Abstract 14871: APD588, a Novel, Selective S1P Receptor Modulator, Regulates Inflammatory Responses and Attenuates Cardiac Dysfunction Following Experimental Myocardial Infarction in Mice

Abstract

Recent studies have determined that chronic inflammation contributes to left ventricular (LV) remodeling following myocardial infarction (MI) leading to heart failure (HF). Evidence points to a critical role of T lymphocytes in driving the maladaptive inflammatory process associated with adverse tissue remodeling and cardiac dysfunction. FTY720, a non-selective sphingosine 1-phosphate (S1P) receptor modulator, elicits anti-inflammatory effects via inhibition of lymphocyte egress from secondary lymphoid organs and has been reported to improve cardiac remodeling and function post-MI. We hypothesized that APD588, a next-generation S1P receptor modulator with optimized S1P 1,5 receptor selectivity, would prevent cardiac remodeling and dysfunction following MI through modulation of T lymphocyte-mediated inflammatory responses. Efficacy of APD588 on cardiac function was assessed using C57BL/6N mice (n=7-10 mice/group) with experimental MI induced by coronary artery occlusion. Vehicle (VEH) or APD588 (0.3 mg/kg) was administered orally once daily starting at Day 3 post-MI and continued until Day 28. Blood samples were collected at Days 7 and 28 for lymphocyte count. Echocardiographic measurements, including LV ejection fraction (LVEF), were performed on Days 7, 14, and 28 post-MI. Administration of APD588 following MI resulted in a reduction of lymphocyte count at Days 7 and 28 post-MI, but only reached significance in the latter (VEH: 3.3 ± 0.5 x10 3 /μL; APD588: 1.3 ± 0.2 x10 3 /μL). Decreased cardiac function was observed at Day 7 post-MI (LVEF: 27.7 ± 3.6%, MI vs 45.7 ± 0.6%, Sham). No difference in LVEF was observed 7 days post-MI, however APD588 significantly improved LVEF at Day 28 post-MI, compared to vehicle (APD588: 35.7 ± 3.9%; VEH: 25.3 ± 3.9%). Therapies targeting inflammation in the pathophysiology of HF have shown limited success in the clinic. Novel strategies based on advancements in understanding the underlying immunobiology are warranted. Our results demonstrate that APD588 was effective at regulating lymphocyte activity and improved cardiac functional recovery following MI in mice. This supports the potential of S1P receptor modulation and other T lymphocyte-directed strategies as a targeted anti-inflammatory approach in HF.