Increased Benefit of Interleukin-1 Inhibition on Vascular Function, Myocardial Deformation, and Twisting in Patients With Coronary Artery Disease and Coexisting Rheumatoid Arthritis

Abstract

Background— We investigated the effects of anakinra, an interleukin-1 receptor antagonist, on coronary and left ventricular function in coronary artery disease (CAD) patients with rheumatoid arthritis. Methods and Results— In a double-blind crossover trial, 80 patients with rheumatoid arthritis (60 with CAD and 20 without) were randomized to a single injection of anakinra or placebo and after 48 hours to the alternative treatment. At baseline and 3 hours after treatment, we assessed (1) flow-mediated dilation of brachial artery; (2) coronary flow reserve, ejection fraction, systemic arterial compliance, and resistance by echocardiography; (3) left ventricular global longitudinal and circumferential strain, peak twisting, untwisting velocity by speckle tracking; and (4) interleukin-1β, nitrotyrosine, malondialdehyde, protein carbonyl, and Fas/Fas ligand levels. At baseline, patients with CAD had 3-fold higher interleukin-1β, protein carbonyl, higher nitrotyrosine, malondialdehyde, and Fas/Fas ligand than non-CAD ( P <0.05). After anakinra, there was a greater improvement of flow-mediated dilation (57±4% versus 47±5%), coronary flow reserve (37±4% versus 29±2%), arterial compliance (20±18% versus 2±17%), resistance (−11±19% versus 9±21%), longitudinal strain (33±5% versus 18±2%), circumferential strain (22±5% versus 13±5%), peak twisting (30±5% versus 12±5%), untwisting velocity (23±5% versus 13±5%), ejection fraction (12±5% versus 0.5±5%), apoptotic and oxidative markers, and, in particular, of protein carbonyl (35±20% versus 14±9%) in CAD than in non-CAD patients ( P <0.01). No changes in the examined markers were observed after placebo. Conclusions— Interleukin-1 inhibition causes a greater improvement in endothelial, coronary aortic function in addition to left ventricular myocardial deformation and twisting in rheumatoid arthritis patients with CAD than in those without. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01566201.

Modulation of Autoimmunity and Atherosclerosis – Common Targets and Promising Translational Approaches Against Disease –

“…59 Anti-IL-1β therapy is under investigation in the CANTOS trial (Canakinumab Anti-inflammatory Thrombosis Outcomes Trial; clinicaltrials.gov: NCT01327846), which is determining whether IL-1β inhibition can reduce CV events and death among stable patients with CAD who remain at high risk, despite current secondary prevention strategies. 60 At the 4-month follow-up, IL-1β blockade showed promising results; it significantly reduced inflammation (decreasing plasma levels of IL-6, CRP, and fibrinogen) without having significant effects on plasma lipid levels.…”

Mechanistic Insights Into the Link Between Inflammation and Cardiovascular Disease

“…Despite the limitations of this study, we think that Ikonomidis et al 12 provide additional mechanistic insight into the relationship between inflammation and cardiovascular risk. Similar to their previous work, they demonstrated that reducing inflammation with an IL-1 inhibitor results in significant short-term improvements in vasomotor and LV function.…”

“…In this issue of Circulation: Cardiovascular Imaging, Ikonomidis et al 12 study the association between short-term IL-1 inhibition on cardiac and vascular function, as well as markers of oxidative stress and apoptosis. They conducted a randomized, double-blind crossover trial of 80 patients with RA: 60 with pre-existing coronary artery disease (CAD) and 20 without known CAD.…”

“How many times must a man look up before he can really see the sky?” Rheumatic cardiovascular disease in the era of multimodality imaging

“…Recently, it was demonstrated that interleukin-1 inhibition contributes to a greater amelioration in endothelial, coronary and aortic function in addition to left ventricular myocardial deformation and twisting in RA patients with CAD than in those without [28] . Additionally, global longitudinal LV/RV strain was reduced in RA patients compared with controls and strain abnormalities were correlated with RA disease severity [29] . Furthermore, 3D-speckle tracking is a new method to detect early abnormalities in SLE patients with normal LV systolic function assessed by 2D echocardiography [30] .…”