Association of LpPLA2 activity with coronary and LV function in patients with coronary artery disease and coexistent rheumatoid arthritis: effects of Interleukin-1 inhibition

Abstract

Lipoprotein-associated phospholipase A2 activity (LpPLA2) and Interleukin-1 are linked with atherogenesis. Anakinra, an interleukin-1a receptor antagonist, is used for the treatment of rheumatoid arthritis (RA). We investigated a)the association of LpPLA2 activity with oxidatve stress, left ventricular (LV) and coronary function and b)the effects of anakinra on LpPLA2 activity in CAD patients with coexistent RA. Methods: Forty patients with CAD and RA were randomized to receive a single injection of anakinra (100mg s.c.) or placebo and after 48 hours the alternative treatment in a double-blind trial. At baseline and 3 hours post-treatment we assessed a) nitrotyrosine (NT), malondialdehyde (MDA) and protein carbonyls (PC) serum levels b) total plasma Lp-PLA2 activity, HDL-LpPLA2 activity and HDL-LpPLA2/LpPLA2 c) coronary flow reserve (CFR), wall motion score index (WMSI), LV Longitudinal and circumferential strain (LongS, CircS), early diastolic (E') mitral annulus velocity and E/E'(indicating LV filling pressures) by echocardiography. Results: At baseline, there was a relation of HDL-LpPLA2 with NT (r=0.359, p=0.07) and PC (r=-0.373, p=0.06). HDL-LpPLA2 was related to increased E/E' (r=0.389) reduced LongS (r=0.488), CircS (r=0.504) and increased WMSI (r=0.438). HDL-LpPLA2/LpPLA2 was related with increased E/E' (r=0.463), decreased CFR (r=-0.350) decreased LongS (r=0.440) and increased WMSI (r=0.412) (p<0.05). Post-anakinra treatment, there was a) a decrease of NT (median 6.66 vs. 6.10 nM/L), PC (0.131 vs. 0.091 nmol/mg protein) and MDA (1.43 vs. 1.30 pg/ml) b) a bordeline increase of total Lp-PLA2 activity, (58.4 vs. 59.2, nmol/min/ml) and decrease of HDL-Lp-PLA2 activity (4.5 vs 4.3 nmol/min/ml) and HDL-LpPLA2/LpPLA2 (0.077 vs 0.067) c)decrease of WMSI (1.2 vs. 1.0) and increase of LongS (-16 vs. -19%), CircS (-15 vs.-18%) and CFR (2.1 vs. 2.8) (p<0.05). No significant changes were observed after placebo. The % changes of a) total LpPLA2 activity were related with the respective change of MDA (r=-0.495), b) HDL-LpPLA2 with the respective change of PC and MDA (r=-0.467 and r=0.639) c)HDL-LpPLA2/LpPLA2 with the respective change of PC and MDA (r=-0.438 and r=0.670) (p<0.05).The % change of LpPLA2 was related to respective change of CircS (r=0.430) and of HDL-LpPLA2 and HDL-LpPLA2/LpPLA2 with the respective change of CFR (r=0.478 and r=0.430) (p<0.05 for all associations). Conclusion: HDL-LpPLA2 is related with oxidative stress, abnormal LV deformation and CFR.IL-1 inhibition causes a secondary decrease in HDL-LpPLA2 activity probably through reduction an excessively high nitrooxidative stress