Frontal cortical neuroinflammation and circulating biomarkers following cardiopulmonary bypass in sheep

Abstract

Cerebral hypoxia and neuroinflammation have been implicated in neurocognitive disorders following cardiac surgery, but their postoperative trajectory and relationship with circulating biomarkers are poorly defined. We investigated cerebral tissue oxygenation, neuroinflammation, and plasma biomarkers of neurodegeneration over 4 weeks after cardiopulmonary bypass (CPB) in sheep. Sixteen adult Merino ewes underwent CPB with a 2-h aortic cross-clamp and recovered for either 48 h (n = 8) or 4 weeks (n = 8). Cerebral tissue oxygenation was monitored. Neuroinflammation was quantified by morphometric analyses of microglia and astrocytes in the frontal cortex in both CPB groups and a naïve control group (n = 8). Plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were measured serially. Compared with pre-CPB baseline, cerebral tissue oxygenation did not change significantly in the 48-h or 4-week period. In the 48-h post-CPB group, microglial soma sphericity was reduced (0.79 ± 0.04 vs. 0.83 ± 0.02, P = 0.018) compared with naïve controls, indicating microglial activation. Astrocytic GFAP-positive area was also elevated (17 ± 2% vs. 10 ± 2%, P = 0.026). In the 4-week post-CPB group, these measures did not differ significantly from naïve controls. Plasma NfL rose from 138 [96–185] pg/mL at baseline to 198 [149–265] pg/mL at 48 h (P = 0.0007), while GFAP peaked at the end of CPB (14.4 [4.7–32.4] vs. 3.0 [1.3–4.5] pg/mL, P < 0.0001) and normalised by 48 h. CPB induced neuroinflammation characterised by frontal cortical microglial activation and astrogliosis, accompanied by temporal elevations in plasma GFAP and NfL. These findings identify microglial activation as a response to CPB in the setting of preserved tissue oxygenation and provide preliminary evidence of an association between perioperative neuroinflammatory changes and circulating biomarkers GFAP and NfL, supporting further investigation.