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Increased transcription factor expression and permeability of the blood brain barrier associated with cardiopulmonary
Marco Cavaglia1, Shivaprakash G Seshadri, James E Marchand
1Department of Anesthesia Research, The Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Insights
Cardiopulmonary bypass (CPB) and hypothermic circulatory arrest impair the blood-brain barrier (BBB) in infant lambs, leading to leakage and molecular changes. This BBB dysfunction may contribute to neurological issues following heart surgery.
Area of Science:
- Neuroscience
- Cardiovascular Surgery
- Pediatric Medicine
Background:
- The mechanisms behind neurocognitive dysfunction and developmental delays post-infant cardiopulmonary bypass (CPB) remain unclear.
- Known causes of blood-brain barrier (BBB) dysfunction include head trauma, stroke, and seizures, which increase transcription factor gene expression.
Purpose of the Study:
- To investigate the impact of CPB and hypothermic circulatory arrest on FOS transcription factor expression.
- To assess the functional integrity of the BBB in an infant animal model under CPB conditions.
Main Methods:
- Infant lambs underwent varying durations of normothermic CPB or hypothermic circulatory arrest.
- Brains were analyzed for FOS protein expression via immunohistochemistry.
- BBB integrity was evaluated by perfusing with fluorescent albumin to detect microvasculature leakage.
Main Results:
- CPB induced FOS expression in barrier-associated cells and caused significant albumin leakage in brain regions.
- Hypothermic circulatory arrest resulted in widespread brain leakage and FOS expression in all cells.
- Control animals showed no BBB leakage or FOS expression.
Conclusions:
- The BBB is dysfunctional throughout normothermic CPB, with worsened dysfunction during hypothermic circulatory arrest.
- BBB dysfunction is linked to heightened molecular activity within barrier cells.
- Impaired BBB function may play a role in the neurological complications observed after pediatric heart surgery.
Background:
The pathophysiology of neurocognitive dysfunction and developmental delay after cardiopulmonary bypass (CPB) in infants is not known. It is known that head trauma, stroke, and seizures cause dysfunction of the blood brain barrier (BBB) that is associated with increased inducible transcription factor gene expression in the cells of the barrier. The purpose of this study was to determine the effects of CPB and hypothermic circulatory arrest on expression of the transcription factor FOS and the function of the BBB in an infant animal model.
Methods:
Infant lambs (n = 36; 10-12 days) were exposed to 0, 15, 30, 60, or 120 minutes of normothermic (38 degrees C) CPB or 2 hours of hypothermic circulatory arrest at 16 degrees C. After terminating bypass 15 animals had their brains perfusion-fixed and removed for immunohistochemical analysis of expression of the transcription factor FOS. The other animals were perfused with fluorescent albumin to visualize the brain microvasculature. Brain sections were analyzed with a laser scanning confocal microscope.
Results:
Control animals (n = 6, sham operated and cannulated) exhibited normal vasculature with negligible leakage and no FOS protein expression in neurons or endothelial cells anywhere in the brain. Significant FOS expression in barrier-associated structures including the blood vessels, choroid plexus, and ependyma but not neurons occurred at all times on bypass. CPB caused leakage of fluorescent albumin from blood vessels in all animals. Two hours of normothermic CPB (n = 4) caused significant (p < 0.01) leakage in the cerebellum, cortex, hippocampus, and corpus callosum. Animals exposed to circulatory arrest experienced severe leakage throughout the brain (p < 0.001) and FOS expression in all cells.
Conclusions:
These experiments indicate that the BBB is dysfunctional after all time points on normothermic CPB, BBB dysfunction is worsened by hypothermic circulatory arrest, and BBB dysfunction is associated with intense molecular activity within the barrier-forming cells. Dysfunction of the BBB may contribute to neurologic complications after heart surgery.
