The Roles Of Interleukin (il)-18 And Macrophage Migration Inhibitory Factor (MIF) In Atrial Fibrillation

Background: The association between atrial fibrillation (AF) and inflammation is suggested by several studies and many inflammatory biomarkers are elevated in patients with AF. Interleukin (IL)-18 and macrophage migration inhibitory factor (MIF) are known as key mediator of the vascular immune response, which are associated with increased cardiovascular risk. Since their expression and role in AF are still unknown, we investigated whether IL-18 and MIF were involved in AF.Methods: In this study, forty patients with rheumatic heart disease undergoing mitral valve replacement were involved. They were divided into AF group (24 cases) and sinus rhythm group (SR group, 16 cases) according to with AF or not. Preoperative fasting peripheral venous blood was collected to determine plasma levels of IL-18 and MIF. Right atrial appendage tissue was obtained during surgery and routine HE staining was performed to examine pathological changes in myocardium. Western blot and immunohistochemical techniques were used to examine the expression of IL-18 and MIF in myocardium; Expression of IL-18 mRNA and MIF mRNA in myocardium were examined by RT-PCR.Results: Result of HE staining indicated that a large number of monocytes and macrophages were accumulated in myocardial tissue of AF patients, but little or no accumulation was found in SR patients. Significant interstitial fibrosis was found in both groups. Myocardial hypertrophy and disarrangement were found in AF group. Contrasted to SR group, Both IL-18 and MIF protein levels were up-regulated in the atrial appendage myocardium in AF group (0.47±0.01 vs. 0.28±0.01, P < 0.01;0.34±0.01 vs. 0.17±0.01, P < 0.01). IL-18 and MIF protein were localized mainly in myocardial cytoplasm and interstitium. Results of RT-PCR revealed that both IL-18 and MIF mRNA levels were up-regulated in AF group contrasted to SR group (0.92±0.04 vs. 0.6±0.02, P<0.01; 0.94±0.03 vs. 0.56±0.02, P<0.01). Results of ELISA indicated that plasma level of IL-18 was significantly elevated in AF group contrasted to SR group (1023.33±142.48 vs. 776.24±80.72, pg/ml, P<0.01). So was MIF (26.94±6.45 vs. 18.10±2.77, ng/ml, P<0.01). This study also found that in the AF group, IL-18 and MIF expression levels were positively correlated with AF duration.Conclusions: This is the first study to show the elevated IL-18 and MIF levels both in atrial appendage myocardium and in plasma in AF patients. Our results indicated that IL-18 and MIF were involved in the pathogenesis and maintenance of atrial fibrillation. Being key regulatory factors in inflammatory reaction, IL-18 and MIF may become new biological markers of atrial fibrillation. Investigation of IL-18 and MIF may provide new ideas for atrial fibrillation treatment in the future.