHDL (80mg/kg of human apoA-I) was delivered at the time of reperfusion following a 30min left anterior descending coronary artery occlusion in both control and HFD mice. Signalling mechanisms were further investigated in primary neonatal rat ventricular cardiomyocytes.
Results: rHDL increased the volume of viable myocardium assessed by [18F]-fluorodeoxyglucose uptake with PET/CT imaging in both chow and HFD mice (mean±SEM; 54±31% and 61±35% vs saline respectively; p<0.05). Three days post-surgery, rHDL also reduced recruitment of leukocytes into the heart in both diet groups, including monocytes, neutrophils, T and B cells (p<0.05). Furthermore, we found more human apoA-1 in left ventricles of mice subjected to ischemia reperfusion versus sham operated mice (p=0.004), consistent with a role for rHDL in direct modulation of the acute post-ischemic responses. At 2 weeks post-surgery, rHDL increased cardiac output in both chow and HFD mice by 11±2% (mean±SEM) and 23±2% respectively compared to saline (p=0.03). rHDL treatment also reduced infarct size by 26±2% in chow mice and by 21±2% in HFD mice (p=0.01), demonstrating that rHDL improves post-ischemic heart function in healthy and insulin resistant mice.
In neonatal rat ventricular cardiomyocytes, HDL treatment (50μg/mL) increased glucose uptake by 47±10%, glycolysis by 54±11% and glucose oxidation rate by 30±6% (all p<0.05). HDL modulated cardiomyocyte glucose metabolism via an Akt-dependent mechanism, which also required the sphingosine-1-phosphate type 3 receptor.
Conclusion: HDL activates cardiac glucose metabolism and increases the volume of viable myocardium after ischemia and reperfusion. The subsequent reduction in myocardial inflammation and injury with improved cardiac function suggests that HDL-targeted therapies may have additional applications related to these novel actions of HDL.
Author Disclosures: A. Richart: None. S.E. Heywood: None. D.C. Henstridge: None. K. Alt: None. H. Kiriazis: None. A.L. Carey: None. H. Kammoun: None. H. Begum: None. L.M. Delbridge: None. P.J. Meikle: None. C.E. Hagemeyer: None. M.A. Febbraio: None. X. Du: None. A.L. Siebel: None. B.A. Kingwell: None.
- © 2016 by American Heart Association, Inc.