Circulating soluble LOX-1 and patient prognosis after an acute coronary syndrome

Background The lectin-like oxidised low-density lipoprotein receptor-1 (LOX-1) mediates atherosclerotic plaque inflammation and vulnerability. On activation, LOX-1 sheds its extracellular domain into the circulation as soluble LOX-1 (sLOX-1). sLOX-1 is markedly elevated in patients with acute coronary syndrome (ACS). Methods We prospectively assessed the associations between plasma sLOX-1 and the development of heart failure (HF), major adverse cardiovascular events (MACE) and coronary and left ventricular (LV) dysfunction in two cohorts of patients with ACS. The first cohort comprised 524 patients recruited during the acute index event at the coronary care unit of Skåne University Hospital, Malmö, Sweden. The second cohort included 363 patients with ACS treated with acute percutaneous intervention at Sahlgrenska University Hospital, Gothenburg, Sweden. Additionally, we examined the anti-inflammatory effects of LOX-1 blockade in vitro using human umbilical vein endothelial cells (HUVECs). Results In the first cohort, acute-phase sLOX-1 was associated with incident HF and MACE independently of cardiovascular risk factors, revascularisation and medication (HR per 1-SD sLOX-1 increase: 1.57 (95% CI: 1.10 to 2.23; p=0.012) for HF and 1.36 (1.08 to 1.71; p=0.009) for MACE). Elevated sLOX-1 was also associated with lower LV ejection fraction and accelerated remodelling, as measured by echocardiography at 1-year post-ACS. In the second cohort, sLOX-1 was negatively associated with left anterior descending coronary artery flow reserve and LV systolic function, and positively correlated with soluble markers of systemic inflammation and cardiac overload at 4 and 16 weeks post-ACS. In vitro, antibody-mediated LOX-1 blockade prevented oxidised low-density lipoprotein-induced HUVEC activation. Conclusions Elevated plasma sLOX-1 at baseline and during follow-up is associated with incident HF and MACE, as well as cardiac and coronary dysfunction in patients with ACS. As plasma sLOX-1 levels may reflect the intensity of LOX-1 expression on vascular and immune cells, these findings support LOX-1 as a potentially important therapeutic target to improve prognosis in patients with ACS.