Abstract
The complex pathogenesis of sepsis and septic shock involves myocardial depression, the pathophysiology of which, however, remains unclear. In this study, cellular mechanisms of myocardial depression were addressed in a clinically relevant, large animal (porcine) model of sepsis and septic shock. Sepsis was induced by fecal peritonitis in eight anesthetized, mechanically ventilated, and instrumented pigs of both sexes and continued for 24 h. In eight control pigs, an identical experiment but without sepsis induction was performed. In vitro analysis of cardiac function included measurements of action potentials and contractions in the right ventricle trabeculae, measurements of sarcomeric contractions, calcium transients and calcium current in isolated cardiac myocytes, and analysis of mitochondrial respiration by ultrasensitive oxygraphy. Increased values of modified sequential organ failure assessment score and serum lactate levels documented the development of sepsis/septic shock, accompanied by hyperdynamic circulation with high heart rate, increased cardiac output, peripheral vasodilation, and decreased stroke volume. In septic trabeculae, action potential duration was shortened and contraction force reduced. In septic cardiac myocytes, sarcomeric contractions, calcium transients, and L-type calcium current were all suppressed. Similar relaxation trajectory of the intracellular calcium-cell length phase-plane diagram indicated unchanged calcium responsiveness of myofilaments. Mitochondrial respiration was diminished through inhibition of Complex II and Complex IV. Defective calcium handling with reduced calcium current and transients, together with inhibition of mitochondrial respiration, appears to represent the dominant cellular mechanisms of myocardial depression in porcine septic shock.
Highlights
Sepsis represents a well-recognized worldwide health problem
Development of sepsis and septic shock with organ dysfunction was manifested by a significant increase of the total modified sequential organ failure assessment (SOFA) score (Figure 1A) and of serum lactate levels (Figure 1B)
Out of eight animals in this group, septic shock requiring vasopressors and with lactate levels over 2 mmol/L developed in six animals; in two animals, vasopressor administration was not required, but the criteria for sepsis was fulfilled based on their SOFA scores
Summary
Sepsis represents a well-recognized worldwide health problem. Based on the meta-analysis of studies from developed high-income countries, global annual estimates were 31.5 million sepsis and 19.4 million severe sepsis cases, with potentially 5.3 million deaths, in the hospital setting (Fleischmann et al, 2016). A common manifestation of sepsis/septic shock is myocardial depression with reversible biventricular dilatation and depressed ejection fraction (Antonucci et al, 2014). The precise mechanistic link between infection, sepsis, and myocardial depression remains unclear, a number of possible pathways have been suggested (Merx and Weber, 2007; Sato and Nasu, 2015). An early theory of global myocardial ischemia due to inadequate coronary blood flow in sepsis was disproved by findings of high coronary blood flow and diminished coronary artery–coronary sinus oxygen difference in septic patients (Cunnion et al, 1986). The list of possible candidates includes various cytokines, endotoxins, prostanoids, and nitric oxide (Merx and Weber, 2007; Sato and Nasu, 2015)
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