HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Mark F. Newman Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Grocott, H. P. Articles by Laskowitz, D. T. Search for Related Content PubMed PubMed Citation Articles by Grocott, H. P. Articles by Laskowitz, D. T. Related Collections Extracorporeal circulation Molecular biology

J Thorac Cardiovasc Surg 2001;122:622-623
© 2001 The American Association for Thoracic Surgery

Brief Communications

Apolipoprotein E genotype differentially influences the proinflammatory and anti-inflammatory response to cardiopulmonary bypass

From the Departments of Anesthesiology^a and Medicine (Neurology),^b Duke University Medical Center, Durham, NC.

Dr Grocott was supported by a Pepper Center Junior Faculty Award (NIA-AG11268); Dr Laskowitz was supported by the Paul Beeson Physician Faculty Award and National Institutes of Health (NIH) grant 1R01NS368087-01A2; Dr Newman was supported by NIH grant 1R01HL54316 and American Heart Association Grants-In-Aid 95010970 and M01-RR-30; Drs Grocott and Laskowitz serve as consultants to Biosite Inc, which performed the cytokine assays.

Received for publication Dec 20, 2000. Accepted for publication Feb 13, 2001. Address for reprints: Hilary P. Grocott, MD, Department of Anesthesiology, Duke University Medical Center, Box 3094, Durham, NC 27710 (E-mail: h.grocott{at}duke.edu).

Neurocognitive deficits are common sequelae of cardiac operations, affecting both long-term functional outcome and quality of life. The cause of perioperative cerebral injury remains incompletely understood, but it is multifactorial and likely represents a complex interaction among cerebral microembolization, global hypoperfusion, temperature modulation, and inflammatory processes. In addition, genetic factors have been shown to influence neurocognitive outcome after cardiac operations. Specifically, the presence of the APOE4 allele, one of the common human polymorphisms of the gene encoding apolipoprotein E (apoE), has been associated with a worsened cognitive outcome after coronary artery bypass grafting. ¹ This is consistent with prior clinical and experimental observations implicating the APOE4 allele in poor outcome after a variety of acute brain insults, including stroke, intracranial hemorrhage, and traumatic brain injury. ²

In addition to its role in cholesterol transport, recent reports have suggested that apoE plays a biologically relevant role in downregulating the systemic and central nervous system immune responses. ^3,4 Thus, one potential mechanism by which apoE influences outcome after acute brain injury is by modulating the inflammatory response. In this study we sought to determine whether APOE genotype influences the systemic inflammatory response to cardiopulmonary bypass (CPB).

Methods
After obtaining institutional review board approval, 338 consenting patients undergoing elective coronary artery bypass grafting with hypothermic CPB (30°C-32°C) were studied. After placement of invasive monitors, anesthesia was induced and maintained with midazolam, fentanyl, and pancuronium. The perfusion apparatus consisted of a membrane oxygenator, a roller pump, and a 40-µm arterial line filter maintaining nonpulsatile CPB flows of 2 to 2.4 L · min^–1 · m^–2. Arterial PCO₂ and PO₂ values were maintained at 35 to 40 mm Hg (uncorrected for body temperature) and 150 to 250 mm Hg, respectively. The hematocrit level during CPB was greater than 0.18, and the mean arterial pressure was maintained between 50 and 90 mm Hg.

Blood samples were taken at baseline (before induction of anesthesia), at the end of CPB, and at 4.5, 24, and 48 hours postoperatively. Collected blood was centrifuged (10,000g), and the resulting supernatant was immediately frozen at –70°C until analysis was completed. Measurements of the representative proinflammatory cytokine interleukin 1ß (IL-1ß) and the anti-inflammatory IL-1ß receptor antagonist (IL-1ra) were performed by Biosite Diagnostics (San Diego, Calif) using a Genesis Robotic Sample Processor 200/8 (Tecan; Research Triangle Park, NC). All assays were performed in a 10-µL reaction volume in 384-well microplates, with the amount of bound antigen detected by means of alkaline phosphatase–conjugated secondary antibodies and AttoPhos substrate (JBL Scientific, San Luis Obispo, Calif). APOE genotype was determined from each patient by a polymerized chain reaction from preoperative whole-blood samples. ¹

Demographic data were compared with either the Fisher exact test for binary variables or the Wilcoxon 2-sample rank sum test for continuous data. A nonparametric generalized estimating equations ⁵ approach, which accounts for the within-subject cytokine correlation, was adopted to compare, after controlling for age and CPB time, the overall temporal pattern of cytokine response between those patients with at least one copy of the APOE4 allele and those without.

Results
Patient demographics are presented in Table 1. Ninety-four (28%) patients had at least one copy of the APOE4 allele. With the exception of age (APOE4 allele, 61 ± 10 years vs no APOE4 allele, 64 ± 11 years; P = .03), there were no significant demographic differences between groups. The overall temporal pattern of IL-1ß and IL-1ra levels were analyzed and modeled, while controlling for both age and CPB time, to examine for an APOE4 effect. There were no significant overall differences between groups with and without the APOE4 allele with respect to the IL-1ß levels over time (P = .8). However, compared with the group without the APOE4 allele, the group with the allele had a lower IL-1ra response overall (P = .04, Figure 1).

View larger version (16K): [in this window] [in a new window]   Fig. 1. The overall temporal pattern of IL-1ra release (mean ± standard error of the mean) in 338 patients undergoing CPB for coronary artery bypass grafting was lower (P = .04) in those having the APOE4 allele (E4), thus representing a decreased anti-inflammatory response to CPB in these patients.

References

1. Tardiff BE, Newman MF, Saunders AM, Strittmatter WJ, Blumenthal JA, White WD, et al. Preliminary report of a genetic basis for cognitive decline after cardiac operations. Ann Thorac Surg. 1997;64:715-20.[Abstract/Free Full Text]
   
2. Laskowitz DT, Horsburgh K, Roses AD. Apolipoprotein E and the CNS response to injury. J Cereb Blood Flow Metab. 1998;18:465-71.[Medline]
   
3. Laskowitz DT, Thekdi AD, Han SK, Myers JK, Pizzo SV, Bennett ER. Downregulation of microglial activation by apolipoprotein E and apoE-mimetic peptides. Exp Neurol. 2001;167:74-85.[Medline]
   
4. Laskowitz DT, Lee DM, Schmechel D, Staats H. Altered immune responses in apoE deficient mice. J Lipid Res. 2000;41:613-20.[Abstract/Free Full Text]
   
5. Liang KY, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika. 1986;71:13-22.
   

This article has been cited by other articles:

				K. J. Hogan, J. K. Burmester, M. D. Caldwell, Q. H. Hogan, D. B. Coursin, D. N. Green, R. M.R. Selzer, T. P. Broderick, D. A. Rusy, M. Poroli, et al. Perioperative Genomic Profiles Using Structure-Specific Oligonucleotide Probes Clin. Med. Res., September 1, 2009; 7(3): 69 - 84. [Abstract] [Full Text] [PDF]

				J. W. Hammon Extracorporeal Circulation: The Response of Humoral and Cellular Elements of Blood to Extracorporeal Circulation Card. Surg. Adult, January 1, 2008; 3(2008): 370 - 389. [Full Text]

				R. O. Hopkins, L. K. Weaver, K. J. Valentine, C. Mower, S. Churchill, and J. Carlquist Apolipoprotein E Genotype and Response of Carbon Monoxide Poisoning to Hyperbaric Oxygen Treatment Am. J. Respir. Crit. Care Med., November 15, 2007; 176(10): 1001 - 1006. [Abstract] [Full Text] [PDF]

				H. P. Grocott Genetic influences on cerebral outcome after cardiac surgery. Seminars in Cardiothoracic and Vascular Anesthesia, December 1, 2006; 10(4): 291 - 296. [Abstract] [PDF]

				R. B. Yates and M. Stafford-Smith The genetic determinants of renal impairment following cardiac surgery. Seminars in Cardiothoracic and Vascular Anesthesia, December 1, 2006; 10(4): 314 - 326. [Abstract] [PDF]

				M. V. Podgoreanu and D. A. Schwinn New Paradigms in Cardiovascular Medicine: Emerging Technologies and Practices: Perioperative Genomics J. Am. Coll. Cardiol., December 6, 2005; 46(11): 1965 - 1977. [Abstract] [Full Text] [PDF]

				H. P. Grocott and G. B. Mackensen Apolipoprotein E Genotype and S100{beta} After Cardiac Surgery: Is Inflammation the Link? Anesth. Analg., June 1, 2005; 100(6): 1869 - 1870. [Full Text] [PDF]

				K. G Manton, X. Gu, H. Huang, and M. Kovtun Fuzzy set analyses of genetic determinants of health and disability status Statistical Methods in Medical Research, October 1, 2004; 13(5): 395 - 408. [Abstract] [PDF]

				G. B. MacKensen, M. Swaminathan, L. K. Ti, H. P. Grocott, B. G. Phillips-Bute, J. P. Mathew, M. F. Newman, C. A. Milano, and M. Stafford-Smith Preliminary report on the interaction of apolipoprotein E polymorphism with aortic atherosclerosis and acute nephropathy after CABG Ann. Thorac. Surg., August 1, 2004; 78(2): 520 - 526. [Abstract] [Full Text] [PDF]

				J. R. Lynch, R. Blessing, W. D. White, H. P. Grocott, M. F. Newman, and D. T. Laskowitz Novel Diagnostic Test for Acute Stroke Stroke, January 1, 2004; 35(1): 57 - 63. [Abstract] [Full Text] [PDF]

				J. R. Lynch, W. Tang, H. Wang, M. P. Vitek, E. R. Bennett, P. M. Sullivan, D. S. Warner, and D. T. Laskowitz APOE Genotype and an ApoE-mimetic Peptide Modify the Systemic and Central Nervous System Inflammatory Response J. Biol. Chem., December 5, 2003; 278(49): 48529 - 48533. [Abstract] [Full Text] [PDF]

				J. W. Gaynor, M. Gerdes, E. H. Zackai, J. Bernbaum, G. Wernovsky, R. R. Clancy, M. F. Newman, A. M. Saunders, P. J. Heagerty, J. A. D'Agostino, et al. Apolipoprotein E genotype and neurodevelopmental sequelae of infant cardiac surgery J. Thorac. Cardiovasc. Surg., December 1, 2003; 126(6): 1736 - 1745. [Abstract] [Full Text] [PDF]

				G. D. Kolovou, D. Ch. Daskalova, M. Hatzivassiliou, N. Yiannakouris, N. D. Pilatis, M. Elisaf, D. P. Mikhailidis, M. A. Cariolou, and D. V. Cokkinos The Epsilon 2 and 4 Alleles of Apolipoprotein E and Ischemic Vascular Events in the Greek Population -- Implications for the Interpretation of Similar Studies Angiology, January 1, 2003; 54(1): 51 - 58. [Abstract] [PDF]

				G. Kolovou, D. Daskalova, and D. P. Mikhailidis Apolipoprotein E Polymorphism and Atherosclerosis Angiology, January 1, 2003; 54(1): 59 - 71. [Abstract] [PDF]

				P. Menasche and L. H. Edmunds Jr. Extracorporeal Circulation: The Inflammatory Response Card. Surg. Adult, January 1, 2003; 2(2003): 349 - 360. [Full Text]

				M. Koistinaho, M. I. Kettunen, D. M. Holtzman, R. A. Kauppinen, L. S. Higgins, and J. Koistinaho Expression of Human Apolipoprotein E Downregulates Amyloid Precursor Protein-Induced Ischemic Susceptibility Stroke, July 1, 2002; 33(7): 1905 - 1910. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Mark F. Newman Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Grocott, H. P. Articles by Laskowitz, D. T. Search for Related Content PubMed PubMed Citation Articles by Grocott, H. P. Articles by Laskowitz, D. T. Related Collections Extracorporeal circulation Molecular biology