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Ann Thorac Surg 2001;71:823-826
© 2001 The Society of Thoracic Surgeons

Original article: cardiovascular

The role of apolipoprotein E in cognitive decline after cardiac operation

Liz Steed, MSca, Robert Kong, FRCAa, Jan Stygall, MSca, Jayshree Acharya, PhDb, Manjeet Bolla, MScb, Michael J.G. Harrison, FRCPc, Steve E. Humphries, PhDb, Stanton P. Newman, DPhila

a Unit of Health Psychology, Department of Psychiatry and Behavioural Sciences, London, England, United Kingdom
b Centre for Cardiovascular Genetics, Department of Medicine, London, England, United Kingdom
c Neurological Studies, University College London, London, England, United Kingdom

Accepted for publication October 18, 2000.

Address reprint requests to Prof Newman, Unit of Health Psychology, Department of Psychiatry, RF & UCL Medical School, Wolfson Bld, 48 Riding House St, London, W1N 8AA, England
e-mail: s.newman{at}ucl.ac.uk


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Recently, Tardiff and colleagues have suggested that the presence of the apolipoprotein E, {epsilon}4 allele was associated with increased likelihood of cognitive decline after coronary artery bypass grafting. The objective of the current study was to replicate this earlier work using an increased sample size. The increased sample also enabled an analysis by individual genotype in cognitive decline after coronary artery bypass grafting.

Methods. Apolipoprotein E genotyping was performed on 111 individuals undergoing coronary artery bypass grafting. Each participant underwent a battery of nine neuropsychological tests before operation and 4 to 7 weeks after operation.

Results. Cognitive decline, assessed by both continuous Z change scores and two categoric measures of cognitive deficit, was not significantly associated with either individual apolipoprotein E genotypes or categorization by the presence or absence of the {epsilon}4 allele. The examination of potential moderating factors did not alter this finding.

Conclusions. This study suggests that the {epsilon}4 allele is not associated with cognitive decline in the weeks after coronary artery bypass grafting.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Mortality after coronary artery bypass grafting (CABG) has declined to as low as 3.3% in recent years [1]. Neuropsychological and cognitive deficits postoperatively still remain a problem, however, with deficits reported in up to 79% of patients, depending on the length of postoperative follow-up, neuropsychological test selection, and method of data analyses [2]. Perioperative factors, such as microemboli or aspects of operation, together with patient characteristics such as age, explain only some of the variance in cognitive decline after operation [2, 3]. This suggests that other, as yet unidentified factors, must be contributing to the changes seen. One patient-related factor that has been proposed as having an explanatory role is the gene coding for apolipoprotein E (APOE) [4, 5], which occurs as three common alleles {epsilon}2, {epsilon}3, and {epsilon}4.

The association of APOE and cognitive deficit is well established in Alzheimer’s disease, where it has been shown that the {epsilon}4 allele predicts risk of Alzheimer’s disease [6]. The hypothesis that APOE could be one of the factors responsible for cognitive deficit after CABG is driven by research indicating an association between the {epsilon}4 allele and recovery from central nervous system injury [7]. In humans the {epsilon}4 allele has been associated with poorer prognosis after closed head injury [8] and chronic traumatic brain injury [9]. Similar findings have been indicated for recovery after stroke [10]. Individuals with the {epsilon}4 allele are also more likely to develop arteriosclerosis and coronary heart disease [11], as well as cerebrovascular disease [12]. The link between APOE and incidence of thromboembolic stroke is, however, less clear, with a number of studies showing no association [13, 14].

Direct evidence of a relationship between APOE and cognitive decline after CABG is limited to a study by Tardiff and colleagues [4], who reported a positive association between the presence of the {epsilon}4 allele and cognitive dysfunction after CABG. Tardiff and associates [4] reported on a study of 65 patients undergoing CABG, 17 (26%) of whom carried one copy of the {epsilon}4 allele. Analysis was performed by comparing a two-level category, based on the presence or absence of the {epsilon}4 allele. No differences were found between those with or without the {epsilon}4 allele on baseline neuropsychological testing. They did, however, find a higher level of cognitive deterioration in those with the {epsilon}4 allele, an effect that was modulated by educational level. Those with higher levels of education showed less deficit and this effect was more marked in those with the {epsilon}4 allele present. This study was, as these researchers acknowledge, limited by a number of factors including small sample size and incomplete follow-up.Therefore, the current study aimed to replicate the work of Tardiff and coworkers [4], but used a larger sample size to enable an analysis by individual APOE genotypes. A measure of cognitive dysfunction, which reflects both preserved learning ability and potential deterioration on tests (Z change score), was also included.


   Material and methods
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Study sample
Following ethical committee approval, participants were recruited as part of a double-blind randomized controlled trial that examined the efficacy of clomethiazole as a neuroprotective agent in CABG. All patients were aged 50 years or older and underwent elective first or repeat CABG. Exclusion criteria were chronic hepatic disease, serum creatinine more than 200 µmol/L, acute or severe chronic respiratory insufficiency, or active neuropsychiatric conditions that could interfere with repeated neuropsychological testing, and cimetidine therapy. Of the 134 patients recruited into the study, APOE genotype was successfully obtained on 117 patients. Seven patients died of whom 6 had APOE genotyping, making a final sample of 111 patients in this study.

Neuropsychological assessment
Baseline neuropsychological assessment was performed on the day before operation and at follow-up 4 to 7 weeks postoperatively. A standard battery of nine tests was administered on both occasions and presented in the order of: Trail Making Test A, Trail Making Test B, Letter Cancellation, Grooved Pegboard dominant: Grooved Pegboard nondominant, Symbol Digit Modalities, Non-Verbal Memory, Rey Auditory Verbal Learning Test, and Two-Choice Reaction Time. Wherever possible the same psychologist administered both assessments.

Surgical and postoperative management
Standard protocol was followed for both surgical and postoperative procedures. Anesthesia was induced with midazolam (0.1 to 0.2 mg/kg) and fentanyl (10 to 15 µg/kg) or sufentanil. After an intravenous injection of pancuronium (0.1 to 0.15 mg/kg) and tracheal intubation, the lungs were ventilated with nitrous oxide and isoflurane (1% to 2%) in oxygen. The extracorporeal circuit, which included a membrane oxygenator and a 40-µm arterial line filter, was primed only with crystalloid solution. Cardiopulmonary bypass was instituted after giving heparin and the activated clotting time was more than 400 seconds. Anesthesia was maintained during cardiopulmonary bypass by isoflurane (0.5% to 1.5%) given with the fresh gas flow to the oxygenator. Mean arterial pressure was kept in the range of 60 to 90 mm Hg by giving an {alpha}1-agonist or by increasing the concentration of isoflurane; a nonpulsatile systemic blood flow was maintained at 2 to 2.4 L · min-1 · m-2 using a roller pump. The heart was arrested by intermittent aortic cross-clamp and fibrillation. The patient was rewarmed to 37°C before separation from cardiopulmonary bypass. Postoperative management was according to the usual practice of the unit. Morphine and midazolam were given by infusion for analgesia and sedation.

Microemboli detection
Microemboli occurring in the middle cerebral artery during cardiopulmonary bypass were measured using transcranial Doppler (Pioneer 4040, Nicolet-EME, Weinheim, Germany). Signals were recorded onto videotape and analyzed off-line by one of the investigators (RK) who was blinded to the neuropsychological test results.

Apolipoprotein E analysis
Venous blood (4.5 mL) was taken either preoperatively or more than 6 weeks postoperatively. The sample was agitated in an ethylenediaminetetraacetic acid tube and transferred to NUNC tubes for storage at -20°C. Deoxyribonucleic acid was extracted by the salting-out method [15]. Genotyping was carried out by polymerase chain reaction and a universal heteroduplex generator method as previously described [16]. All genotypes were read and cross-checked against their computer database (manual) entry by two independent observers blinded to case/control status. Any discrepancies were resolved by a repeat polymerase chain reaction and analysis.

Statistical analysis
Comparison of participants receiving either clomethiazole or placebo was performed for all baseline and follow-up testing. No significant differences were found between treated and placebo groups on any of the neuropsychological tests. The groups were, therefore, combined to allow subsequent analysis on one group.

Apolipoprotein E was analyzed in two ways. The six common genotypes of APOE ({epsilon}2{epsilon}2, {epsilon}2{epsilon}3, {epsilon}3{epsilon}3, {epsilon}3{epsilon}4, {epsilon}4{epsilon}4, and {epsilon}4{epsilon}2) were analyzed to allow for a separate examination of the role that {epsilon}4{epsilon}4 plays in cognitive decline. In addition, participants were grouped as {epsilon}4 present or {epsilon}4 absent to replicate the analysis performed in the study by Tardiff and colleagues [4].

Neuropsychological deterioration was calculated using the Z change score method [17]. This is a continuous measure that reflects the potential deterioration and potential learning effects found on repeated administration of these tests. A score is calculated for each individual test, and in addition a composite score for total performance on tests can be calculated. To allow for comparability to other studies two further measures of cognitive dysfunction were calculated. These were (1) cognitive deficit defined as a decline of more than one standard deviation on two or more tests and (2) cognitive decline defined as a 20% decrement in 20% or more of completed tests [18]. These latter indices are both categoric and do not account for the impact of learning associated with repeated testing on neuropsychological assessments.

The Kolmogorov-Smirnov goodness-of-fit test was applied to examine the normality of distributions for each neuropsychological test. Seven of the nine tests were not normally distributed. Square root transformations rendered the Non-Verbal Memory and Trail Making Test A to a normal distribution. Natural log transformed the Grooved Pegboard (nondominant), Symbol Digit, and Trail Making test B to a normal distribution, and the Two-Choice Reaction Time and Grooved Pegboard (dominant) were transformed using the reciprocal function. Transformed scores were used in analysis where appropriate. The statistical tests used for continuous measures were analysis of variance and t tests, and for categorical variables were {chi}2 and logistic regression. Due to the multiple comparisons performed, significance level was set at p less than 0.01.


   Results
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Apolipoprotein E genotype distribution
The frequency of each APOE genotype for the 111 individuals is as follows: {epsilon}2{epsilon}2, 2 (1.8%); {epsilon}2{epsilon}3, 17 (15.3%); {epsilon}3{epsilon}4, 19 (17.1%); {epsilon}4{epsilon}4, 8 (7.2%); {epsilon}4{epsilon}2, 3 (2.7%); the {epsilon}3{epsilon}3 genotype is the most common with 62 individuals (55.9%). The grouping of {epsilon}4 present and {epsilon}4 absent genotypes gave 30 (27%) and 81 (73%) participants in each group, respectively. Of the 6 patients who died, 5 had the {epsilon}3{epsilon}3 genotype and 1, the {epsilon}3{epsilon}4 genotype.

Patient characteristics
Table 1 indicates the baseline and operative characteristics of study participants. There were no significant differences between individuals with the {epsilon}4 allele present or {epsilon}4 absent on demographic, operative values, or baseline cognitive functioning. In addition, comparisons between the separate APOE genotypes indicated no difference on baseline or operative characteristics of patients. No comparisons between the groups were possible on untreated lipid as these data were not collected.


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  		Table 1. Baseline Characteristics of Study Population

 
Neuropsychological functioning at 6 weeks
No significant association was found between change in cognitive functioning and apolipoprotein E at 6-week follow-up, when Z-based change scores were compared for either the presence or absence of the {epsilon}4 allele (Table 2), or for individual genotype groups. This held for all neuropsychological tests plus the total Z score of all tests. In addition no significant difference between APOE groups, either {epsilon}4 present or absent, or genotype grouping, was seen when examined on the two categoric measures of neuropsychological deficit.


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  		Table 2. Z Change Scores for Cognitive Functioning at 6-Week Follow-up

 
Examination of moderating factors for the relationship between APOE and cognitive dysfunction showed no significant outcomes when education, embolic load, length of operation, or bypass time were considered. This was found irrespective of APOE grouping or measure of cognition.


   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
This study provides no support for the assertion that the apolipoprotein E, {epsilon}4 allele plays an explanatory role for cognitive dysfunction after CABG. This finding was consistent regardless of measure of cognitive dysfunction, and whether APOE was examined either by individual genotype or with the {epsilon}4 allele present or absent. The results for change in total Z score for neuropsychological functioning (Table 2) indicate a nonsignificant trend in the opposite direction to that hypothesized. This reinforces confidence in the lack of association found in this study. No factors were found to moderate this relationship. The results of this study are in contrast to those presented by Tardiff and colleagues [4] who suggested that the presence of the {epsilon}4 allele could reflect a genetic predisposition to cognitive dysfunction after CABG. The increased sample size in the present study, along with the variety of techniques that were used to examine the potential role of the {epsilon}4 allele, results in a greater robustness in this study.

The distribution of genotypes in this study indicates a higher frequency of {epsilon}4{epsilon}4 (7.2% versus 1.0%) than would be expected in the general population [19]. An increased frequency of {epsilon}4{epsilon}4 is expected, however, with subjects who have coronary heart disease, and a metaanalysis by Wilson and associates [11], indicated that for both men and women the frequency of {epsilon}4{epsilon}4 was higher in patients with coronary heart disease than in general population controls. This suggests that our sample is representative.

No association was found between APOE alleles and baseline cognitive functioning. This is in line with previous work that has also found no association [4]. If there is no association at baseline, and no evidence that APOE genotype is associated with incidence of thromboembolic events, it may be questioned whether we should expect to find differences in cognitive functioning by APOE genotype. The study reported here and that of Tardiff and coworkers [4] both assessed patients in the weeks after operation. One can speculate that the impact of cardiac operation combined with the role of the {epsilon}4 allele in reducing the possibility of neuronal repair may only become evident with follow-up periods longer than conducted in this study, when the aging brain may be more sensitive to insults of this nature.

Limitations of study
Although the number of participants was almost double that reported in the study by Tardiff and colleagues [4], the sample size is still relatively small, especially given the frequency with which some of the genotypes occur in the population. A much larger study of patients undergoing CABG would be useful to examine in more detail the relationship of APOE to cognitive dysfunction. The inclusion of participants taking part in a trial of a drug did not influence the lack of APOE effect as no difference in cognitive change was found between the active drug and placebo-treated groups. In addition, there was no interaction between the drug and the impact of APOE on cognitive functioning.


   Acknowledgments
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
We are grateful to Astra Pharmaceuticals for their support of Liz Steed, Robert Kong, and Jan Stygall. Steve E. Humphries, Jayshree Acharya, and Manjeet Bolla are all supported by the British Heart Foundation (RF95007 and SP98003).


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
This article has been selected for the open discussion forum on the STS Web site: http://www.sts.org/section/atsdiscussion/


   References
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Clark R.E., Brillman J., Davis D.A., Lovell M.R., Price T.R.P., Magovern G.J. Microemboli during coronary bypass grafting. Genesis and effect on outcome. J Thorac Cardiovasc Surg 1995;109:249-258.[Abstract/Free Full Text]
  2. Newman S.P., Stygall J. Neuropsychological outcome following cardiac surgery. In: Newman S.P., Harrison M.J.G., Stump D.A., Smith P., Taylor K., eds. The brain and cardiac surgery: causes of neurological complications and their prevention. Amsterdam: Harwood, 2000:21-49.
  3. Harrison M.J.G., Newman S.P. Impact of embolism in cardiac surgery. In: Newman S.P., Harrison M.J.G., Stump D.A., Smith P., Taylor K., eds. The brain and cardiac surgery: causes of neurological complications and their prevention. Amsterdam: Harwood, 2000:173-184.
  4. Tardiff B.E., Newman M.F., Saunders A.M., et al. Preliminary report of a genetic basis for cognitive decline after cardiac operations. Ann Thorac Surg 1997;64:715-720.[Abstract/Free Full Text]
  5. Newman M.F., Croughwell N.D., Blumenthal J.A., et al. Predictors of cognitive decline after cardiac operation. Ann Thorac Surg 1995;59:1326-1330.[Abstract/Free Full Text]
  6. Edwardson J., Morris C. The genetics of Alzheimer’s disease. BMJ 1998;317:361-362.[Free Full Text]
  7. Laskowitz D.T., Horsburgh K., Ross A.D. Apolipoprotein E and the CNS response to injury. J Cereb Blood Flow Metab 1998;18:465-471.[Medline]
  8. Teasdale G.M., Nicoll J.A.R., Fiddes H., Murray G. Association of apoE polymorphism with outcome after head injury. Lancet 1997;350:1069-1071.[Medline]
  9. Jordan B.D., Relkin N.R., Ravdin L.D., Jacobs A.R., Bennett A., Gandy S. Apolipoprotein E epsilon-4 associated with chronic traumatic brain injury in boxing. JAMA 1997;278:136-140.[Abstract/Free Full Text]
  10. Slooter A.J.C., Tang M.X., van Duijn C.M., et al. Apolipoprotein E{epsilon}4, and the risk of dementia with stroke: a population-based investigation. JAMA 1997;277:818-821.[Abstract/Free Full Text]
  11. Wilson P.W.F., Schaefer E.J., Larson M.G., Ordovas J.M. Apolipoprotein E alleles and risk of coronary disease: a meta-analysis. Arterioscler Thromb Vasc Biol 1996;16:1250-1255.[Abstract/Free Full Text]
  12. McCarron M.O., Delong D., Alberts M.J. APOE genotype as a risk factor for ischemic cerebrovascular disease: a meta-analysis. Neurology 1999;53:1308-1311.[Abstract/Free Full Text]
  13. Basun H., Corder E.H., Guo Z., et al. Apolipoprotein E polymorphism, and stroke in a population sample aged 75 years or more. Stroke 1996;27:1310-1315.[Abstract/Free Full Text]
  14. Kuusisto J., Mykkanen L., Kervinen K., Kesaniemi Y.A., Laakso M. Apolipoprotein E4 phenotype is not an important risk factor for coronary heart disease or stroke in elderly subjects. Arterioscler Thromb Vasc Biol 1995;15:1280-1286.[Abstract/Free Full Text]
  15. Miller S.A., Dykes D.D., Polesky H.F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16:1215.[Free Full Text]
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  18. Mahana E.P., Blumenthal J.A., White W.D., et al. Defining neuropsychological dysfunction after coronary artery bypass grafting. Ann Thorac Surg 1996;61:1342-1347.[Abstract/Free Full Text]
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