Abstract 17001: Reconstituted High-density Lipoprotein (CSL-111) Infusion Improves Post-ischemic Heart Function Through Modulating the Acute Inflammatory Response and Angiogenesis

Aims: High-density lipoprotein (HDL) has multiple actions which may benefit post-ischemic heart function. We have shown in patients with type 2 diabetes that a single infusion of reconstituted HDL (rHDL, CSL-111) reduces inflammation1 including the number of circulating monocytes, neutrophils and lymphocytes. Whether such effects may contribute to improved heart function after ischemia and reperfusion is unknown. This study aimed to determine the effect of HDL on post-ischemic inflammatory response and heart function in insulin resistant mice. Methods and Results: A left coronary artery ligation model was used to study acute ischemia (30min) and reperfusion (I/R) in mice fed a chow (CD) or high fat diet (HFD) for 8 weeks. A single intravenous bolus of rHDL (CSL-111; 80mg/kg) or placebo (saline) was delivered at the time of reperfusion. At 15 days post I/R, rHDL increased ejection fraction from 40±3% to 48±2% in both diet groups (p=0.004). rHDL also increased stroke volume (p=0.002) and cardiac output in both diet groups (p=0.015). Histological analysis revealed that rHDL increased the myocardial capillary density by 22±4% and 15±4% in CD and HFD mice respectively (p=0.0007; p=0.042). However, rHDL did not alter cardiomyocyte hypertrophy. Interestingly, rHDL infusion modulated acute post-ischemic inflammatory response by decreasing the total number of circulating leucocytes (p=0.030) and neutrophils (p=0.005) in both diet groups 1 day following I/R. However, rHDL reduced the number of circulating monocytes (p=0.044) and B lymphocytes (p=0.009) only in HFD mice. In both diet groups, at 3 days post-I/R, rHDL reduced recruitment of leukocytes into the heart including monocytes (p=0.038, p=0.014), neutrophils (p=0.005, P=0.020), T lymphocytes (p=0.044, p=0.018) and B lymphocytes (p=0.043, p=0.010). Moreover, rHDL decreased the proportion of B lymphocytes recruited into the heart in HFD mice only (p=0.040), highlighting its strong anti-inflammatory effect particularly in the insulin-resistant state. Conclusion: A single infusion of rHDL at time of reperfusion improves post-ischemic heart function through modulation of angiogenesis and acute inflammatory response in insulin-resistant mice.