Coronary Artery Disease Clinical Trial
Official title:
The Effect of Inhibition of Interleukin-1 Activity on Vascular and Left Ventricular Function in Patients With Coronary Artery Disease and Coexistent Rheumatoid Arthritis
Inhibition of interleukin-1 (IL-1) activity in patients with RA without CAD ameliorates vascular and LV function. Moreover, data from species shows beneficial effect of this treatment on LV function after experimental myocardial infarction. The purpose of this study is to investigate whether anakinra, an IL-1 receptor antagonist, improves vascular and left ventricular (LV) function in patients with coronary artery disease (CAD) and coexistent rheumatoid arthritis (RA).
The inflammatory processes observed in patients with rheumatoid arthritis (RA) are strongly
linked to enhanced interleukin-1 (IL-1) activity. Increased IL-1 activity causes myocardial
cell damage and endothelial dysfunction. The adverse effects of IL-1 on myocardial and
endothelial cells are mediated by an enhanced nitrooxidative stress and the promotion of
apoptotic cardiomyocyte death through increased nitrooxidative stress and inflammation.
Anakinra, a recombinant form of human IL-1 receptor antagonist, is commonly used for the
treatment of RA. Experimental data indicates that administration of anakinra after acute
myocardial infarction ameliorates cardiac remodeling by reducing cardiomyocyte apoptosis.
Moreover, in our previous studies we have shown that treatment with anakinra reduces
IL-1-mediated nitrooxidative stress and apoptotic markers leading to an improvement in
Tissue Doppler and speckle tracking-derived parameters of left ventricular (LV) function in
RA patients. However it has not been defined whether inhibition of IL-1 activity by anakinra
shows beneficial effects on endothelial, coronary, arterial and LV systolic and diastolic
function in patients with coronary artery disease (CAD).
For this purpose, we studied 60 patients with CAD and coexistent RA (American Rheumatism
Association criteria) as well as 20 patients with RA and without CAD. All the above subjects
had an inadequate response to disease modifying antirheumatic drugs (DMARDs) and
corticosteroids and were going to initiate treatment with IL-1 activity inhibitor
(anakinra). All patients were on treatment with statins and cardioactive medications
respectively, for the last 6 months. In the 20 patients with only RA, the presence of CAD
was excluded with a non-invasive test and/or a negative recent coronary arteriogram.
In a double-blind, placebo-controlled fashion, all patients were randomized to receive a
single injection of anakinra(100 mg s.c.) or placebo. After 48-hours patients were crossed
over to the alternate treatment (placebo or anakinra) and measurement of the examined
markers was repeated. The 48h interval between the 2 consecutive studies was decided to
secure a sufficient wash-out period of anakinra in accordance to the drug's half-life time.
Twenty asymptomatic subjects matched for age and sex as the RA patients and with a normal
ECG, echocardiogram, and treadmill test were selected as healthy control subjects among
subjects attending the cardiology outpatients' clinic.
At baseline in all RA subjects and controls as well as 3-hours after the single injection of
anakinra in RA subjects, we assessed by means of echocardiography the following parameters
a) the LV dimensions,fractional shortening and wall motion score index (WMSI) b) the
systolic (Sm), early diastolic (Em) and late diastolic (Am) myocardial velocities of the
mitral annulus by using of tissue Doppler (TDI) as well as the ratio of E wave of the mitral
inflow measured by pulsed wave Doppler to the mean Em as an index of LV diastolic filling
pressures c) the LV longitudinal, circumferential and radial strain and strain rate, as well
as Global Longitudinal strain and Torsion using speckle tracking echocardiography d) the
coronary flow reserve (CFR)after adenosine infusion to assess coronary vasomotor function e)
the flow-mediated endothelial-dependent dilation of the brachial artery (FMD) to assess
peripheral endothelial function f) the diameters of aorta at systole and diastole to
calculate the aortic strain as an index of local aortic properties. At the same time
periods, we measured in blood samples a) nitrotyrosine (NT), protein carbonyls (PC)and
malondialdehyde(MDA)to assess nitrooxidative stress b)soluble Fas and Fas-ligand )to assess
apoptosis c) interleukin-1b and tumor necrosis factor-a to assess inflammation
;
Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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