Custodiol-N™ cardioplegia lowers cerebral inflammation and activation of hypoxia-inducible factor-1α

Abstract

Objectives: Cardioplegic solutions induce cardiac arrest and protect cardiac tissue from ischaemia-reperfusion injury. However, the effects on the brain, which is vulnerable to cardiopulmonary bypass (CPB) surgery and ischaemia-reperfusion injury, mostly remain unknown. We investigated if cardioplegic solutions differ in their effects in altered oxygen conditions and in their ability to induce cerebral inflammation.

Methods: Thirty pigs were subjected to a midline sternotomy and CPB at 34°C with 90 min cardiac arrest followed by 120 min reperfusion. Following randomization on a 1:1:1 basis, they received either a single shot of histidine-tryptophan-α-ketoglutarate (HTK)-Bretschneider solution (n = 10), histidine-tryptophan-α-ketoglutarate-N (HTK-N; n = 10) or HTK plus 1.2 mg/l cyclosporine A (HTK/CsA; n = 10). Brain regions of interest (frontal cortex, cerebellum, brain stem, diencephalon, colliculus superior) were analysed by real time quantitative reverse transcriptase polymerase chain reaction for hypoxia-inducible factor-1α (HIF-1α), tumour necrosis factor-α, interleukin (IL)-10, IL-1β and IL-1β receptor as well as by immunohistochemical analysis for HIF-1α. Blood gas and electrolyte analyses were performed.

Results: Comparisons between baseline and reperfusion period levels revealed that HTK-N cardioplegia induced a smaller reduction of the haemoglobin content and blood calcium concentrations (hbbaseline: 5.97 ± 0.63 mmol/l; hbreperfusion: 6.16 ± 0.66 mmol/l; P = 0.428; Cabaseline2+: 1.36 ± 0.05 mmol/l; Careperfusion2+: 1.28 ± 0.05 mmol/l; P < 0.001) compared to HTK (hbbaseline: 5.93 ± 0.45 mmol/l; hbreperfusion: 4.72 ± 0.79 mmol/l; P = 0.001; Cabaseline2+: 1.34 ± 0.07 mmol/l; Careperfusion2+: 1.24 ± 0.06 mmol/l; P = 0.004) and HTK/CsA cardioplegia (hbbaseline: 5.88 ± 0.44 mmol/l; hbreperfusion: 5.14 ± 0.87 mmol/l; P = 0.040; Cabaseline2+: 1.38 ± 0.04 mmol/l; Careperfusion2+: 1.20 ± 0.14 mmol/l; P = 0.001). Brain region-specific regulation of the HIF-1α expression, no general HIF-1α activation and a lower tumour necrosis factor-α expression (pto HTK = 0.050, pto HTK/CsA = 0.013) were documented for HTK-N cardioplegia.

Conclusions: HTK-N (Custodiol-N) induced fewer cerebral effects and less inflammation during CPB surgery than HTK and HTK/CsA cardioplegia. These data suggest that HTK-N exerts brain protective effects during and after CPB surgery.

Keywords: Cardioplegia; Cardiopulmonary bypass; Cerebral inflammation; Custodiol-N; Ischaemia reperfusion injury.