خصومت، خشم، افسردگی و پیش بینی افزایش C3 در طی یک دوره 10 ساله

We examined the relation of hostility, anger, and depression to 10-year changes in the third (C3), and fourth (C4) complement in 313, apparently healthy male participants enrolled in the Air Force Health Study (AFHS), a 20-year study designed to evaluate the health consequences of dioxin exposure. Hostility, depression, and anger were assessed using subscales from the Minnesota Multiphasic Personality Inventory (MMPI), which was administered in 1985. Given the high intercorrelations among these psychological scales, we used a principal component analysis to generate a composite score representing the linear combination of the hostility, anger, and depression scales. The dependent variables, C3 and C4 levels, were determined from samples collected in 1992, 1997, and 2002. Regression analyses controlling for age, race, alcohol use, body mass index, and cigarette use as well as onset of disease, and use of lipid lowering and blood pressure medications during follow-up revealed a significant time × composite score interaction for C3 complement (p < .0003), but not C4. Post-hoc analyses revealed that high composite scores were associated with larger 10-year increases in C3. These observations suggest that men who are hostile and are prone to experience frequent and intense feelings of anger, and depression show activation of the complement system, and specifically increases in C3, that may contribute to the development of coronary heart disease.

Epidemiological evidence continues to support the psychosomatic hypothesis that hostility, anger, and depression are associated with an increased risk of atherosclerotic cardiovascular disease (ACVD) (e.g., Ahmad, 2000 and Ferketich et al., 2000), Type 2 diabetes (T2D) (Arroyo et al., 2004), and essential hypertension (EH) (Everson et al., 1998). Although the mechanisms accounting for those associations are not well delineated, one emerging hypothesis posits that psychological attributes contributes to adverse health via inflammation (Black, 2003). Support for this hypothesis comes from a number of cross-sectional studies that have reported significant associations between biomarkers of inflammation, such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP), and anger (Suarez, 2004), hostility (Graham et al., 2006 and Suarez, 2003a), and depression (e.g., Miller et al., 2002 and Suarez et al., 2003), as well as to a composite score representing the linear combination of those variables (Suarez, 2003b and Suarez, 2004). While compelling, the cross-sectional nature of those prior observations limits any conclusions regarding prospective associations. If inflammation is an important pathophysiological mechanism whereby psychological attributes contribute to the development and progression of chronic diseases, it is critical to demonstrate that individuals characterized by high levels of hostility, anger, and depression exhibit increasing or elevated levels of inflammatory biomarkers over time. One aspect of the immune system that has been associated with ACVD and T2D is the complement system. While there are a number of components to the immune complement system (Ritchie et al., 2004), studies investigating its role in the development of chronic diseases have focused on the major protein C3, and to a lesser extent, C4. The emphasis placed on C3 is due, in part, to its production by activated macrophages and its role as a cytokine (Zimmer et al., 1982), and its control of lipid and glucose metabolism (Baldo et al., 1993), pathways leading to cardiovascular disease and diabetes. C4, on the other hand, has been linked with obesity and glucose metabolism (Engstrom et al., 2005). Cross-sectional studies have shown that C3 is associated not only with risk factors of CHD (Onat et al., 2005) and diabetes (Engstrom et al., 2005), but also with the presence and severity of CAD (Figueredo et al., 1993 and Ylitalo et al., 1997), and ischemic stroke (Di Napoli et al., 2001). In one prospective study, C3, but not C4, was associated with incident T2D (Engstrom et al., 2005). C3 has also been associated with incident myocardial infarction (Muscari et al., 1995) and incident atrial fibrillation (Dernellis and Panaretou, 2006). Only a few studies have examined the relation of psychological attributes and/or psychological stress to activation of the complement system. Elevations in C3 and C4 have been noted in depressed patients in some (Berk et al., 1997, Kronfol and House, 1989 and Song et al., 1994), but not all (Spivak et al., 1989) studies. Other studies have shown that the stress of academic examination evokes increases in C3c, but only among those students who perceived the examination as stressful, whereas C4 showed a significant reduction in students with low-stress perception (Maes et al., 1997). Although few in number, the findings of the previous studies suggest that psychological attributes, and emotional stress are associated with activation of the complement system. To date, no study has examined the relation of the complement system to anger and hostility or has examined these potential associations over time. The aim of the present study, therefore, was to examine the relation of psychological risk factors to changes in serum levels of C3 and C4 over a 10-year period. In light of our previous cross-sectional observations (Suarez, 2004), we hypothesized that the linear combination of hostility, anger, and depression would be similarly associated with elevations in C3 and C4 levels, and with greater changes in these proteins over time.1

The results of the current study fill a critical gap in the existing literature with respect to the longitudinal association between inflammatory biomarkers and psychological factors. In so doing, we showed positive associations between psychological attributes and 10-year changes in C3 among initially healthy middle-aged males. These data add to the growing body of evidence supporting the hypothesis that inflammation is an important mediator in the relation of psychosocial factors to chronic medical conditions such as CHD, Type 2 diabetes and essential hypertension.