How to protect and resuscitate the mitochondrium: Role of Metformin and Cyclosporin
(Jean-Charles Preiser)
3 post-injury phases: Early Phase attempts to protect cellular integrity at the expense of functionality
- changes in macro / microcirculation
- decreased oxygen consumption
- decreased energy expenditure
- metabolic shutdown
Mitochondria in critical illness– more than just a powerhouse – also key roles in cell signalling (ROS), calcium homeostasis, regulation of apoptosis. Stressed mitochondria release DAMPs, further increasing inflammation and systemic toxicity
Metformin directly decreases mitochondrial respiration and increases aerobic glycolysis
Several studies have shown improved outcomes associated with metformin use in ITU patients
Cyclosporin A inhibits opening of mitochondrial permeability transition pore (mPTP), thereby preventing cell death
Rabbit model: cardiac arrest –> resuscitation with either 1. Control or 2. Cyclosporin A or 3. Non-immunosuppressive analogue-Inhibitor of mPTP opening –> organs harvested with functional markers recorded
Clinical:
- Cyclosporine before PCI for acute MI (800 pts): randomisation to bolus of Cyclosporine or Placebo –> disappointingly same primary outcome (death any cause / cardiac compromise) in both groups ??dose ??timing-related
- Out-of-hospital cardiac arrest (800pts): randomisation to bolus of cyclosporine vs placebo – No difference in SOFA scores 24 hrs post-admission ??dose ??timing-related ??inclusion criteria
Late and Recovery phases post-injury: Long stayers >5 days – decreased mitochondrial biogenesis, dysregulated lipid oxidation –> weakness, muscle inflammation, impaired anabolic recovery
Inhibitors of mitochondrial function may prevent later organ failure if given very early post-injury BUT prolonged mitochondrial dysfunction is not desirable
Recommended reading: Feeding mitochondria: Potential role of nutritional components to improve critical illness convalescence
The role of the Glucocorticoid (GC) receptor in circulatory shock
(Sabine Vettorazzi)
GC production and function is required for efficient response to inflammation – abnormal GC production associated with higher sepsis mortality in animal models and humans
GC binds to Glucocorticoid receptor (GR) –> translocates to nucleus
- GR monomer –> Represses inflammation
- GR dimer –> Induces inflammation
GR Dimerisation-deficient mouse model (GRdim) created, to clearly discriminate effects of GR monomers from GR dimers (which are completely absent)
Mice subjected to endotoxin-mediated shock: GRdim mice died faster than wild-type mice
- more severe lactate acidosis
- higher inotropic requirement for haemodynamic stability
- impaired lung compliance
- increased osteopontin levels (with decreased levels of anti-inflammatory IL-10)
GR Dimer is important for survival during LPS induced toxic shock, at least during the first 6 hours of shock in GRdim mice (only observed for 6 hours with intensive care support)
Why and how the heart fails
(Alain Rudiger)
Four shock states –
- shock –> cardiac dysfunction, MOF
- combination of shock states commonly occur
Cardiac dysfunction during Inflammatory Shock:
- Elevated BNP and Troponin
- Arrhythmia
- Systolic and diastolic dysfunction
Is this myocardial injury the reason for cardiac dysfunction?
Little evidence of myocyte necrosis in pts dying of sepsis + impaired contractility is Reversible = functional impairment rather than structural damage
Adaptive myocardial depression when myocardium is at risk
- reprogramming of genes
- activation of fetal genes (survival program)
- decreased energy expenditure to keep cells viable
Complex process of gene activation / down regulation in multiple cell-types at different times
Rat model 6 hours post-onset of faecal peritonitis: 500+ genes up/down regulated
- –> downstream: signalling cascades e.g. blunted adrenergic cascade / blunted calcium transport
- –> further downstream: affects electromechanical coupling and decreases myocardial contractility
Close interactions between shock, cardiac dysfunction and MOF
The heart fails as a result of multiple factors:
- Insufficient preload
- Excessive RV afterload
- Arrhythmia, dyssynchrony
- Diastolic dysfunction and impaired contractility