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J Thorac Cardiovasc Surg 2007;134:996-1005
© 2007 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Genomic expression pathways associated with brain injury after cardiopulmonary bypass

^a Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Boston, Mass
^b Genomics Center, Beth Israel Deaconess Medical Center, Boston, Mass
^d Primary Care/General Medicine, Beth Israel Deaconess Medical Center, Boston, Mass
^c Children’s Hospital Informatics Program, Children’s Hospital, Boston, Mass
^e VA Boston Healthcare System, Geriatric Research Education and Clinical Center, Harvard Medical School, Boston, Mass.

Received for publication November 8, 2006; revisions received January 16, 2007; accepted for publication January 29, 2007.

^_* Address for reprints: Frank W. Sellke, MD, Division of Cardiothoracic Surgery, BIDMC, LMOB 2A, 110 Francis St, Boston, MA 02215. (Email: fsellke{at}caregroup.harvard.edu).

	Abstract

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Objectives: Neurologic injury after cardiac surgery, often manifested as neurocognitive decline, is a common postoperative complication without clear cause. We studied acute variations in gene-expression profiles of patients with neurocognitive decline (NCD group) compared with those without neurocognitive decline (NORM group) after cardiopulmonary bypass.

Methods: Forty-two patients undergoing coronary artery bypass grafting, valve procedures, or both by using cardiopulmonary bypass were administered a validated neurocognitive battery preoperatively and postoperatively at day 4. Neurocognitive decline was defined as 1 standard deviation from baseline on 25% or greater of tasks. Whole-blood mRNA was isolated preoperatively and at 6 hours after surgical intervention for fold-change calculation. Relative gene expression in the NCD versus the NORM group was assessed by using Affymetrix GeneChip U133 Plus 2.0 (>40,000 genes) from mRNA samples collected. Differential expression, clustering, gene ontology, and canonical pathway analysis were performed. Validation of microarray gene expression was performed with SYBR Green real-time polymerase chain reaction.

Results: Patients with neurocognitive decline (17/42 [40.5%] patients) were associated with a significantly different gene-expression response compared with that of healthy patients. Compared with preoperative samples, 6-hour samples had 531 upregulated and 670 downregulated genes uniquely in the NCD group compared with 2214 upregulated and 558 downregulated genes uniquely in the NORM group (P < .001; lower confidence bound, 1.2). Compared with patients in the NORM group, patients with neurocognitive decline had significantly different gene-expression pathways involving inflammation (including FAS, IL2RB, and CD59), antigen presentation (including HLA-DQ1, TAP1, and TAP2), and cellular adhesion (including ICAM2, ICAM3, and CAD7) among others.

Conclusions: Patients with neurocognitive decline have inherently different genetic responses to cardiopulmonary bypass compared with those of patients without neurocognitive decline Genetic variations in inflammatory, cell adhesion, and apoptotic pathways might be important contributors to the pathophysiology of neurologic injury after cardiopulmonary bypass and could become a target for prevention and risk stratification.

	Introduction

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Dr Basel Ramlawi Dr Frank W. Sellke

Brain injury after cardiopulmonary bypass (CPB) remains a common and serious complication that is often misdiagnosed.^1,2 Brain-protective strategies include improved operative approach selection (eg, "no-touch" technique for the calcified aorta), preoperative investigation (eg, carotid duplex scanning), and intraoperative measures (eg, hypothermia and CPB filters). Despite these advances in surgical technique, CPB, and anesthesia, central neurologic system (CNS) injury remains an important complication for patients. The American College of Cardiology/American Heart Association guidelines for coronary artery bypass graft surgery divide postoperative neurologic deficits into 2 categories.³ Type 1 deficits (incidence of 1%-5%) include major focal neurologic events, stupor, and coma. Type 2 deficits, with an incidence as high as 65% in some studies,^4,5 describe more global cognitive deficits, such as deterioration in intellectual function, memory, and confusion without evidence of focal injury. Type 1 deficits are usually caused by identifiable sources of cerebral hypoxia caused by intraoperative hypoperfusion or embolic phenomena. In contrast, the cause of type 2 deficits is unclear and likely multifactorial, where factors such as hypoxia, time on CPB, age, type of procedure, preoperative creatinine levels, and perioperative inflammatory response have been implicated in its pathophysiology.⁶

The remarkably high incidence of type 2 brain injury (measured at 1 week postoperatively), usually improves and decreases to around 10% to 30% at 1 year. Interestingly, Newman and colleagues⁷ have reported that the occurrence of early neurocognitive decline (NCD) in cardiac surgical patients is predictive of long-term decline. One of the reasons why the incidence of type 2 CNS injury remains so high in spite of recent advances might be a fundamental lack in the understanding of the pathophysiology of this type of injury.^1,6

The inflammatory response and associated oxidative stress have been implicated in the development of postoperative CPB-associated complications.^8-12 These are triggered by the activation of blood components on the artificial surface of the extracorporeal circuit, such as the activation of leukocytes, complement, expression of adhesion molecules, cytokine release, and an increase in reactive oxygen species, such as peroxides, that mediate oxidative stress. It is increasingly recognized that there exists a certain amount of variability in the magnitude and duration of response to CPB between patients, which has been implicated in transient and permanent end-organ damage. Our group, among others, has reported on the strong association between NCD and the magnitude of the inflammatory response after CPB.^13,14

Transcriptional profiling with high-density microarrays provides unique data about disease mechanisms, drug responses, regulatory pathways, and gene function by comparing the level of mRNA transcribed in cells in a given pathologic state versus a control. This technology can potentially elucidate complex pathophysiologic association mechanisms directly at the gene-expression level. The present study was conducted to examine the differences in gene-expression profiles of patients who have NCD after cardiac surgery compared with those who do not have this complication in an effort to improve our understanding of type 2 brain injury and provide perioperative strategies aimed at prevention and treatment.

	Materials and Methods

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Patient Enrollment
We carried out a single-institution, prospective cohort study that was approved by the Beth Israel Deaconess Medical Center Institutional Review Board/Committee on Clinical Investigations. Forty-three patients scheduled for elective or urgent primary coronary artery bypass grafting, valvular surgery (aortic or mitral), or a combination of the 2 with CPB provided informed written consent and were enrolled. Exclusion criteria included the following: patients undergoing aortic arch/root procedures and those with calcified aorta, recent stroke, severe preoperative neurologic deficits, known high-grade carotid stenosis, advanced hepatic disease (cirrhosis), and chronic renal failure (serum creatinine, >2.0 mg/dL). Patients who were unable to complete the baseline neuropsychological battery because of severe cognitive impairment, psychiatric disease, substance abuse, blindness, or poor English were also excluded. One patient was excluded from the analysis because of inability to complete the neuropsychological assessment before discharge. Thus 42 patients were included in the analysis.

Anesthetic and Surgical Techniques
The conventional operative approach at our institution was followed, including induction of general anesthesia, invasive monitoring, midline sternotomy, and systemic heparinization. CPB was initiated through cannulation of the right atrium and ascending aorta with a nonpulsatile system, membrane oxygenator, and 40-µm arterial filter. Crystalloid pump prime was used. For all patients, mild hypothermic CPB (minimum temperature, 32°C-34°C) with intermittent cold blood hyperkalemic (25 mmol/L) cardioplegia was used. Serum glucose levels were monitored, and we attempted to maintain a value of less than 130 mg/dL by means of intermittent intravenous insulin injections or insulin infusion. During CPB, pump blood flow was maintained at 2 to 2.4 L · min^–1 · m^–2 body surface area. Arterial partial oxygen pressure was maintained at between 150 and 250 mm Hg, and alpha-stat pH monitoring was used. Mean blood pressure was maintained between 50 and 90 mm Hg by using conventional vasoactive medications.

Neurocognitive Assessment
Patients underwent neurocognitive testing with a battery of evaluations preoperatively (1-10 days before surgical intervention) and postoperatively before discharge at postoperative day 4, as well as at 3 months. Before baseline neurocognitive assessment, all patients underwent a depression assessment by using the Geriatric Depression Scale (positive if score 9 of 15). All evaluations were carried out by trained and dedicated psychometricians who were blinded to serologic testing. The battery was chosen to be consistent with the "Statement of consensus on neurobehavioral outcomes after cardiac surgery"¹⁵ and consisted of 8 validated assessments covering memory, executive function, attention, language, and global cognition.

From the Hopkins Verbal Learning Test, a validated 12-item verbal learning, retention, and recall measure, we assessed the number of items learned, the number of items recalled after a 20-minute delay divided by the maximum number of items learned, and the number of items correctly identified from a list. Confrontational naming was measured with the Boston Naming Test.¹⁶ Time to complete Trailmaking A and B, a measure of shifting attention abilities, was recorded. Digit span forward and backward of the Revised Wechsler Adult Intelligence Scale is a measure of working memory and sustained attention requiring participants to hold and manipulate information. Fluency tasks are measures that assess language and knowledge storage patterns by requiring the patient to spontaneously generate words in a category (semantic) or beginning with a specific letter (phonemic). Performance on the Weschler Test of Adult Reading, an irregular-word reading task, was used as a measure of premorbid intelligence. The Stroop Color-Word Interference test assesses executive function, and we recorded the number of correct responses. The visual search and acuity test requires visuospatial abilities and executive function.

Following the "Consensus statement on neurobehavioral changes following cardiac surgery" guidelines, we defined cognitive decline as a 1-standard-deviation (SD) decline from baseline on 25% of the tasks (2/8 measures).¹⁷ The SD was derived by performing the cognitive battery in a similar population undergoing cardiac surgery.¹⁸

Blood Sampling and Microarray Processing
For each of the 42 patients, blood samples were collected from the central venous line preoperatively after induction of anesthesia and before skin incision (PRE), as well as 6 hours postoperatively in the cardiovascular intensive care unit (6h). Blood samples were collected into PAXgene tubes (QIAGEN, Inc, Valencia, Calif) for immediate mRNA stabilization and extraction, as per the manufacturer’s recommendation. Transcriptional profiles of samples were probed by using Affymetrix HG (Affymetrix Inc, Santa Clara, Calif) U133 Plus 2.0 chips for a total of 84 chips. Total RNA extraction and purification, cDNA synthesis, in vitro transcription reaction for production of biotin-labeled cRNA, hybridization of cRNA with Affymetrix GeneChips, and scanning of arrays were done according to previously described protocols.¹⁹ All arrays went through stringent quality control assessment with regard to 3'/5' ratios (by using glyceraldehyde-3-phosphate dehydrogenase and ß-actin probes), percentage of present calls, and array outlier call percentage within 2 SDs of the mean. All scanned array images passed the quality controls and were analyzed by using dChip,²⁰ which has been shown to be more robust than Affymetrix software Microarray Analysis Suite 5.0 in signal calculation for about 60% of genes.²¹ In the dChip analysis a smoothing spline normalization method was applied before obtaining model-based gene-expression indices, also known as signal values. There were no outliers identified by using dChip, and therefore all samples were carried on for subsequent analysis.

Unsupervised and Differential Expression Analysis
A hierarchic clustering technique was used to construct an unweighted pair group method with arithmetic-mean tree by using the Pearson correlation as the metric of similarity. When comparing 2 groups of samples to identify genes enriched in a given group, we used the lower confidence bound (LCB) of the fold change (FC) between the 2 groups (6H vs PRE) as the cutoff criteria. If 90% LCB of FC between the 2 groups was greater than 1.2, the corresponding gene was considered to be differentially expressed. LCB is a stringent estimate of the FC and has been shown to be the better ranking statistic.²⁰ Recently, dChip’s LCB method for assessing differentially expressed genes has been shown to be superior to other commonly used approaches, such as Microarray Analysis Suite 5.0– and Robust Multiarray Average–based methods.^22,23 By using custom arrays and quantitative reverse transcriptase real-time polymerase chain reaction, it has been suggested that Affymetrix chips might underestimate differences in gene expression.¹⁷ Based on this work and others,²⁴ a criterion of selecting genes that have an LCB of greater than 1.2 most likely corresponds to genes with an "actual" FC of at least 3 in gene expression.

Gene Ontology Analysis
Once gene lists that are differentially expressed between various groups have been calculated, we identified the gene ontology (GO) categories for each of these input gene sets.²⁵ This approach suggests biologic areas that warrant further study by discovering GO categories that exist in significant abundance in the input gene list by using hypergeometric distribution (P < .05). For each category, the actual number represents the number of upregulated genes in that category. The expected number is a calculated value obtained by determining the ratio of genes in the particular category to the total number of genes and multiplying by the number of genes found to be upregulated. The expected number is therefore the number of genes predicted to be upregulated if the genes were distributed randomly among categories.

Pathway Analysis
Pathway analyses of genes were performed by using the Ingenuity Pathways Knowledge Base (Redwood City, Calif), which is a manually curated database of previously published findings on mammalian biology from the public literature. We used the network analysis, using the knowledge base to identify interactions of input genes within the context of known biologic pathways. To this end, we investigated the established pathways in the knowledge base.

Real-time Polymerase Chain Reaction
After total RNA extraction, concentrations were determined by means of spectrophotometry; each sample yielded a minimum of 10 µg of total RNA with an A260/A280 ratio ranging between 1.7 and 1.9. Integrity of total RNA was confirmed by means of Agarose gel electrophoresis, and only samples with a ratio of 2:1 28S/18S were used for analysis.

The quantitative real-time SYBR Green reaction was performed in duplicate, according to recommended protocols provided by the TaqMan ABI 7700 (Applied Biosystems, Foster City, Calif). RT2 polymerase chain reaction primers for the human genes analyzed were obtained commercially available (Superarray Bioscience Corp, Frederick, Md). Primers for the 3' ends of genes were used for microarray validation, including the downregulated genes HLA-DQA1, FBP2, and PYGB and the upregulated genes CYCL2, IFIH1, and TFAP2B.

Clinical Data Analysis
Clinical data were expressed as means ± SD. Following the "Statement of consensus on assessment of neurobehavioral outcomes after cardiac surgery" guidelines,¹⁵ we defined cognitive decline through a dichotomous variable as a 1-SD decrease from baseline on 25% of the tasks (2/8 measures). The ² test or Fisher exact test was used to compare proportions, and the Student t test was used to compare continuous variables. Software packages used were GraphPad Prism 4 (GraphPad, San Diego, Calif) and SPSS (SPSS 11.5 for Windows; SPSS, Inc, Chicago, Ill).

	Results

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Patient Characteristics
From 68 patients who were eligible for the study and approached for enrollment/consent during the study period, 24 refused enrollment. One patient was approached but was subsequently not consented because of delirium. Forty-three patients provided informed written consent and were enrolled. One patient was subsequently excluded from the analysis because of refusal to complete neuropsychologic assessment before discharge (voluntary withdrawal). Thus 42 patients were included in the analysis.

Early NCD rate at postoperative day 4 was 40.5% (17/42). Almost all patients returned to baseline cognitive function at the 3-month time point because the NCD rate was 2.5% (1/42). Baseline patient characteristics and key perioperative data were similar between patients who had NCD (NCD group) at postoperative day 4 compared with those who did not have NCD (NORM group) and are summarized in Table 1. Patients underwent similar intraoperative courses with respect to CPB technique, temperature, anesthesia, and perioperative monitoring. No focal neurologic deficits or stroke occurred in enrolled patients. Similarly, no differences were observed in other postoperative complications for patients in the NCD group compared with those in the NORM group. All patients had negative test results for depression preoperatively.

Cluster analysis of complete array expression values produced expression similarities across the samples. Hierarchic clustering of all samples demonstrated a clear distinction based on the sample collection time: PRE versus 6h. In the NCD group 6490 genes were upregulated and 1147 genes were downregulated at 6h compared with PRE. In the NORM group 8173 genes were upregulated and 1035 genes were downregulated at 6h compared with PRE. When these gene lists were compared, we found that 5959 genes were commonly upregulated at 6h versus PRE regardless of the NCD status, 531 genes were uniquely upregulated in NCD group patients, and 2214 genes were uniquely upregulated in NORM patients. Among the genes that were downregulated at 6h versus PRE, 477 genes were commonly downregulated regardless of the NCD status, 670 genes were uniquely downregulated in patients with NCD, and 558 genes were uniquely downregulated in patients without NCD (Figure 1). Selected upregulated and downregulated genes are presented for NCD group patients only (Tables E1 and E2) and NORM patients only (Tables E3 Õand E4).

View larger version (49K): [in this window] [in a new window]   Figure 1. Genes that were differentially expressed after cardiopulmonary bypass (CPB) in patients with (NCD group) and without (NORM group) neurocognitive decline: A, upregulated genes; B, downregulated genes. 6H, Six hours postoperatively in the cardiovascular intensive care unit; PRE, preoperatively after induction of anesthesia and before skin incision.

Table 2 summarizes selected categories of genes that contained significantly more than expected numbers of genes for a particular pathway when comparing the NCD and NORM groups (P < .05). Among the genes that were downregulated uniquely in the NCD group compared with the NORM group, GO BP categories of pathways that were significant included immune response, antigen presentation, antigen processing, humoral immune response, T-cell activation, and cell-cell adhesion (Figure 2). Genetic pathways that were uniquely downregulated in NORM patients included defense response and neuropeptide signaling pathway categories. When upregulated genes in patients with NCD were analyzed, we identified blood coagulation as an important GO BP category that was represented with a significantly greater number of genes than the NORM group. Similarly, cell redox homeostasis, response to stress, antiapoptosis, and fatty acid ß-oxidation were identified as selected GO BP categories that were in significant abundance among the genes that were upregulated in NORM patients. A complete list of GO BP categories that are represented significantly in genes that were uniquely upregulated or downregulated depending on their NCD status can be found in online supplementary data (http://www.bidmcgenomics.org/NCD).

View larger version (96K): [in this window] [in a new window]   Figure 2. Heat maps with hierarchic clustering of genes in pathways showing differential expression in patients with neurocognitive decline (NCD) versus those without neurocognitive decline (NORM group). The cell-cell adhesion (A) and immune response (B) pathways were both downregulated postoperatively uniquely in the NCD group. The blood coagulation pathway (C) was upregulated uniquely in the NCD group. Also, the response-to-stress pathway (D) was uniquely upregulated in the NORM group.

View larger version (24K): [in this window] [in a new window]   Figure 3. Significantly different expression of genes involved in the antigen presentation pathway in patients with neurocognitive decline (NCD; A) in contract to patients without neurocognitive decline (NORM; B). Red, Upregulation; green, downregulation.

View larger version (21K): [in this window] [in a new window]   Figure 4. Confirmation of microarray gene-expression data by means of SYBR Green real-time polymerase chain reaction in 6 differentially expressed genes. Human 18S ribosomal RNA (18SrRNA) was used to normalize mRNA levels between samples. Values are shown for each gene as fold change (FC) in mRNA expression at 6 hours postoperatively (6H) compared with preoperative expression (PRE). Mean fold change ± standard error of the mean is shown.

	Discussion

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We believe that this study sheds some light on this issue because it highlights the important inherent differences that exist at the genetic level between patients who have type 2 brain injury after CPB, as manifested by NCD, and those who do not have this complication. By using genome-wide microarray gene-expression methods, we identified several genetic pathways that were differentially regulated in patients with NCD with statistical significance. For example, patients in the NCD group had significant downregulation of pathways involving inflammation, antigen presentation, T-cell activation, and intercellular adhesion. Such pathways are critical components of the patients’ response to the CPB insult. We cannot, however, determine exactly from this study how such downregulation affects the complex cascade of intracellular and extracellular events that eventually culminate in NCD because their clinical significance might not be entirely clear. It is possible that downregulation of the cell-cell adhesion pathway leads to increased vascular permeability and increased brain edema in these patients. Similarly, it might be that upregulation of the blood coagulation pathway in patient with NCD leads to increased microthrombotic events, which lead to decreased perfusion to the hippocampus and cerebrum. Also, upregulation of genes involved in the response-to-stress pathway in NORM patients might have had a protective effect against brain injury.

Our data point to the fact that CPB does not cause an indiscriminate variation in gene expression in all patients. Rather, depending on the patient, CPB induces a distinct pattern of changes in specific pathways that are highly associated with NCD postoperatively. These data and subsequent conclusions were based on patients with similar baseline clinical and perioperative characteristics and then subjected to stringent bioinformatics analysis and validation by using conventional techniques. Sample size is a clear limitation to this study because some of the baseline clinical parameters between the 2 groups might have reached significance if the sample size was larger. This study, however, demonstrates these strong associations despite the sample size, which attests to the strength of relationships between particular pathway regulation and NCD status.

Another important observation from this study is that inflammatory and immunologic responses to CPB are inherently different at the genetic level in patients, depending on NCD status. This corroborates previous work by our group that revealed proteomic differences in which patients with NCD after CPB had significantly higher serologic inflammatory indices compared with those of patients without NCD after CPB.¹⁴ This link to the patients’ differential inflammatory response to brain injury is not isolated to the cardiac surgical sphere. During the inflammatory response, peripheral cytokines have been found to penetrate the blood-brain barrier directly through active transport mechanisms or indirectly through vagal nerve stimulation.³¹ It has been shown that inflammatory mechanisms within the CNS contribute to cognitive impairment through cytokine-mediated interactions between neurons and glial cells (eg, neurodegenerative diseases, such as Alzheimer’s and vascular dementia).³¹ Also, this response promotes membrane permeability and edema, contributing to end-organ dysfunction and possible neurologic injury observed in many patients.

In a recent study it was found that long-term cognitive outcomes after cardiac surgery are no different in patients undergoing conventional coronary revascularization with CPB compared with those in medically treated cardiac patients as control subjects.³² Such important studies, as well as this one (NCD rate at 3 months decreases to 2.5%) underscore the increasing body of evidence that such type 2 neurologic deficits are transient rather than long term. Potentially, in genetically susceptible patients the cognitive deficits are manifested during times of perioperative inflammatory stress and subsequently resolve as the inflammatory response subsides.

Our data certainly point to an inherently different response to CPB at the genetic level in patients who have NCD postoperatively. Certainly, such findings also point to a bigger question: Do these patients, or other cohorts, react differently to different insults, and thus are they more prone to increased complications? Such studies might prove to be beneficial in improving preoperative risk assessment and elucidating the pathophysiology of other surgical complications. We hope that further study of differentially expressed genetic pathways, in addition to established knowledge on clinical risk factors and perioperative factors, will translate into better understanding of NCD pathophysiology after CPB. In the short-term, however, it might be that such data would form the basis for a database of genetic information that could prove beneficial gene-based risk-stratification strategies.

	Footnotes

 
Supported by the Irving Bard Memorial Fellowship.

¹ Dr Basel Ramlawi is supported by grant HL04095-06 from the National Institutes of Health (NIH), as well as a CIHR/Canadian Stroke Network Postdoctoral Research Fellowship.

² Dr Frank Sellke is supported by grant HL-46716 from the NIH.

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