Abstract 4031: Nitric Oxide Synthase 3 Deficiency Worsens Myocardial Dysfunction and Survival in Murine Polymicrobial Sepsis

Abstract

Background: Myocardial dysfunction during sepsis contributes to the high mortality of patients with septic shock. The role of NOS3 on cardiac function during sepsis remains incompletely understood. Here, we examined impact of NOS3 deficiency on myocardial function and survival during peritonitis-induced polymicrobial sepsis. Methods: Severe polymicrobial sepsis was induced by colon ascendens stent peritonitis (CASP) in wild-type (WT) and NOS3 deficient (KO) mice. Cardiac function was examined both in vivo hemodynamic study and in isolated left ventricular cardiomyocytes, where sarcomere length (SL) and intracellular calcium transients ([Ca 2+ ] i ) were measured by video-edge detection and Fura-2 fluorescence, respectively. Mitochondrial function was assessed by measuring the ATP production rate in isolated mitochondria from left ventricle. Results: Mortality at 24 hours after CASP was higher in KO (15/15, 100%) than in WT (13/20, 65%, P<0.05 vs KO). In vivo hemodynamic study 22 hours after CASP revealed both systolic and diastolic cardiac functions were impaired to a greater extent in KO than in WT. In isolated cardiomyocytes, CASP induced-reduction in percent SL shortening and the peak amplitude of [Ca 2+ ] i was more marked in NOS3KO than in WT. The time constants for SL relengthening and diastolic [Ca 2+ ] i decay were prolonged to a greater extent in KO than in WT after CASP. Cardiac inflammation estimated by expression levels of inflammatory cytokines (TNF-α, IL-1β, IL-6) was more pronounced in KO than in WT. CASP-induced reduction in ATP production rate of myocardial mitochondria was more marked in KO than in WT, which was associated with reduction in mitochondrial complex I activity. Conclusions: These results suggest that NOS3 deficiency aggravates myocardial dysfunction through mitochondrial dysfunction and decreases survival after peritonitis-induced polymicrobial sepsis in mice. Table Hemodynamic and myocyte study 22 hours after CASP or sham