Toll-like receptor 2 plays a critical role in cardiac dysfunction during polymicrobial sepsis*

Abstract

Objective: To determine the role of toll-like receptor 2 in cardiac dysfunction during polymicrobial sepsis. Design: Controlled animal study. Setting: University hospital research laboratory. Subjects: Male C57BL/6, wild-type, toll-like receptor 2^−/−. Intervention: Polymicrobial peritonitis, a clinically relevant model of sepsis, was generated by cecum ligation and puncture. Wild-type and toll-like receptor 2^−/− mice were divided into sham and cecum ligation and puncture groups. The sham animals underwent laparotomy but without cecum ligation and puncture. Twenty-four hours after surgeries, the cardiac function was assessed by serial echocardiography in vivo, a pressure transducer catheter was inserted into the left ventricles of isolated hearts (Langendorff model), and in vitro measurement of Ca²⁺ transients and sarcomere shortening in adult cardiomyocytes were isolated from the sham and septic animals. In addition, myocardial and serum cytokines, blood white blood cell counts, peritoneal neutrophil recruitment, chemokine receptor expression, and survival rates were examined. Measurements and Results: Compared to septic wild-type mice, toll-like receptor 2^−/− mice had markedly improved cardiac function during sepsis, as demonstrated by in vivo tissue Doppler imaging, better-preserved left ventricle function in isolated heart, and improved sarcomere shortening measured in single cardiomyocytes. There was also a significant survival benefit in toll-like receptor 2^−/− mice compared to wild-type mice. These favorable outcomes in toll-like receptor 2^−/− mice were associated with attenuated cardiodepressant cytokine levels in the myocardium and serum and enhanced neutrophil migratory function. Conclusions: These studies suggest that toll-like receptor 2 signaling plays a critical role in mediating cardiomyopathy, deleterious myocardial and systemic inflammation, and high mortality during polymicrobial sepsis.