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Ann Thorac Surg 2004;78:520-526
© 2004 The Society of Thoracic Surgeons
a Division of Cardiothoracic Anesthesia and Critical Care Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA
b Cardiothoracic Surgery Division of the Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
Accepted for publication February 23, 2004.
* Address reprint requests to Dr Stafford-Smith, Box 3094, Duke University Medical Center, Durham, NC, USA 27710
e-mail: staff002{at}mc.duke.edu
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Abstract |
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4 allele has been linked to the occurrence of both postcardiac surgery acute renal injury (4 favorable) and ascending aortic arteriosclerosis (4 unfavorable), the role of 4 in the relationship between these two conditions is unknown. We hypothesized that patients with and without the 4 allele (E4/non-E4) would have different associations between atheroma burden and postoperative renal dysfunction.
METHODS: Ascending, arch, and descending aorta atheromatous burden and APOE status were evaluated for 130 coronary bypass patients. Multivariable analyses were performed for aortic regions to assess the relationship of atheroma burden and APOE 4 status with peak in-hospital postoperative serum creatinine. All p < 0.05 were considered significant.
RESULTS: We found an interaction between E4 status (E4/non-E4; 24/106) and atheroma burden, with a much greater predicted peak in-hospital postoperative serum creatinine for increases in ascending aorta atheroma load for non-E4 patients versus E4 patients (beta coefficient –0.13; p = 0.002). We also confirmed the association between ascending aorta atheroma and peak creatinine (beta coefficient 0.11; p = 0.0008), after controlling for E4 status, preoperative creatinine, and the E4–atheroma interaction.
CONCLUSIONS: Equivalent ascending aortic atheroma burden is associated with a greater susceptibility to postoperative renal injury among patients undergoing cardiac operation who lack the APOE 4 allele. Findings may be attributable to APOE-related differences in inflammation, susceptibility to atheroma detachment (eg, during operative aortic manipulation), or renal vulnerability to embolic injury.
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Introduction |
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Apolipoprotein E (APOE = gene; apoE = protein; = allele) has a central role in lipid metabolism but is also involved in many other physiologic processes, including small protein reuptake in the brush border of the proximal renal tubule. The APOE gene has three major alleles, designated 2, 3, and 4, at its gene locus on chromosome 19q13.2 [8]. Differing associations of APOE genotype with the occurrence and severity of postoperative acute renal dysfunction (4 favorable) and aortic arteriosclerosis (4 unfavorable) are known. We recently reported an association of the 4 allele with reduced acute postoperative rise in serum creatinine levels after cardiac operation compared with both the 2 and 3 alleles [6]. This finding is consistent with patterns observed in the setting of chronic renal disease [9, 10] but contrasts with the increased occurrence and severity of aortic arteriosclerosis and coronary artery disease associated with the APOE 4 allele; patients with this allele also present earlier in life for coronary bypass operation [7, 11–13].
However, whether APOE genotype affects the interaction between aortic arteriosclerosis and postoperative renal dysfunction is unknown. Therefore, using postoperative peak serum creatinine values, a widely used index of renal injury after cardiac operation, we hypothesized that possession of the APOE 4 allele (E4 versus non-E4) predicts the relationship between aortic atheroma burden and acute renal dysfunction after cardiac operation.
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Material and methods |
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Anesthesia and operation
Anesthesia was managed per the attending anesthesiologist's preference. In general, patients were premedicated with oral diazepam or lorazepam and methadone hydrochloride 90 minutes before anesthesia induction. Anesthesia was induced with intravenous thiopentone, midazolam, and fentanyl. Anesthesia maintenance was achieved with 0.5% to 1.0% isoflurane. Vecuronium or pancuronium was given as required to maintain neuromuscular blockade, and all patients received metoprolol 10 mg intravenously before cardiopulmonary bypass. Use of agents with potential renal effects (eg, intravenous dopamine, diuretics, and antifibrinolytic agents) was not controlled. Cardiopulmonary bypass (CPB) was performed using a Cobe CML Duo blood oxygenator with sealed hard-shell filtered venous reservoir (Cobe Laboratories, Lakewood, CO), a Cobe Century Perfusion System (Cobe Laboratories), and a 43-micron arterial line filter (Cobe Sentry arterial line filter with Primegard, Cobe Cardiovascular Inc, Arvada, CO). Blood obtained by cardiotomy suction was routed by the roller pump into the integrated oxygenator-venous reservoir. Nonpulsatile perfusion was maintained at 2 to 2.4 L · min–1 · m–2. The bypass circuit was primed with mannitol (50 g of a 20% solution) and crystalloid solution (0.9% normal saline). The arterial carbon dioxide tension was maintained throughout bypass at 35 to 40 mm Hg (uncorrected for temperature), with the arterial oxygen tension maintained at 150 to 250 mm Hg. Mean arterial pressure was maintained between 50 and 70 mm Hg during bypass using intravenous phenylephrine or sodium nitroprusside as required. Patients were cooled to a nasopharyngeal temperature of 34°C to 28°C during CPB and rewarmed to a nasopharyngeal temperature of 37°C or a bladder temperature of at least 36°C before separation from cardiopulmonary bypass. Typically, at the time of the study, transesophageal echocardiography (TEE) findings were not incorporated into aortic cross-clamping decisions, and epiaortic studies were not routinely performed. Standard practice included two aortic clamp applications: one full aortic cross-clamp for cardioplegia and a second side-biter clamp for proximal vein anastomosis.
Apolipoprotein E analysis
Genomic DNA from a blood sample was analyzed for APOE genotype using a published method with minor modifications for fluorographic rather than autoradiographic detection of DNA [15]. Briefly, high molecular weight DNA was extracted from prepared crude leukocyte nuclei by the Genepure automated nucleic acid extractor (P.E. Applied Biosystems, Foster City, CA). The three major APOE alleles are then identified using a polymerase chain reaction-based restriction enzyme genotyping protocol. For the current analysis, homozygote and heterozygote carriers of the APOE 4 allele were grouped together (E4 group) and compared with patients without any APOE 4 allele (non-E4 group). Study personnel were blinded to the results.
Atheroma assessment
Aortic atheroma data were extracted from the comprehensive TEE examination performed as part of routine care in all patients. The thoracic aorta was imaged with the following method in accordance with published Society of Cardiovascular Anesthesiologists/American Society of Echocardiography guidelines:
All examinations were performed either by cardiothoracic anesthesiology fellows not directly involved in the care of the anesthetized patient or by the attending anesthesiologist. The examinations were performed before initiation of CPB and completed according to recommended guidelines [16]. Each TEE study was recorded on videotape and later evaluated off-line for study purposes.
The videotaped TEE examination of each segment of the aorta was reviewed in a frame-by-frame fashion to select the frame that displayed the most atheromatous area in each aortic segment (ascending, arch, and descending). The frame was digitized and analyzed using image analysis software (NIH Image 1.6.2; National Institutes of Health, Bethesda, MD). Atheroma burden in each segment was calculated as the percent area of the aorta containing atheroma; the areas "A" (reflecting the area of plaque) and "B" (reflecting the total vessel area including the plaque) depicted in Figure 1 were used as a ratio to calculate the percent of vessel area represented by plaque (% atheroma). All measurements were done in consensus between two investigators certified in perioperative TEE by the National Board of Echocardiography (G.B.M., L.T.). These investigators were blinded to the APOE 4 status and perioperative creatinine levels of the patients.
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Cr = CrmaxPost – CrPre) were used for analysis of postoperative renal function. Creatinine clearance (CrCl) values were derived from CrPre and CrmaxPost values using the Cockroft-Gault equation [17].
Statistical analysis
Demographic and perioperative characteristics were compared between E4 and non-E4 patients. Continuous variables were compared with t tests; categorical variables were compared with 
2 tests. All p < 0.05 were considered significant. To investigate the relationship between % atheroma burden, E4 status, and peak postoperative serum creatinine, separate linear multivariable regression models were created for each of the three aortic locations. Each model contained as covariates E4 status, % atheroma burden for the aortic location being assessed, and CrPre. To investigate the possibility that the relationship between atheroma burden and CrmaxPost was different for apoE E4 and non-E4 subjects, we also tested for an interaction effect between apoE status and atheroma burden (E4 x % atheroma burden). Assumptions of the linear regression analysis were verified. All p < 0.05 were considered significant. All statistical analyses were performed using the SAS statistical software version 8.0 (SAS Institute, Cary, NC).
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Results |
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4 allele (Table 1).
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4 allele was present in 24 of 130 patients (18.5%), a distribution comparable to those previously reported in large populations undergoing coronary angiography or CABG operation [6, 18]. Genotypes included 4/3 (n = 22; 16.9%), 4/2 (n = 2; 1.5%), 3/3 (n = 89; 68.5%), and 2/3 (n = 17; 13.1). No subjects had 4/4 or 2/2 genotypes.
Perioperative renal data and atheroma burden
Renal function variables were similar between E4 (n = 24) and non-E4 (n = 106) groups (Table 2). Descriptive raw data for % atheroma are presented in Table 3. We observed a trend in our raw data that was consistent with the association of ascending aortic % atheroma with CrmaxPost as reported previously [4]. However, no significant univariate relationship was noted between atheroma burden and CrmaxPost at any of the aortic locations (ascending, p = 0.13; arch, p = 0.78; descending, p = 0.87).
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4 allele (E4/non-E4) would have different associations between atheroma burden and postoperative renal dysfunction, a multivariable analysis was performed, including apoE status and % atheroma and the interaction between the two variables. In addition, preoperative serum creatinine was included in the model because it is by far the largest predictor of peak postoperative creatinine [1, 3]. In terms of other demographic variables and known renal risk factors (Table 1), no other covariates were different between the groups; therefore none were included in the multivariable model. In our multivariable linear regression model (Table 4) with CrmaxPost as the principal outcome of interest and E4 status as a covariate, we observed a strong association between % atheroma in the ascending aorta and CrmaxPost (beta coefficient 0.11; p = 0.0008). We also found a significant interaction between E4 status and % atheroma with a much greater predicted CrmaxPost for increases in ascending aorta atheroma burden for non-E4 seconds versus E4 seconds (beta coefficient –0.13; p = 0.002; Fig 2, Table 4), after controlling for preoperative creatinine.
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Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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The results of this study are in agreement with our previous finding that non-E4 patients are more vulnerable to renal injury after cardiac operation whereas the 4 allele is associated with a nephroprotective effect [6]. These findings are also consistent with the APOE allele-specific pattern that has been described for some chronic renal diseases. Whereas the 3 and the 2 allele have been associated with chronic nephropathies [10], the 4 allele has been linked with reduced risk of diabetic nephropathy [9]. Although this "renal" pattern of APOE allele-associated risk (ie, 4 favorable) appears to be consistent for acute (eg, operation-related) and chronic renal dysfunction, this finding is in marked contrast to the association observed for arteriosclerosis, onset and severity of ischemic heart disease, and several acute and chronic neurologic disorders (ie, 4 unfavorable) [7, 8, 15, 19]. The crux of this "4 conflict," in light of known associations, is the apparent contradiction inherent in the risk increase for arteriosclerosis but reduction for renal injury associated with this allele.
The APOE 4 allele is associated with the development of arteriosclerosis. Possibly related to the important role of the apoE protein in lipoprotein metabolism, genotype is a significant predictor of the progression and complications of arteriosclerosis. In a meta-analysis of 14 observational studies, the APOE 4 allele was found to be associated with a greater risk (odds ratio 1.26) of coronary heart disease in both men and women [20]. An age-dependent effect of the APOE 4 allele on coronary arteriosclerosis may explain our recent finding that APOE 4-positive patients present earlier in life for coronary bypass operation [13]. The association between the APOE 4 allele and the percentage of the abdominal and thoracic aorta atherosclerotic involvement has been confirmed by others [7]. Arteriosclerosis of the ascending aorta is a significant predictor of acute renal dysfunction after cardiac operation [4]; our findings are consistent in this regard. At autopsy after cardiac operation, Blauth and colleagues [5] found 10.4% of 221 patients to have had acute renal atheroembolic disease, and a high correlation between emboli and severity of arteriosclerosis of the ascending aorta. The numerous manipulations of the ascending aorta during cardiac operation, such as palpation, cannulation, cross-clamping, and decannulation, may make this region susceptible to detachment of atheromatous material. Therefore, we speculate that the association of atheroma with renal dysfunction may be related to increased embolic load with greater atheroma burden.
In this regard, the E4 allele would be expected to be associated with increased postcardiac operation renal injury. Paradoxically, compared with E4 patients, non-E4 patients have a greater rise in peak postoperative creatinine with equivalent atheroma burden. The apoE phenotype may predict different susceptibilities to atheroma detachment (eg, during operative aortic manipulation) or renal vulnerability to injury from an embolic load [21]; during cardiac operation, these factors may assume greater significance than the direct association between atheroma burden and renal injury.
Our study is unique in examining the relationship of APOE genotype, arteriosclerosis, and renal dysfunction in cardiac surgical patients. Using a sensitive method of arteriosclerosis assessment that evaluated the greatest two-dimensional plaque area as a marker of aortic regional atheroma burden, we confirmed the association of increasing ascending aortic atheroma burden with greater peak postoperative serum creatinine values. Limitations of our study include the fact that our atheroma assessment technique utilized a two-dimensional image of a specific segment of the aorta. Preferably, a three-dimensional image of the entire length of the aortic segment would be used to allow a volumetric quantification of atheroma burden. Accepting the current technological limitations of TEE imaging, our new method to assess the percent atheroma does at least account for total plaque area that can be visualized. In addition, the ability of TEE to adequately image the distal portion of the ascending aorta is limited because of masking by the large airways. Epiaortic imaging is a more sensitive measure of assessing plaque in the ascending aorta, and it is possible that a greater degree of arteriosclerosis may have been detected with epiaortic scanning [22]. Finally, our technique did not account for a mobile atheroma component. While our method of aortic plaque assessment is quantitative only, others have found qualitative assessment of plaque (eg, mobile, protruding debris/thrombus, calcification, ulceration) to also contribute to risk stratification. Using epiaortic ultrasound to assess the ascending aorta in 978 patients undergoing cardiac operation, Davila-Roman and colleagues [4] demonstrated the greatest postoperative renal dysfunction to be associated with these complex plaques. Nonetheless, without this added information, we found a positive association, in interaction with apoE E4, between ascending aorta arteriosclerosis and postoperative renal dysfunction.
We acknowledge the small number of patients in this genotype-phenotype association study; caution is necessary in deriving general conclusions, particularly for negative findings such as the lack of association of arch or descending aortic atheroma burden, in interaction with apoE status, with postoperative renal dysfunction. It is possible that larger numbers of subjects would also demonstrate associations with arch and descending aorta arteriosclerosis. To address this power issue, we calculated the sample size that would be required to have 80% power to find effect sizes in the arch and descending aorta equivalent to those reported here as significant. In the arch, analysis shows that 266 patients would be required to detect a significant interaction between % atheroma and E4 status. In the descending aorta, 389 patients would be required to detect a significant interaction between % atheroma and E4 status. These interaction terms test the hypothesis that the slopes of the E4 and non-E4 patients (as depicted in Fig 2) are equivalent.
Analysis of serum creatinine values is only a marker of renal filtration function and may not be the ideal method to assess perioperative changes in renal function. However, maximum postoperative values repeatedly have been shown to be independently associated with morbidity and mortality after cardiac operation, which allows for a better comparison of our data [1, 3]. Other more accurate tests of renal function, such as 24-hour urine collections for creatinine clearance, have been less studied in their relationship to outcome after cardiac operation and have their own limitations during the perioperative period. Although diabetes has been identified as an independent predictor of postoperative acute renal injury [1, 3], this variable was not significant when inserted into the multivariable model (p = 0.14). Possibly with larger populations this trend would become a significant effect.
In conclusion, we found that equivalent ascending aortic atheroma burden is associated with greater susceptibility to postoperative renal injury after cardiac operation in patients lacking the APOE 4 allele. We also confirmed the association of ascending aortic atheroma burden with peak serum creatinine after cardiac operation. These findings may be attributable to APOE allele-related differences in inflammation, susceptibility to atheroma detachment (eg, aortic manipulation during operation), or renal vulnerability to embolic injury. Testing for the APOE 4 allele may be useful for preoperative renal risk stratification. Insight into the mechanisms underlying the differences in renal injury among APOE alleles may ultimately facilitate the development of novel renoprotective strategies.
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Acknowledgments |
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