Impact of Custodiol N and Low Dose Cyclosporine A Cardioplegia on Inflammation and HIF1a Inhibition in the Brain

Objectives: Cardioplegic solutions undergo constant improvement to reduce ischemia/reperfusion injury (IRI) during cardiac surgery. Addition of antioxidants in the Custodiol N solution or of low-dose cyclosporine A (CsA), an inhibitor of the mitochondrial transition pore, diminishes IRI in cardiac tissue, but effects on other organs are often neglected. Therefore, we investigated the effects of substances added to cardioplegic solutions on the brain.

Methods: Pigs underwent 90 min of cardiopulmonary bypass at 34°C and cardiac arrest during which they were randomly assigned to receive either standard cold Custodiol (n = 5), Custodiol N (n = 5) or Custodiol plus 1.2 mg/L CsA (n = 5) followed by 120 min of reperfusion. Pigs without cardiopulmonary bypass operation but with anesthesia served as controls (n = 5). Following the surgical procedure, brain tissue was fixed or snap frozen. qPCR for hypoxia inducible factor 1a (HIF1a), TNFa, IL-10, IL-1b and IL-1b receptor as well as immunohistochemistry for HIF1a was performed. Blood gas and electrolyte analyses were performed.

Results: Blood gas analyses did not show significant differences between the cardioplegia groups. An electrolyte imbalance with low concentrations of sodium (<135 mmol/L), calcium (<1.9 mmol/L) and chloride (<100 mmol/L) was detected after administration of cardioplegic solution, during 90min ischemia and after 120min reperfusion. IL-1b expression was increased in distinct brain areas of all groups (Custodiol: cortex p = 0.01, cerebellum p = 0.01; Custodiol N: cortex p = 0.05, cerebellum p = 0.01, brain stem p = 0.02; Custodiol plus CsA: cerebellum p = 0.04), whereas TNFa expression was increased in the Custodiol N (cortex p = 0.05) and the Custodiol plus CsA group (cortex p = 0.01, basal ganglia p = 0.02), but not in the Custodiol group. Expression of the anti-inflammatory IL-10 did not differ. HIF1a expression and activation was reduced throughout the brain following cardioplegia, whereas this effect was stronger after Custodiol N and Custodiol plus CsA administration than in the Custodiol group.

Conclusions: There is evidence that the inflammation in the brain was increased after cardioplegia with Custodiol N or Custodiol plus CsA in pig brain. Addition of antioxidants and of low-dose CsA to cardioplegic solutions affected the cellular response to IRI in the brain through inhibiting HIF1a activation and expression. Further studies should investigate, how HIF1a inhibition during IRI affects neurological outcome.

No conflict of interest has been declared by the author(s).