Myocardial Ischemia Induces Interleukin-6 and Tissue Factor Production in Patients With Coronary Artery Disease

Abstract

Background-Interleukin-6 (IL-6) and macrophage colony stimulating factor plasma levels are elevated in acute coronary syndromes. IL-6 has an inherent negative inotropic action and, with tissue factor (TF), mediates the ischemiareperfusion myocardial injury. We hypothesized that inducible ischemia leads to cytokine production, TF expression, and consequently persistent left ventricular dysfunction after dobutamine stress echocardiography (DSE) in coronary artery disease patients. Methods and Results-DSE was performed in 103 patients with angiographically documented coronary artery disease.Blood samples were obtained at rest, at peak stress, and 30 minutes after cessation of dobutamine infusion for measurement of macrophage colony stimulating factor, IL-6, and TF. New or worsening wall motion abnormalities at peak stress and their duration into recovery were noted. Median IL-6 and TF levels were increased at peak stress and at 30 minutes into recovery compared with rest (2.7 and 2.4 versus 2.1 pg/mL for IL-6, 310 and 385 versus 266 pg/mL for TF [PϽ0.01] in patients with an ischemic response; nϭ55). Compared with rest, a greater release of IL-6 at peak stress and recovery was observed in patients with increasing number of ischemic segments at peak DSE (2 versus 3 to 4 versus 5 to 6 versus 7 to 8 segments; Pϭ0.03). The time to recovery of wall motion abnormalities was also associated with IL-6 levels at peak stress and recovery (rϭ0. 51 and rϭ0.39, PϽ0.05). Macrophage colony stimulating factor levels remained unchanged throughout DSE. Conclusions-Reversible ischemia induced during DSE increases IL-6 and TF plasma levels. IL-6 is related to the extent of left ventricular dysfunction at peak stress and to persistent LV dysfunction during recovery. (Circulation. 2005;112: 3272-3279.)

Inhibition of Interleukin-1 by Anakinra Improves Vascular and Left Ventricular Function in Patients With Rheumatoid Arthritis

“…11,[15][16][17] In the present study, the reduction in IL-6 and nitrotyrosine was related to an acute improvement in LV function after anakinra. This association is in line with studies demonstrating that IL-1ra rapidly inhibits IL-6 production and reduces peroxynitrate 18,34 -37 and that the IL-6 -mediated negative inotropic effect is completely reversed by 40 minutes after removal of this cytokine in vitro.…”

“…Because biomarkers had a nonnormal distribution, data are expressed as median (interquartile range) and were analyzed after transformation into ranks. 17 ANOVA (general linear model, SPSS 13, SPSS Inc, Chicago, Ill) for repeated measurements was applied for the following comparisons: (1) in the acute study, for measurements of the examined markers at baseline, 3 hours after placebo, and 3 hours after anakinra; and (2) in the chronic study, for the effects of anakinra versus prednisolone, with measurements at baseline and 30 days after treatment used as a within-subject factor and type of treatment used as a between-subject factor. The F and P values of the interaction between time of measurement of the examined markers and type of treatment were calculated.…”

“…This association is in line with studies demonstrating that IL-1ra rapidly inhibits IL-6 production and reduces peroxynitrate 18,34 -37 and that the IL-6 -mediated negative inotropic effect is completely reversed by 40 minutes after removal of this cytokine in vitro. 16,17 Additionally, the significant improvement in CFR and aortic function may have contributed to the improvement in LV performance after anakinra.…”

Pharmacogenomics and end-organ susceptibility to injury in the perioperative period

“…The length of ischemia (in the case of cardiac surgery this is tracked as aortic cross-clamp time), is a clinical variable that predicts perioperative myocardial events [3] and therefore must be taken into account as a co-variate in analysis of this endpoint. Both myocardial ischemia and catecholamine-induced stress induce IL-6 and tissue factor (TF) production in patients with coronary artery disease [19], and decrease the PI3-kinase survival pathway [20]. Ischemia inactivates oxidative phosphorylation, leading to loss of adenine nucleotides and cytochrome c, accumulation of free phosphate, fatty acids, lactic acid, increased cellular calcium, and a decrease in cellular pH [21].…”

“…IL6 -572G>C is associated with significantly higher postoperative plasma IL-6 levels [67] and longer hospital stay [68]. IL-6 is also known to induce TF expression in a variety of cells, giving it procoagulant properties [19,34]. ICAM1 1462A>G is a non-conservative SNP encoding Lys469Glu, located in an immunodominant epitope involved in integrin-mediated B-cell adhesion and neutrophil transmigration; it has been associated with a variety of proinflammatory phenotypes such as transplant rejection, vasculopathy, vascular restenosis, multiple sclerosis, and asthma [82,83].…”