Enhanced monocyte chemoattractant protein-1 production in aging mice exaggerates cardiac depression during endotoxemia

Abstract

Introduction: Endotoxemia and the systemic inflammatory response syndrome have a significant impact on post-surgery outcome, particularly in the elderly. The cytokine response to endotoxin is altered by aging. We tested the hypothesis that vulnerability to endotoxemic cardiac depression increases with aging due to age-related augmentation of myocardial inflammatory responses.Methods: Adult (4 to 6 months) and old (20 to 22 months) C57/BL6 mice were treated with endotoxin (0.5 mg/kg, iv). Left ventricle (LV) function was assessed using a microcatheter system. Chemokines and cytokines in plasma and myocardium were analyzed by enzyme-linked immunosorbent assay (ELISA). Mononuclear cells in the myocardium were examined using immunofluorescence staining.Results: Old mice displayed worse LV function (cardiac output: 3.0 ± 0.2 mL/min versus 4.4 ± 0.3 mL/min in adult mice) following endotoxin treatment. The exaggerated cardiac depression in old mice was associated with higher levels of monocyte chemoattractant protein-1 (MCP-1) and keratinocyte chemoattractant (KC) in plasma and myocardium, greater myocardial accumulation of mononuclear cells, and greater levels of tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6) in plasma and myocardium. Neutralization of MCP-1 resulted in greater reductions in myocardial mononuclear cell accumulation and cytokine production, and greater improvement in LV function in old mice while neutralization of KC had a minimal effect on LV function.Conclusion: Old mice have enhanced inflammatory responses to endotoxemia that lead to exaggerated cardiac functional depression. MCP-1 promotes myocardial mononuclear cell accumulation and cardiodepressant cytokines production, and plays an important role in the endotoxemic cardiomyopathy in old mice. The findings suggest that special attention is needed to protect the heart in the elderly with endotoxemia.