Sepsis, a state of deregulated systemic inflammation following an infectious insult, can lead to multi-organ failure. This is the commonest cause of death in the critically ill yet the pathophysiology remains uncertain. Mitochondrial ultrastructural and functional abnormalities are associated with sepsis-induced organ dysfunction. Though cause-and-effect was not yet definitively established, bioenergetic failure appears a plausible factor in the causation of organ failure. Mitochondria are not only involved in energy provision but also intracellular calcium regulation. These aspects may be highly relevant in impaired myocardial function, which is clinically identifiable in 40-50% of septic shock patients and linked with a poor prognosis. In an awake, fluid-resuscitated, clinically relevant rodent faecal peritonitis model, septic cardiomyopathy was characterized in vivo by depressed contractility and cardiac output. In non-survivors echocardiography-derived kinetic energy, an in vivo measure of work, failed to increase in response to inotropes, suggesting failure to sustain adequate levels of energy demand. Hearts isolated from septic animals prognosticated to die based on a 24-hour echocardiography (severe sepsis) presented decreased efficiency, despite preserved basal MvO2. Cardiomyocytes isolated from septic animals showed similar maximal respiration and bioenergetic reserve capacity to controls, suggesting absence of major disturbances in the respiratory chain. On the other hand, in mild sepsis, increased NADH oxidation and tighter coupling between substrate oxidation and ATP synthesis, could support increased contractile efficiency. In summary, these studies demonstrate that, in my fluid resuscitated sepsis model, cardiac mitochondria are not able to adequately respond to high-energy demand. Decreased phosphorylation capacity or disturbances in the supply-demand relationship may be involved. The reversibility of the myocardial depression seen ex vivo suggests the possibility of a circulating myocardial depressant factor(s). Finally, my observations highlight the importance of studying mitochondria with dynamic challenges within physiological boundaries in models that preserve cellular integrity and the cellular milieu.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:626711 |
| Date | January 2014 |
| Creators | Bollen Pinto, B. A. M. M. |
| Contributors | Singer, M. ; Duchen, M. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1415297/ |
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