Ann Thorac Surg 2006;82:895-901
© 2006 The Society of Thoracic Surgeons
Original article: Cardiovascular
Gene Polymorphism and Requirement for Vasopressor Infusion After Cardiac Surgery
Ronan Ryan, MB, FRCSIa,
Jacinta Thornton, PhDb,
Edel Duggan, MB, FFARCSIb,c,
Eilis McGovern, MB, FRCSIa,
Michael J. O'Dwyer, MB, FFARCSIb,c,
Anthony W. Ryan, PhDb,
Dermot Kelleher, MD, FRCPIb,
Ross McManus, PhDb,
Thomas Ryan, MB, MRCPIc,*
a Department of Cardiothoracic Surgery, St. James's Hospital, Dublin, Ireland
b Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College, Dublin, Ireland
c Department of Anaesthesia and Intensive Care Medicine, St. James's Hospital, Dublin, Ireland
Accepted for publication April 7, 2006.
Abbreviations and Acronyms ADMA = asymmetrical dimethylarginine; CSNK2B = casein kinase 2 beta subunit; DDAH = dimethylarginine dimethylaminohydrolase; ICU = intensive care unit; IkBL, NFkBIL1 = inhibitor of kappa B like protein; LD = linkage disequilibrium; LTA = lymphotoxin alpha; SNP = single nucleotide polymorphism; TNF = tumor necrosis factor
* Address correspondence to Dr Thomas Ryan, Department of Anaesthesia, St. James's Hospital, James St, Dublin 8, Ireland (Email: ryants{at}iol.ie).
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Abstract
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BACKGROUND: Genes in the class III region of the MHC, encoding proteins involved in inflammation and vascular regulation, were investigated for association with the occurrence of vasodilation and requirement for vasopressor infusion.
METHODS: A cohort of 236 elective cardiac surgical patients was studied. Hemodynamic and metabolic variables and dosage of vasopressor medications were recorded for the first 12 hours of intensive care unit admission after cardiac surgery on an electronic patient record. Demographic factors and operative details were recorded from other institutional databases. The DNA was extracted from peripheral blood mononuclear cells and genotyped for the presence of polymorphic alleles in genes coding for inflammation-related proteins.
RESULTS: Carriage of the dimethylarginine dimethylaminohydrolase II (DDAH II) –449 G allele and the lymphotoxin alpha +252 G allele was significantly less frequent in patients who required infusions of vasopressors after cardiac surgery. On multivariate analysis, prior myocardial infarction, prolonged bypass, and the homozygous carriage of the DDAH II C allele were associated with postoperative vasopressor requirement.
CONCLUSIONS: Vasopressor requirement after surgery may be related to an interaction of genotype, preoperative morbidity, and prolonged surgery.
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Introduction
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Systemic inflammation in postoperative cardiac surgical patients manifests as systemic arterial vasodilation with a high cardiac index and a low systemic vascular resistance [1], and may require treatment with vasopressor agents to maintain adequate organ perfusion. In this context, the catecholamines epinephrine and norepinephrine are in common usage. This acute inflammatory response is likely due to surgical trauma and the continuous exposure of heparinized blood to nonendothelial cell surfaces during cardiopulmonary bypass. However, the host response to cardiopulmonary bypass is likely a result of interaction of the intensity and duration of the precipitant with certain innate patient characteristics. These characteristics may have a genetic basis due to carriage of specific functional polymorphic alleles in genes coding for proteins involved in inflammation and vascular regulation.
The major histocompatibility complex encodes the human leukocyte antigen class I and class II molecules, which play an important role in adaptive immunity. Between these two gene clusters is a region densely packed with a selection of genes involved in a variety of biological activities predominantly related to immunity. The best characterized of these is probably tumor necrosis factor alpha (TNF
), a powerful proinflammatory cytokine involved in a wide variety of functions. Altered regulation of this gene due to variation in its regulatory regions has been shown to be associated with a number of diseases including sepsis, autoimmune diseases, rheumatoid arthritis, and cancer [2–5].
Other important genes in this region, in which variation has been implicated in disease, include lymphotoxin alpha (LTA), which is believed to be involved in modulation of immune function. Lymphotoxin alpha polymorphisms have been linked with susceptibility to myocardial infarction and outcome in community-acquired pneumonia [6, 7]. Also in close proximity is another gene of interest, inhibitor of kappa-B-like protein (IkBL or NFkBIL1), which has been associated with both rheumatoid arthritis and ulcerative colitis susceptibility [8, 9]. This region also contains the casein kinase II beta subunit (CSNK2B) gene, a ubiquitous highly conserved enzyme, and the gene encoding dimethylarginine dimethylaminohydrolase II (DDAH II), which regulates cellular methylarginine concentrations, which in turn inhibit nitric oxide synthase activity [10]. Expression of DDAH II predominates in more highly vascularized tissues and in immune tissues.
Common single-nucleotide polymorphisms (SNPs) in some of these genes may be implicated in the occurrence of systemic inflammation with consequent hemodynamic instability after cardiac surgery. To investigate this hypothesis, a study was performed to determine whether there was a relation between requirement for vasopressor infusions in patients after cardiac surgery and carriage of specific alleles in genes coding for TNF and the aforementioned adjacent genes on the sixth chromosome.
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Patients and Methods
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Patients having elective and uneventful cardiac surgery between July 2001 and December 2002 were considered for inclusion in this study, which was approved by the Institutional Ethics Review Committee, which also waived the need for consent for data publication.
All patients had similar cardiopulmonary bypass, with heparin-coated circuits and roller pumps. After surgery all patients were admitted to a dedicated cardiac surgical intensive care unit (ICU).
A clinical information system (Care Vue, Phillips Medical, Eindhoven, the Netherlands) in the cardiac surgical ICU captures data from physiologic monitoring, mechanical ventilators, and blood gas analyzers, and from laboratory-based servers storing biochemical and hematology results. Intensive care unit admission was timed from the timing of the first recorded heart rate in the ICU, and this time point was used to calculate the interval between ICU admission and subsequent events. Patient demographics, historic comorbidity, and operative details were retrieved from a separate institutional database.
Patients who required support with potent vasopressors such as epinephrine or norepinephrine in the first 12 hours after ICU admission were identified from the electronic archive, and the dosage of vasopressor infusion was retrieved. Hemodynamic variables, including cardiac index and systemic vascular resistance, and arterial blood gases, including lactic acid levels and hemoglobin were retrieved for the study interval.
The first 12 hours after ICU admission was divided into four 3-hour-long periods. Mean arterial pressure was averaged for each period, and the relation between mean arterial pressure and requirement for vasopressor infusion was analyzed to determine whether vasopressor use was appropriate. Similarly, mean arterial pressure in patients who were administered dopamine infusion for renal preservation without vasopressor agents was compared with mean arterial pressure in patients with no vasopressor or dopaminergic infusions. Clinical practice was not changed or modified for the purpose of the study.
On enrollment to the study, blood was drawn on all study patients and frozen at –70C for subsequent genomic analysis. Genomic DNA was extracted using the QIAmp DNA Midi kit (Qiagen, Hilden, Germany) following the manufacturer's instructions.
The SNPs used in this study comprised both polymorphisms that were previously identified in the literature, and associated with disease, as in the case of variations in TNF, LTA, and IkBL. In addition two SNPs were selected from CSNK2B, one of which, CSNK2B+2054 (rs805256), causes a synonymous nucleotide change, whereas the other, CSNK2B+4151 (rs4569) occurs in the 3 prime (3') untranslated region. One SNP was also chosen in the second intron of DDAH II. This variation has been designated DDAH II -449 (rs805305), relative to the translation start site because this gene has multiple transcription start sites [11]. Allelic variation for the SNPs was assayed using Amplifluor technology by Kbiosciences (Hoddeston, Herts, United Kingdom; http://www.kbioscience.co.uk/). Primer sequences are given in the Appendix for each of the assays used in this study.
Data were analyzed by t test, 
2 test, and Fisher's exact test where appropriate. Serial measures of mean arterial pressure was analyzed with analysis of variance for repeated measures. Factors that were significantly associated with vasopressor requirement on univariate analysis were included in a stepwise logistic regression analysis with the JMP (SAS Institute, Cary, North Carolina) statistical pack. All p values of less than 0.05 were considered significant. Haplotype frequency estimation was performed using the expectation maximation method as implemented by HITAGENE software (www.hitagene.com) and Phase 2.0 [12]. The significance of haplotype frequency differences between the two groups was determined using a modification of the haplotype association test described by Zaykin and associates [13] and implemented by HITAGENE.
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Results
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The study included 236 patients, with 56 (23%) requiring either epinephrine or norepinephrine infusion in the first 12 hours after ICU. Two patients died, 1 from each group. Forty-nine patients received epinephrine and 28 patients received norepinephrine infusions; 21 patients received both infusions. The details of these vasopressor infusion rates are in Table 1. The relation between postoperative vasopressor requirement, preoperative demographic factors, preexisting comorbidity, and operative details are listed in Table 2. Prior myocardial infarction and duration of aortic cross-clamping were significantly associated with requirement for vasopressor infusion after cardiac surgery.
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Table 2. Demographic Details, Preoperative Comorbidity and Operative Details in Relation to Requirement for Vasopressor Infusion After Cardiac Surgery
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Mean arterial pressure was significantly lower in the group of patients who required vasopressor infusion. The average central venous pressure over the 12-hour study period was significantly greater in patients who required infusion of vasopressor substances. Heart rate was greater in the vasopressor group. Thirty-four patients had thermodilution pulmonary artery catheters inserted at the time of surgery. In these patients, the systemic vascular resistance index was lower in the group of patients receiving vasopressors (Table 3).
In the group of patients receiving vasopressor support, the average pH, bicarbonate, and base deficit were lower, and the peak arterial lactic acid level was greater than in patients not receiving vasopressor support (Table 4). There was a trend toward a lower hemoglobin in the vasopressor group (9.2 ± 0.2 versus 9.6 ± 0.1; p = 0.07), but this did not reach statistical significance.
Dopamine infusion was administered, for preservation of renal function, to 40 patients, with 16 of these also receiving either epinephrine or norepinephrine. In the 24 patients who received dopamine without vasopressors, the average dose infused was 3.7 ± 0.3 µg · kg–1
· min–1. Mean arterial pressure was similar in patients who received dopamine infusion alone and those that did not receive either vasopressor or dopamine infusions.
The allele frequency for TNF, LTA, IkBL, CSNK2B, and DDAH II polymorphisms in the two groups are listed in Table 5. There was significant association between carriage of specific DDAH II and LTA alleles and requirement for vasopressor infusion after cardiac surgery. There was a significant difference between groups in the allele frequency and genotype frequency distributions of DDAHII-449 (p = 0.036 and 0.013, respectively). In particular, there is a significant difference in the frequency of patients homozygous for the DDAH II –449 G allele, with 16 patients in the vasopressor group (28.6%) homozygous for the DDAH II G allele compared with 91 patients (50.5%) in the group without vasopressors (odds ratio = 0.4, 95% confidence interval: 0.21 to 0.76; p = 0.005). Dominant/ recessive models, which are used to compare homozygous carriers of an allele with a combined group of heterozygotes and homozygotes for the alternative allele, indicate that presence of the C allele at this locus is associated with vasopressor requirement (p = 0.005). There was no significant association between DDAH II genotype and hemodynamic or arterial blood gas parameters. There was no association between DDAH II genotype and preexisting medical comorbidity such as prior myocardial infarction, prior congestive heart failure, peripheral vascular disease, cerebrovascular disease, or type of surgery.
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Table 5. Allele Frequency for Specific Polymorphic Alleles in Relation to Requirement for Vasopressor Infusion After Cardiac Surgery
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On stepwise multivariate logistic regression analysis, which included preoperative and operative factors significantly associated with postoperative inotrope requirement on univariate analysis, and including DDAH II -449 genotype (with DDAH II -449 G homozygotes contrasted with all other carrier states), only DDAH II -449 genotype, prior myocardial infarction and aortic cross-clamp time were associated with postoperative vasopressor requirement (Table 6).
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Table 6. Multivariate Logistic Regression Model of the Factors Associated With Vasopressor Infusion after Cardiac Surgery
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Haplotypes were generated composed of all markers genotyped in the region and subsets thereof. The distribution of haplotypes composed of all markers showed a differential trend between the vasopressor positive and negative groups that did not reach statistical significance (overall p = 0.065). However, when CSKN2B, the most central gene, is removed, haplotypes composed of the remaining markers showed statistically significant differences in haplotype distribution using a permutation based haplotype association test (described in Zaykin and coworkers [13]) despite the small numbers in the vasopressor group. The most striking associations are of haplotypes comprising the DDAH II –449, LTA 252, IKBL –62, TNF –863, TNF –857, and TNF –856 SNPs (overall p = 0.03). Thus, we show the frequency of the 12222 haplotype (where 1 is the more common allele) is 36.4% compared with 22.4% in the vasopressor negative versus positive groups (p = 0.01). Haplotype 2, composed of 21122, had a frequency of 18.2% compared with 29.3% (p = 0.02; Table 7).
Linkage disequilibrium (LD) analysis of the markers in the region confirm the previously established pattern of haplotype blocks in the region with SNPs in TNF, LTA, and IKBL all showing D prime (D') values approaching 1.0. As with previous studies, DDAH II does not show evidence of being in LD with these markers (D' < 0.5 for all significant comparisons). It is interesting to note that DDAH II shows high levels of LD with the CSNK2B 1942 and 3854 alleles in the vasoconstrictor positive group (D' = 1.00 and 0.90; p = 3.3 x 10–4 and 5.0 x 10–5, respectively), whereas this is not the case in the vasoconstrictor negative group (D' = 0.58 and 0.63; p < 1 x 10–3 in each case), indicating a difference in the haplotype structures in the two groups.
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Comment
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In this study of elective cardiac surgical patients, carriage of specific DDAH II -449 and LTA+252 alleles was associated with more frequent requirement for infusion of vasopressors after cardiac surgery.
The group of patients who did not require vasopressor infusion showed patterns of LD that were similar to that reported in previous studies of haplotype structure in this region [14], studies that have reported that DDAH II is inherited on a separate haplotype block from TNF, LTA, IKBL, and CSNK2B. In this study, however, haplotype analysis indicated the presence of an extended haplotype in the region, including DDAH II, that was significantly associated with requirement for vasopressor infusion. Furthermore, the patterns of LD in the two groups suggest extensive difference in haplotype structure. As the genetic polymorphisms that account for the variation in vasopressor requirement may reside anywhere within this extended haplotype, the LTA and DDAH II SNPs investigated in this study may not necessarily be the cause of the observed requirements, but may simply be linked on the haplotype to the actual causative SNPs. A further study, with a larger patient population and more extensive genotyping within this area, may help to clarify this issue.
In the limited number of patients with cardiac output measurements, systemic vascular resistance was less in patients who required vasopressor infusion, which is consistent with the well-described "low vascular resistance syndrome" seen after cardiac surgery, rather than cardiogenic shock related to impaired myocardial contractility. Furthermore, mean arterial pressure immediately after surgery was lower in patients who received vasopressors, confirming that infusion of vasopressors was appropriate.
The patient group studied were elective surgical patients, and experienced a low mortality rate. Within this relatively low risk group, prolonged surgery and prior myocardial infarct increased the likelihood of postoperative vasopressor requirement. This finding is consistent with studies of outcome after cardiac surgery, which have observed that these factors are associated with complicated recovery from surgery and prolonged intensive care stay [15]. In this context, it is likely that prolonged surgery represents a cofactor that increases the propensity to develop systemic inflammation with associated systemic vasodilation.
Endothelium-derived nitric oxide is a potent vasodilator that antagonizes the effects of endogenous vasopressors [16]. Nitric oxide is produced by a number of enzymes (synthases) that exist in constituitive or inducible isoforms. The endothelial isoform regulates vascular tone and interactions between leukocytes and endothelium. Nitric oxide production is increased in disease states associated with systemic arterial vasodilation, such as septic shock and after cardiac surgery [17, 18]. Furthermore, nitric oxide synthase inhibitors ameliorate the pathologic vasodilation seen in septic shock [19].
Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase found in circulating serum, may induce endothelial dysfunction [20]. A potent vasopressor, ADMA is elevated in patients with chronic renal failure [21]. Asymmetric dimethylarginine is derived from the catabolism of nuclear protein by protein arginine methyltransferase and is metabolized to citrulline by DDAH [22], which is thus an important regulator of ADMA levels. There are two forms of this enzyme (encoded by genes DDAH I and DDAH II located on chromosomes 1 and 6, respectively), with DDAH II found in tissues that express endothelial isoforms of nitric oxide synthase [10]. As DDAH II regulates ADMA levels, it is plausible that functional DDAH II gene polymorphisms may account for variation in ADMA levels and individual propensity to develop pathogenic vasodilation after cardiopulmonary bypass.
There are limited data on the role of ADMA and DDAHII in systemic inflammation. One study of critically ill patients observed a relationship between elevated ADMA levels and renal and hepatic failure in patients with severe sepsis [23]. Genetic variation has been observed in the promoter region of DDAH II, which may have functional significance [11]. Thus, DDAH II is a candidate gene for susceptibility to the vasodilation observed after cardiac surgery. However the extended haplotype seen in patients requiring vasopressor infusion extends over a large segment of the major histocompatability complex class III region, a region of the genome displaying significant LD. Therefore, it is possible that variation in a gene not included in this study is causative.
This study is consistent with similar but smaller studies of TNF and TNFß (otherwise known as LTA) bi-allelic polymorphism and clinical events after cardiac surgery. While Westerberg and colleagues [24] failed to find any link between carrier status for specific TNF and TNFß alleles and plasma TNF levels in a study of 86 cardiac surgical patients, Schroeder and associates [25] documented an association between greater TNF levels and TNFß allele carriage. However, Tomasdottir and associates [26], in a study of 95 patients, found an association between carriage of specific TNFß (LTA) alleles and ventricular dysfunction after cardiac surgery. This study adds to the expanding literature that attributes common clinical events after cardiac surgery to common constitutional genetic variations in the host. Thus, pulmonary dysfunction after surgery, lactic acidosis, and atrial fibrillation have been associated with cytokine or angiotensin-converting enzyme gene polymorphisms [25, 27, 28]. Indeed, the recovery phase after cardiac surgery may prove a very useful human model for studying systemic inflammation.
In conclusion, preoperative morbidity, prolonged surgery, and a particular DDAH II –449 allele are associated with an increase in the likelihood of hemodynamic instability after cardiac surgery.
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Appendix
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Acknowledgments
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Ross McManus, PhD, is funded by grants from the Wellcome Trust, Health Research Board of Ireland, and Hitachi Europe Ltd.
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Abstract
Introduction
