Kiss, G.; Joulin, O.; Habchi, S.; Akkad, R.; Desbordes, J.; Robin, E. Author Information

Departments of Anesthesiology and Intensive Care and Thoracic Surgery, University Hospital of Lille, Lille, France

This study was designed to measure nitrite/nitrate and cytokine levels of serum obtained from septic shock patients and to describe potential depressant effects of human septic serum on rat cardiomyocytes. Serum was prepared from 10 non-septic patients and 10 patients with documented septic shock. Adult rat ventricular myocytes were exposed to 20 % serum in the medium. Cardiomyocyte contractility was assessed by measuring shortening fraction and shortening velocity. Serum levels of nitrite/nitrate, a marker of nitric oxide final metabolites, and cytokines (tumor necrosis factor (TNF)-alpha interleukin (IL) 1 beta, 6, 10, 8 and 12p70) were measured. Compared with serum from non-septic patients, serum of septic shock patients induced rapid reduction of the extent and velocity of shortening in isolated cardiomyocytes. Nitrite/nitrate, TNF-alpha, IL-1 beta and IL-12p70 concentrations of tested serum for cardiomyocyte studies were not increased in septic serum compared with controls. In contrast, septic serum that induced a depression of in vitro contractility, had increased levels of IL-6, IL-8 and IL-10. We can conclude that the depression of in vitro contractility induced by septic serum is not directly dependent on elevated levels of nitric oxide metabolites, TNF-alpha or IL-1 beta. Our results support the view that other cytokines, including IL-6, IL-8 and IL-10, are potent circulating mediators of myocardial depression in cardiomyocytes.

Background—Although most of the deleterious effects of sepsis-induced apoptosis have been attributed to increased lymphocyte cell death, caspase activation may directly alter cell function of different organ systems. We postulated that left ventricular (LV) cardiomyocyte caspase activation is directly involved in sepsis-induced heart contractile dysfunction. Methods and Results—LV cardiomyocytes isolated 4 hours after rat treatment with endotoxin injection (10 mg/kg) displayed major reductions in contractile reserve and myofilament response to Ca2+. Concomitantly, endotoxin also induced increases in LV cardiomyocyte caspase-3, -8, and -9-like activities, which were associated with sarcomeric structure destruction and cleavage of components of the cardiac myofilament. Interestingly, zVAD.fmk treatment of septic rat prevented LV cardiomyocyte contractile dysfunction, reductions in myofilament response to calcium, troponin T cleavage, and sarcomere destruction. Serum (10%) of endotoxin-treated rats induced contractile dysfunction, caspase-3–like activity increase, and troponin T cleavage of naive LV cardiomyocytes. The effects of septic serum were prevented in LV cardiomyocytes isolated from zVAD.fmk- or zDEVD.cmk-treated rats or LV cardiomyocytes preincubated with zVAD.fmk or zDEVD.cmk. Conclusions—The results show an important relationship between endotoxin-induced caspase activation and reduced contractile reserve and sarcomere disarray at the level of single LV cardiomyocytes.