SEP-10: COMPLEMENT ALTERS CARDIAC FUNCTION DURING SEPSIS.

INTRODUCTION: In sepsis myocardial dysfunction is correlated with high mortality rates. Damage associated molecular patterns are released from cells during sepsis. Furthermore, the complement activation product C5a resulted in murine cardiomyocyte in defective contractility and relaxation, suggesting that interaction of C5a with its receptors is involved in the development of septic cardiomyopathy. We hypothesized that during sepsis interaction of C5a with its receptors contribute to cardiac dysfunction.

METHODS: Sepsis was induced by cecal ligation and puncture (CLP) procedure. The isolation of adult rat or mouse cardiomyocytes was performed using a Langendorff perfusion system. Intracellular calcium ([Ca2+]i) and reactive oxygen species (ROS) were measured by flow cytometry using cell permeable dyes. Cardiac hemodynamic function in mice was determined with echocardiograms.

RESULTS: Absence of C5a receptors resulted in a significant decrease in plasma histone levels during sepsis, indicating a linkage between complement and histone appearance. In isolated rodent cardiomyocytes presence of C5a or histones resulted in time- and dose-dependent increases in [Ca2+]i and ROS. After infusion of FITC-labeled histones intravenously in wild type mice heart homogenates contained histones. Echocardiographic parameters showed improved cardiac function after CLP in absence of C5a receptors or in presence of histone neutralizing antibody.

CONCLUSION: The current studies indicate that addition of C5a or extracellular histones to CMs are associated with buildup of [Ca2+]i and ROS. Cardiac dysfunction during sepsis was correlated with presence of both C5a receptors and extracellular histones. Collectively, these alterations may explain at least in part, the cardiomyopathy in sepsis.