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Anesth Analg 2004;99:1323-1325
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000135345.03635.6A

CARDIOVASCULAR ANESTHESIA

The Effect of Apolipoprotein E Genotype on Neuron Specific Enolase and S-100ß Levels After Cardiac Surgery

W. Andrew Kofke, MD MBA, FCCM, Patrick Konitzer, MD, Qing Cheng Meng, PhD, Jia Guo, MD, and Albert Cheung, MD

Department of Anesthesia, University of Pennsylvania, Philadelphia, Pennsylvania

Address correspondence to W. Andrew Kofke, MD, MBA, FCCM, Department of Anesthesia, University of Pennsylvania, 7 Dulles, 3400 Spruce St, Philadelphia, PA 19104–4283. Address email to kofkea{at}uphs.upenn.edu


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We tested the hypothesis that two biochemical markers of brain injury would be increased after cardiac surgery in patients with the apolipoprotein (Apo) {epsilon}4 allele. Arterial blood samples were drawn before and 8 and 24 h after induction of anesthesia and later assayed for neuron specific enolase (NSE), S-100ß, and apoE genotype. There was a highly significant temporal effect with increases in NSE (2.2 ± 1.6 ng/L to 11.8 ± 8.9 ng/L; P < 0.0001) (mean ± SD) and S-100ß (0.15 ± 0.1 µg/L to 0.45 ± 0.42 µg/L, P < 0.0001). At 8 and 24 h after induction of anesthesia S-100ß (0.28 ± 0.18 µg/L versus 0.91 ± 0.54 µg/L; P =0.004) and NSE (8.6 ± 5.6 ng/L versus 19.0 ± 19.7 ng/L; P = 0.02) levels, respectively, were higher in patients with the Apo{epsilon}4 allele. Patients with the Apo{epsilon}4 allele may be more susceptible to perioperative neural insults.

IMPLICATIONS: Two blood tests thought to be biomarkers for brain injury were found to be increased after cardiac surgery with larger increases in patients with the apolipoprotein {epsilon}4 gene, a gene linked to Alzheimer’s disease. There may be genetic differences in susceptibility to neurologic problems after surgery.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Apolipoprotein E (ApoE), a serum protein that mediates extracellular cholesterol transport, regulates multiple metabolic pathways and is a major susceptibility gene for Alzheimer’s disease (1,2). Isoform-specific ApoE effects have been implicated in recovery from several types of brain stress, including head trauma, stroke, and cardiac surgery (1,3–5). The Apo{epsilon}4 allele (versus Apo{epsilon} 2, 3) seems to demonstrate negative effects with regards to predisposition to the development of Alzheimer’s disease and recovery from neurologic stresses (1,3–5). It may also play a significant role in other neurodegenerative diseases (1). Although the role of ApoE in these processes has been studied, the relationship between levels of biochemical markers for brain injury, such as neuron specific enolase (NSE) or S-100ß (6,7) and a particular ApoE genotype, has not been studied. We tested the hypothesis that a biochemical marker of brain injury would be increased after cardiac surgery in patients with the Apo{epsilon}4 allele to a greater extent than those without this genotype.


   Methods
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 Abstract
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 Methods
Results
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The protocol was implemented after approval by the IRB and securing patient consent. Patients scheduled for cardiac or thoracic aortic surgery were eligible, and consecutive patients were enrolled. Arterial blood samples were drawn within 1 h before and 8 and 24 h after induction of anesthesia. Samples were frozen and later assayed for NSE and S-100ß by radioimmunoassay and for Apo{epsilon} genotype by polymerase chain reaction in the University of Pennsylvania Molecular Pathology laboratory (8). NSE and S-100ß were determined by radioimmunoassay using kits obtained from Sangtec, Inc. (Dietzenbach, Germany). The detection limit of S-100ß is 0.06 µg/L and for NSE is 0.5 ng/L. The sensitivity was determined by plotting the standard curve and then measuring the point of the curve at a distance of 3 SD from the standard. Kolmogorov-Smirnov testing for normality of the data indicated a non-normal distribution of the data. Thus, nonparametric statistics were used for hypothesis testing. Kruskal-Wallis analysis of variance was used to examine overall effects for time and ApoE group and, where significance was indicated, to further test for specific time and group effects (Analyze-It for Microsoft Excel; Analyze-It Software Ltd, Leeds, UK).


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Twenty-eight patients were enrolled (Table 1 contains a demographic summary). Genotyping revealed 21 to be without the Apo{epsilon}4 allele and 7 to have at least 1 Apo{epsilon}4 allele. Overall, Kruskal-Wallis analysis of variance revealed a highly significant effect over time with progressive increases in NSE (P < 0.0001) and S-100ß (P < 0.0001), and there was a significant group effect for S-100ß (P = 0.005) and NSE (P = 0.02) with higher levels in the Apo{epsilon}4 patients. There were no differences between groups at baseline for NSE and S-100ß or 8 h after anesthetic induction for NSE. However, at 8 h for S-100ß (P = 0.004) and 24 h for S-100ß (P = 0.02) and NSE (P = 0.02) after induction of anesthesia the biomarker levels were higher in patients with the Apo{epsilon}4 allele (Figure 1).


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  		Table 1. Demographic Summary
 


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  		Figure 1. NSE and S-100ß notched box whisker plots. Boxes indicate the medians and 25th and 75th percentile points. Notches indicate the 95% upper and lower confidence intervals. Times refer to time after induction of anesthesia. 0 h indicates within 1 h before start of anesthesia. Groups refers to patients without (E2, E3, n = 21) and patients with (E4, n = 7) the Apo{epsilon}4 allele. A significant effect is present for time and for group for both neuron specific enolase (NSE) and S100ß. In Apo{epsilon}4 patients significantly higher levels were observed, for S100ß at 8 h and 24 h and for NSE at 8 h after induction of anesthesia.

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
We have demonstrated a robust increase in biochemical markers of brain damage, but without examination for occurrence of brain damage, in a relatively heterogeneous and small group of cardiac surgery patients with a more pronounced effect in patients with the Apo{epsilon}4 allele. The extent of increase in NSE and S100ß is consistent with other reports describing an associated presence of neural injury (7,14).

ApoE
The ApoE allele, {epsilon}2, {epsilon}3, or {epsilon}4, has an important role in the pathogenesis of Alzheimer’s disease (1). The likelihood of developing Alzheimer’s disease is increased in carriers of the {epsilon}4 allele (9). Notably, the Apo{epsilon}4 allele has been associated with deleterious outcome after intracerebral hemorrhage (4) and head trauma (5) and worsened neurocognitive decline after cardiopulmonary bypass (3). Humans undergoing vascular surgery are exposed to a variety of events, including anesthesia, emboli, and hypoperfusion, that might be less well tolerated by those with the Apo{epsilon}4 allele.

Brain-Specific Biomarkers as Indicators of Brain Damage
Many reports support the use of S-100ß and NSE as useful markers of brain damage. Moore (10) reported on the isolation of astrocyte S-100 and NSE, which are thought to be relatively brain-specific proteins found in all vertebrates (11,12) with efflux from cells observed as a function of damage in neuronal cell cultures (13). Several investigators have reported increases of these enzymes after disparate brain insults with excellent correlation between severity of injury and increase in S-100ß and NSE (12,14–17). However, others, in the context of traumatic brain injury, suggest that NSE may not offer the same sensitivity and specificity as S-100 (18).

Possible Role of Genetic Polymorphisms as Contributors to Risk of Perioperative Neurologic Dysfunction
All of the surgical procedures we examined have been associated with cerebral ischemia. It is thus plausible that an element of ischemia contributed to the enzyme increases that we observed with a clear implication that those with the Apo{epsilon}4 allele suffered worse injury, as reflected by biochemical markers of such injury. If so, this has implications for our understanding of cerebral ischemia in humans. Georgiadis et al. (7) reported an increase of S-100ß values >0.5 µg/L and NSE values >14.4 ng/L to be significant predictors for adverse neurologic outcomes in cardiac surgery patients. Our Apo{epsilon}4 patients sustained increases of NSE and S100ß into these ranges. Our data, although preliminary, provide support for the notion that genomic makeup affects tolerance to ischemic insults.

Although our data and those of Tardiff et al. (3) might be reasonably interpreted to indicate the presence of gene-induced susceptibility to injury from ischemia or anesthesia, the possibility nonetheless exists that our observations are an epiphenomenon related to the known relationship between the Apo{epsilon}4 genotype and arteriosclerosis (9). That is, we may have merely found that patients with arteriosclerosis tend to have impaired cerebrovascular reserve and thus tolerate physiologic variations associated with this type of surgery relatively poorly.

Postoperative Cognitive Deficits
It is also possible that our data reflect previous investigators’ observations of postoperative cognitive deficits (19,20). Such deficits have not been found to have a physiological cause, with concern that some other factor, such as the anesthetics themselves, could be neurotoxic. Although not yet demonstrated in humans, there is nonetheless ample data in animals to make this a reasonable consideration in interpreting our data. Opioids (21,22), nitrous oxide (23–25), ketamine (24,25), and volatile anesthetics (26) have all been implicated with disparate possible mechanisms. If this is the cause of our observations then our data would indicate genomic variability in this phenomenon, the actual clinical relevance of which at this time must nonetheless be considered speculative.

In conclusion, our data indicate a predisposition of patients with the Apo{epsilon}4 allele to sustain higher levels of biomarkers of brain injury after vascular surgery. However, these data cannot be used to make any inferences regarding risk of perioperative stroke or cognitive deficits. Further knowledge is required to ascertain whether our observations can be shown to reflect real morphologic or behavioral evidence of genomic susceptibility to anesthetic neurotoxicity or cerebral ischemia.


   Acknowledgments
 
Supported, in part, by a grant from Clinical Practices of the University of Pennsylvania (to PK).


   References
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 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication May 26, 2004.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press