More than 40 million patients undergo surgery annually in the United States at a cost of $450 billion. Each year approximately 1 million patients sustain medical complications after surgery, resulting in costs of $25 billion annually. The proportion of the US population older than 65 years is estimated to double in the next 2 decades, leading to a 25% increase in the number of surgeries, a 50% increase in surgery-related costs, and a 100% increase in complications from surgery. Recognizing the significant increase in surgical burden due to accelerated aging of the population and increased reliance on surgery for treatment of disease, the National Heart, Blood and Lung Institute recently convened a working group on perioperative medicine. The group concluded that perioperative complications are significant, costly, variably reported, and often imprecisely detected; and they identified a critical need for accurate comprehensive perioperative outcome databases. Furthermore, presurgical risk profiling is inconsistent and deserves further attention, especially for noncardiac, nonvascular surgery and older patients.69
Although many preoperative predictors have been identified and are constantly being refined, risk stratification based on clinical, procedural, and biologic markers explains only a small part of the variability in the incidence of perioperative complications. As mentioned earlier, it is becoming increasingly recognized that perioperative morbidity arises as a direct result of the environmental stress of surgery occurring on a landscape of susceptibility that is determined by an individual's clinical and genetic characteristics, and it may even occur in otherwise healthy individuals. Such adverse outcomes will develop only in patients whose combined burden of genetic and environmental risk factors exceeds a certain threshold, which may vary with age. Identification of such genetic contributions not only explains disease causation and susceptibility but also influences the response to disease and drug therapy; and incorporation of genetic risk information in clinical decision making may lead to improved health outcomes and reduced costs. For instance, understanding the gene–environment interactions involved in atherosclerotic cardiovascular disease and neurologic injury may facilitate preoperative patient optimization and resource utilization. Furthermore, understanding the role of allotypic variation in proinflammatory and prothrombotic pathways, the main pathophysiologic mechanisms responsible for perioperative complications, may contribute to the development of target-specific therapies, thereby limiting the incidence of adverse events in high-risk patients. To increase clinical relevance for the practicing perioperative physician, we summarize the existing evidence by specific outcome while highlighting candidate genes in relevant mechanistic pathways (Tables 4-4, 4-5, and 4-6).
Biomarkers of Adverse Perioperative Cardiovascular Outcomes
Perioperative Myocardial Infarction and Ventricular Dysfunction
Patients with underlying cardiovascular disease can be at increased risk for perioperative cardiac complications. Over the last few decades, several multifactorial risk indices have been developed and validated for both noncardiac (eg, Lee's Revised Cardiac Risk Index) and cardiac surgical patients (eg, Hannan scores), with the specific aim of stratifying risk for perioperative adverse events. However, these multifactorial risk indices have only limited predictive value for identifying patients at the highest risk of perioperative myocardial infarction (PMI).70 In this context, it has been proposed that genomic approaches could aid in refining an individual's risk profile. Several reports from animal models, linkage analysis, and family, twin, and population association studies have confirmed the role of genetic factors in the etiology and progression of CAD. Specifically, both deaths from CAD as well as hazardous patterns of angiographic CAD (left main and proximal disease), known to be major risk factors for adverse perioperative events, are highly heritable. Similarly, a number of linkage and association studies,10,16 including a well-powered and replicated GWAS,39 have identified genetic susceptibility to MI in ambulatory population-based cohorts. The collective evidence from these studies suggests a strong genetic contribution to the risk of adverse cardiovascular outcomes in general but do not directly address the heritability of adverse perioperative myocardial events.
The incidence of PMI following cardiovascular surgery remains between 7% and 19%,71,72 despite advances in surgical, cardioprotective, and anesthetic techniques, and it is consistently associated with reduced short- and long-term survival in these patients. The pathophysiology of PMI after cardiac surgery involves systemic and local inflammation, "vulnerable" blood, and neuroendocrine stress.3 In noncardiac surgery, PMI occurs as a result of two distinct mechanisms: (1) coronary plaque rupture and subsequent thrombosis triggered by a number of perioperative stressors including catecholamine surges, proinflammatory, and prothrombotic states; and (2) myocardial oxygen supply-and-demand imbalance.73 Interindividual genetic variability in these mechanistic pathways is extensive, which may combine to modulate overall susceptibility to perioperative stress and ultimately the magnitude of myocardial injury. Nevertheless, until recently, only a few studies have explored the role of genetic factors in the development of PMI,25,74,75 mainly conducted in patients undergoing CABG surgery (Table 4-4).
Inflammatory Biomarkers and Perioperative Myocardial Outcomes
Although the role of inflammation in cardiovascular disease biology has long been established, we are just beginning to understand the relationship between genetically controlled variability in inflammatory responses to surgery and PMI pathogenesis. Recently, three inflammatory gene SNPs were described to have an independent predictive value for incident PMI after cardiac surgery performed with CPB.17 These include the proinflammatory cytokine interleukin-6 (IL6-572G>C) and two adhesion molecules: intercellular adhesion molecule-1 (ICAM1 Lys469Glu) and E-selectin (SELE 98G>T). Furthermore, the predictive ability of a PMI model based only on traditional risk factors was improved by the addition of genotypic information. Similarly, Collard et al identified a combined haplotype in the mannose-binding lectin gene (MBL2LYQA secretor haplotype), an important recognition molecule in the lectin complement pathway, to be independently associated with PMI in a cohort of white patients undergoing first-time CABG with CPB.18 Genetic variants in IL6 and TNFA have also been described in association with increased incidence of postoperative cardiovascular complications including PMI after lung surgery for cancer.76 Several polymorphisms in key proinflammatory genes have been associated with robust increases in perioperative inflammatory responses in patients undergoing cardiac surgery with CPB. These include the promoter SNPs in IL6 (-572G>C and -174G>C),77 also shown to prolong the hospital length of stay78; the apolipoprotein E genotype (the ϵ4 allele)79; SNPs in the tumor necrosis factor genes (TNFA-308G>A, LTA+250G>A),80 also associated with postoperative left ventricular dysfunction81; and a functional SNP in the macrophage migration inhibitory factor (MIF).82 Conversely, a genetic variant modulating the release of the anti-inflammatory cytokine interleukin-10 (IL10-1082G>A) in response to CPB has been described, with high levels of IL-10 surprisingly being associated with postoperative cardiovascular dysfunction.83 In patients undergoing elective surgical revascularization for peripheral vascular disease, several SNPs in IL6 (-174 G>C, nt565 G>A) and IL10 (-1082 G>A, -819 C>T, -592 C>A, and the ATA haplotype) were associated with endothelial dysfunction and an increased risk of a composite end point of acute postoperative cardiovascular events.84
C-reactive protein (CRP) is the prototypical acute-phase reactant and the most extensively studied inflammatory marker in clinical studies, and high-sensitivity CRP (hs-CRP) has emerged as a robust predictor of cardiovascular risk at all stages, from healthy subjects to patients with acute coronary syndromes and acute decompensated heart failure.85 Whether CRP is merely a marker or also a mediator of inflammatory processes is yet unclear, but several lines of evidence support the latter theory. In perioperative medicine, elevated preoperative CRP levels have been associated with increased short- and long-term morbidity and mortality in patients undergoing primary elective CABG (cut-off >3 mg/L)86 as well as in higher acuity CABG patients (cut-off >10 mg/L).87 Interestingly, in a retrospective analysis of patients with elevated baseline hs-CRP levels undergoing off-pump CABG surgery, preoperative statin therapy was associated with reduced postoperative myocardial injury and need for dialysis.88 In elective major noncardiac surgery patients, preoperative CRP levels (cut-off >3.4 mg/L) independently predicted perioperative major cardiovascular events (composite of MI, pulmonary edema, and cardiovascular death) and significantly improved the predictive power of the Revised Cardiac Risk Index (RCRI) in receiver operating characteristic analysis.89
In addition to the already established heritability of elevated baseline plasma CRP levels, recent reports indicate that the acute-phase rise in postoperative plasma CRP levels is also genetically determined. The CRP1059G>C polymorphism was associated with lower peak postoperative serum CRP following both elective CABG with CPB,90 as well as esophagectomy for thoracic esophageal cancer.91 Furthermore, CRP-717C>T polymorphism was associated with stress hyperglycemia in patients undergoing esophagectomy for cancer, leading to increased postoperative infectious complications and intensive care unit length of stay.92
Hemostatic Biomarkers and Perioperative Myocardial Outcomes
The host response to surgery is also characterized by alterations in the coagulation system, manifested as increased fibrinogen concentration, platelet adhesiveness, and plasminogen activator inhibitor (PAI)-1 production. These changes can be more pronounced after cardiac surgery, where the complex and multifactorial effects of hypothermia, hemodilution, and CPB-induced activation of coagulation, fibrinolytic, and inflammatory pathways are combined. Dysfunction of the coagulation system following cardiac surgery may manifest on a continuum ranging from increased thrombotic complications such as coronary graft thrombosis, PMI, stroke, pulmonary embolism at one end of the spectrum, to excessive bleeding as the other extreme. The balance between normal hemostasis, bleeding, and thrombosis is markedly influenced by the rate of thrombin formation and platelet activation, with genetic variability known to modulate each of these mechanistic pathways,93 suggesting significant heritability of the prothrombotic state (see Table 4-6 for an overview of genetic variants associated with postoperative bleeding). Several genotypes in hemostatic genes have been associated with increased risk of coronary graft thrombosis and myocardial injury following CABG. A genetic variant in the promoter of the PAI-1 gene, consisting of an insertion (5G)/deletion (4G) polymorphism at position -675 has been associated with changes in the plasma levels of PAI-1. Because PAI-1 is an important negative regulator of fibrinolytic activity, its polymorphism has been associated with increased risk of early graft thrombosis after CABG94 and, in a meta-analysis, with increased incidence of MI.95 Similarly, a polymorphism in the platelet glycoprotein IIIa gene (ITGB3), resulting in increased platelet aggregation (PlA2 polymorphism), has been associated with higher levels of postoperative troponin I release following CABG96 and with increased risk of thrombotic coronary graft occlusion, MI, and death 1 year following CABG.97 In the setting of noncardiac surgery, two polymorphisms in platelet glycoprotein receptors (ITGB3 and GP1BA) have been shown to be independent risk predictors of PMI in patients undergoing major vascular surgery and resulted in improved discrimination of an ischemia risk assessment tool when added to historic and procedural risk factors.98 Finally, a point mutation in coagulation factor V (1691G>A), resulting in resistance to activated protein C (factor V Leiden), was also associated with various postoperative thrombotic complications following noncardiac surgery.27 Conversely, in patients undergoing cardiac surgery, factor V Leiden was associated with significant reductions in postoperative blood loss and overall risk of transfusion.99 Nevertheless, in a prospective study of CABG patients with routine 3-month postoperative angiographic follow-up, carriers of factor V Leiden had a higher incidence of graft occlusion.100
Natriuretic Peptides and Perioperative Myocardial Outcomes
Circulating B-type natriuretic peptide (BNP) is a powerful biomarker of cardiovascular outcomes in many circumstances. Produced mainly in the ventricular myocardium, BNP is formed by cleavage of its prohormone by the enzyme corin into the biologically active C-terminal fragment (BNP) and an inactive N-terminal fragment (NT-proBNP). Known stimuli of BNP activation are myocardial mechanical stretch (from volume or pressure overload), acute ischemic injury, and a variety of other proinflammatory and neurohormonal stimuli inducing myocardial stress. Although secreted in a 1:1 ratio, circulating levels of BNP and NT-proBNP differ considerably due to different clearance characteristics.
A large number of studies have reported consistent associations of baseline plasma BNP or NT-proBNP levels with a variety of postoperative short- and long-term morbidity and mortality end points, independent of the traditional risk factors. For noncardiac surgery, these were summarized in two meta-analyses that overall indicate an approximately 20-fold increase in risk of adverse perioperative cardiovascular outcomes.101,102 Similarly, for cardiac surgery patients, preoperative BNP was a strong independent predictor of in-hospital postoperative ventricular dysfunction, hospital length of stay, and 5-year mortality following primary CABG,103 performing better than peak postoperative BNP.104 The current guidelines for preoperative cardiac risk assessment in noncardiac surgery list BNP and NT-proBNP measurements as class IIa/level B indications.105 However, despite the large number of studies conducted in both cardiac and noncardiac surgery, precise cut-off levels for BNP still need to be determined and adjusted for age, gender, and renal function. Similarly, no BNP-based goal directed therapies have been reported in the perioperative period. However, a role for BNP assays in monitoring aortic valve disease for optimal timing of surgery has been described.106
Furthermore, a recent study by Fox et al identified genetic variation in natriuretic peptide precursor genes (NPPA/NPPB) to be independently associated with a decreased risk of postoperative ventricular dysfunction following primary CABG, whereas variants in natriuretic peptide receptor NPR3 were associated with an increased risk (Table 4-4),107 offering additional clues into the molecular mechanisms underlying postoperative ventricular dysfunction.
The Role of Genetic Variability in Perioperative Vascular Reactivity
The perioperative period is characterized by robust activation of the sympathetic nervous system, which plays an important role in the pathophysiology of PMI. Thus patients with CAD who carry specific polymorphisms in adrenergic receptor (AR) genes can be at high risk for catecholamine toxicity and cardiovascular complications. Several functionally important SNPs modulating the AR pathways have been described.108 One of them is the Arg389Gly polymorphism in β1-AR gene (ADRB1), a SNP associated with increased risk of composite cardiovascular morbidity at 1 year after noncardiac surgery under spinal anesthesia.109 Of note, perioperative β-blockade had no effect. These findings prompted the investigators to suggest that stratification on AR genotype in future trials may help identify patients likely to benefit from perioperative β-blocker therapy. Significantly increased vascular responsiveness to α-adrenergic stimulation (phenylephrine) has been observed in carriers of the endothelial nitric oxide synthase (NOS3) 894>T polymorphism110 and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism28,111 undergoing cardiac surgery with CPB. Differences in perioperative vascular reactivity in relation to genetic variants of the β2-AR (ADRB2) have also been noted in patients undergoing noncardiac surgery. In patients with a common functional ADRB2 SNP (Glu27), increased blood pressure responses to endotracheal intubation were observed in one study.112 In a different study, in obstetric patients who had spinal anesthesia for cesarean delivery, the incidence and severity of maternal hypotension and response to treatment was affected by ADRB2 genotype (Gly16 and/or Glu27 led to lower vasopressor use for the treatment of hypotension).113 In patients undergoing cardiac surgery, the frequently observed vasoplegic syndrome and vasopressor requirements have been associated with a common polymorphism in the dimethylarginine dimethyl-aminohydrolase II (DDAH II) gene, an important regulator of nitric oxide synthase activity.114
Two recent studies have revealed the association of a common SNP at the 9p21 locus with both perioperative myocardial injury115 and all-cause mortality after primary CABG.116 This SNP was previously correlated with a wide array of vascular phenotypes in ambulatory populations (including CAD, MI, carotid atherosclerosis, abdominal aortic aneurysms, intracranial aneurysms) in replicated GWAS analyses. The mechanism of action of this SNP in the development of PMI and mortality is not completely understood, but it involves altered regulation of cell proliferation, senescence, and apoptosis. It seems that cardiac surgery with CPB may trigger the effects of the 9p21 gene variant leading to accumulation of senescent cells or cells that show evidence of necrotic death with cellular edema and lysis.
Perioperative Atrial Fibrillation
Perioperative atrial fibrillation (PoAF) remains a significant clinical problem after cardiac and noncardiac thoracic procedures. With an incidence of 27% to 40%, PoAF is associated with increased morbidity, hospital length of stay, rehospitalization, health care costs, and reduced survival. The high incidence of PoAF has prompted several investigators to develop comprehensive risk indices for the prediction of PoAF based on demographic, clinical, electrocardiographic, and procedural risk factors. Nevertheless, the predictive accuracy of these risk indices remains limited,117 suggesting that genetic variation may play a significant role in the occurrence of PoAF. Heritable forms of AF have been described in the ambulatory nonsurgical population, and it appears both monogenic forms like "lone" AF as well as polygenic predisposition to more common acquired forms like PoAF do exist.118 A recent GWAS for AF found two polymorphisms on chromosome 4q25 to be significantly associated with AF,42 findings replicated in other patient groups from Sweden, the United States, and Hong Kong. Recently, this locus was also associated with new-onset PoAF after cardiac surgery with CPB (CABG with or without concurrent valve surgery).119 The mechanism of action of the genetic locus identified by the 2 noncoding SNPs is unknown, but it lies close to several genes involved in the development of the pulmonary myocardium, or the sleeve of cardiomyocytes extending from the left atrium into the initial portion of the pulmonary veins. Clinical studies have demonstrated that ectopic foci of electric activity arising from within the pulmonary veins and posterior left atrium play a substantial role in initiating and maintaining AF.
Other candidate susceptibility genes for PoAF include those determining the duration of action potential (voltage-gated ion channels, ion transporters), responses to extracellular factors (adrenergic and other hormone receptors, heat shock proteins), remodeling processes, and magnitude of inflammatory and oxidative stress. It has been described that inflammation, reflected by elevated baseline CRP or IL6 levels and exaggerated postoperative leukocytosis, predicts the occurrence of PoAF. A link between inflammation and the development of PoAF is also supported by evidence that postoperative administration of nonsteroidal anti-inflammatory drugs may reduce the incidence of PoAF. Several recent studies have found that a functional SNP in the IL6 promoter (-174G>C) is associated with higher perioperative plasma IL6 levels and several adverse outcomes after CABG, including PoAF.120-122 In noncardiac surgery, polymorphisms in IL6 and TNFA genes have been shown to be associated with an increased risk of postoperative morbidity, including new-onset arrhythmias.76 There is, however, a contradictory lack of association between CRP levels (strongly regulated by IL6) and PoAF in women undergoing cardiac surgery,123 which may reflect gender-related differences. However, a recent study reported that both pre- and postoperative PAI-1 levels were independently associated with development of PoAF following cardiac surgery.124
Several investigations in the transcriptional responses to AF in human atrial appendage myocardium collected at the time of cardiac surgery or in preclinical models (Table 4-3) have identified a ventricular-like genomic signature in fibrillating atria, with increased ratios of ventricular to atrial isoforms, suggesting dedifferentiation.125 It remains unclear whether this "ventricularization" of atrial gene expression reflects cause or effect of AF, but it likely represents an adaptive energy-saving process to the high metabolic demand of fibrillating atrial myocardium, akin to chronic hibernation. Recently, a different mechanism was proposed as being involved in PoAF; it has been found that patients who exhibit PoAF after cardiac surgery display a differential genomic response to CPB in their peripheral blood leukocytes, characterized by upregulation of oxidative stress genes, which correlated with a significantly larger increase in oxidant stress both systemically (as measured by total peroxide levels) as well as at the myocardial level (as measured in the right atrium).126
Cardiac Allograft Rejection
Identification of peripheral blood gene- and protein-based biomarkers to noninvasively monitor, diagnose, and predict perioperative cardiac allograft rejection is an area of rapid scientific growth. Although several polymorphisms in genes involved in alloimmune interactions, the renin-angiotensin-aldosterone system, and the transforming growth factor-β superfamily have been associated with cardiac transplant outcomes, their relevance as useful clinical monitoring tools remains uncertain. However, peripheral blood mononuclear cell–based molecular assays have shown much promise for monitoring the dynamic responses of the immune system to the transplanted heart, discriminating immunologic allograft quiescence and predicting future rejection.127 A noninvasive molecular test to identify patients at risk for acute cellular rejection is commercially available (Allomap, XDx), in which the expression levels of 11 genes are measured by quantitative real-time polymerase chain reaction (qRT-PCR) and translated using a mathematical algorithm into a clinically actionable AlloMap score that enhances the ability to deliver personalized monitoring and treatment to heart transplant patients.128 Furthermore, several clinically available protein-based biomarkers of alloimmune activation, microvascular injury (troponins), systemic inflammation (CRP), and wall stress and remodeling (BNP) correlate well with allograft failure and vasculopathy and have good negative predictive values, but they require additional studies to guide their clinical use. Similarly, molecular signatures of functional recovery in end-stage heart failure following left ventricular assist device (LVAD) support using gene expression profiling have been reported using only mRNA129 or combined microRNA and mRNA profiling,130 and they could be used to monitor patients who received an LVAD as destination therapy or assess the timing of potential device explantation.
Genetic Variability and Postoperative Event-Free Survival
Several large randomized clinical trials examining the benefits of CABG surgery and percutaneous coronary interventions relative to medical therapy and/or to one another have refined our knowledge of early and long-term survival after CABG. These studies have helped define the subgroups of patients who benefit from surgical revascularization, and they also demonstrated a substantial variability in long-term survival after CABG, altered by important demographic and environmental risk factors. Increasing evidence suggests that the ACE gene indel polymorphism may influence post-CABG complications, with carriers of the D allele having higher mortality and restenosis rates after CABG surgery compared with the I allele.75 As discussed earlier, a prothrombotic amino acid alteration in the β3-integrin chain of the glycoprotein IIb/IIIa platelet receptor (the PlA2 polymorphism) is associated with an increased risk for major adverse cardiac events (a composite of MI, coronary bypass graft occlusion, or death) following CABG surgery (Table 4-4).97 We found preliminary evidence for association of two functional SNPs modulating β2-adrenergic receptor activity (Arg16Gly and Gln27Glu) with incidence of death or major adverse cardiac events following cardiac surgery,131 and recently identified a functional polymorphism in thrombomodulin (THBD Ala455Val; OR: 2.64) gene associated with increased 5-year mortality after CABG independent of EuroSCORE.132
Genetic Susceptibility to Adverse Perioperative Neurologic Outcomes
Despite advances in surgical and anesthetic techniques, significant neurologic morbidity continues to occur following cardiac surgery, ranging in severity from coma and focal stroke (incidence: 1%-3%) to more subtle cognitive deficits (incidence up to 69%), with a substantial impact on the risk of perioperative death, quality of life, and resource utilization. Variability in the reported incidence of both early and late neurologic deficits remains poorly explained by procedural risk factors, suggesting that environmental (operative) and genetic factors may interact to determine disease onset, progression, and recovery. The pathophysiology of perioperative neurologic injury is thought to involve complex interactions between primary pathways associated with atherosclerosis and thrombosis, and secondary response pathways like inflammation, vascular reactivity, and direct cellular injury. Many functional genetic variants have been reported in each of these mechanistic pathways involved in modulating the magnitude and the response to neurologic injury, which may have implications in chronic as well as acute perioperative neurocognitive outcomes. For example, Grocott at al examined 26 SNPs in relationship to the incidence of acute postoperative ischemic stroke in 1635 patients undergoing cardiac surgery, and they found that the interaction of minor alleles of the CRP (1846C>T) and IL6 promoter SNP -174G>C significantly increases the risk of acute stroke.133 Similarly, a recent study suggests that P-selectin and CRP genes both contribute to modulating the susceptibility to postoperative cognitive decline (POCD) following cardiac surgery.21 Specifically, the loss-of-function minor alleles of CRP 1059G>C and SELP 1087G>A are independently associated with a reduction in the observed incidence of POCD after adjustment for known clinical and demographic covariates (Table 4-5).
Our group has demonstrated a significant association between the apolipoprotein E (APOE) E4 genotype and adverse cerebral outcomes in cardiac surgery patients.19,134 This is consistent with the role of the APOE genotype in recovery from acute brain injury, such as intracranial hemorrhage,135 closed-head injury,136 and stroke,137 as well as experimental models of cerebral I/R injury138; two subsequent studies in CABG patients, however, have not replicated these initial findings. Furthermore, the incidence of postoperative delirium following major noncardiac surgery in the elderly139 and in critically ill patients140 is increased in carriers of the APOE ϵ4 allele. Unlike adult cardiac surgery patients, infants possessing the APOE ϵ2 allele are at increased risk for developing adverse neurodevelopmental sequelae following cardiac surgery.141,142 The mechanisms by which the APOE genotypes might influence neurologic outcomes are yet to be determined, but they do not seem to be related to alterations in global cerebral blood flow of oxygen metabolism during CPB143; however, genotypic effects in modulating the inflammatory response,79 extent of aortic atheroma burden,144 and risk for premature coronary atherosclerosis145 may play a role.
Recent studies have suggested a role for platelet activation in the pathophysiology of adverse neurologic sequelae. Genetic variants in surface platelet membrane glycoproteins, important mediators of platelet adhesion and platelet–platelet interactions, have been shown to increase the susceptibility to prothrombotic events. Among these, the PlA2 polymorphism in glycoprotein IIb/IIIa has been related to various adverse thrombotic outcomes, including acute coronary thrombosis146 and atherothrombotic stroke.147 We found the PlA2 allele to be associated with more severe neurocognitive decline after CPB,20 which could represent exacerbation of platelet-dependent thrombotic processes associated with plaque embolism.
Cardiac surgical patients who develop POCD demonstrate inherently different genetic responses to cardiopulmonary bypass from those without POCD, as evidenced by acute deregulation in peripheral blood leukocytes of gene expression pathways involving inflammation, antigen presentation, and cellular adhesion.148 These findings corroborate with proteomic changes, in which patients with POCD similarly have significantly higher serologic inflammatory indices compared with those patients without POCD149,150 and add to the increasing level of evidence that CPB does not cause an indiscriminate variation in gene expression but rather distinct patterns in specific pathways that are highly associated with the development of postoperative complications such as POCD. The implications for perioperative medicine include identifying populations at risk who might benefit not only from an improved informed consent, stratification, and resource allocation, but also from targeted anti-inflammatory strategies.
In noncardiac surgery, a study conducted in patients undergoing carotid endarterectomy demonstrated that preoperative plasma levels of fibrinogen and hs-CRP were independently associated with new periprocedural cerebral ischemic lesions caused by microembolic events, as determined by MRI diffusion-weighted imaging.151
Genetic Susceptibility to Adverse Perioperative Renal Outcomes
Acute renal dysfunction is a common, serious complication of cardiac surgery; about 8% to 15% of patients develop moderate renal injury (>1.0 mg/dL peak creatinine rise), and up to 5% of them develop renal failure requiring dialysis.152 Acute renal failure is independently associated with in-hospital mortality rates of greater than 60% in patients requiring dialysis.152 Several studies have demonstrated that inheritance of genetic polymorphisms in the APOE gene (ϵ4 allele)24 and in the promoter region of the IL6 gene (−174C allele)121 are associated with acute kidney injury following CABG surgery (Table 4-6). Stafford-Smith et al reported that major differences in peak postoperative serum creatinine rise after CABG are predicted by possession of combinations of polymorphisms that interestingly differ by race: the angiotensinogen (AGT) 842T>C and IL6 -572G>C variants in whites and the endothelial nitric oxide synthase (NOS3) 894G>T and angiotensin-converting enzyme (ACE) insertion/deletion in African Americans are associated with >50% reduction in the postoperative glomerular filtration rate.22 Further identification of genotypes predictive of adverse perioperative renal outcomes may facilitate individually tailored therapy, risk stratify the patients for interventional trials targeting the gene product itself, and aid in medical decision making (eg, selecting medical over surgical management).
Genetic Variants and Risk for Prolonged Postoperative Mechanical Ventilation
Prolonged mechanical ventilation (inability to extubate patient by 24 hours postoperatively) is a significant complication following cardiac surgery, occurring in 5.6% and 10.5% of patients undergoing first and repeat CABG surgery, respectively.153 Several pulmonary and nonpulmonary causes have been identified, and scoring systems based on preoperative and procedural risk factors have been proposed and validated. Recently, genetic variants in the renin-angiotensin pathway and in proinflammatory cytokine genes have been associated with respiratory complications post-CPB. The D allele of a common functional insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE) gene, accounting for 47% of variance in circulating ACE levels,154 is associated with prolonged mechanical ventilation following CABG155 and with susceptibility to and prognosis of acute respiratory disease syndrome (ARDS).156 Furthermore, a hyposecretor haplotype in the neighboring genes tumor necrosis factor α (TNFA) and lymphotoxin α (LTA) on chromosome 6 (TNFA-308G/LTA+250G haplotype)157 and a functional polymorphism modulating postoperative IL6 levels (IL6-174G>C)121 are independently associated with higher risk of prolonged mechanical ventilation post-CABG. The association is more dramatic in patients undergoing conventional CABG than in those undergoing off-pump CABG (OPCAB), suggesting that in high-risk patients identified by preoperative genetic screening, OPCAB may be the optimal surgical procedure.
A next crucial step in understanding the complexity of adverse perioperative outcomes is to assess the contribution of variations in many genes simultaneously and their interaction with traditional risk factors to the longitudinal prediction of outcomes in individual patients. The use of such outcome predictive models incorporating genetic information may help stratify mortality and morbidity in surgical patients, improve prognostication, direct medical decision making both intraoperatively and during postoperative follow-up, and even suggest novel targets for therapeutic intervention in the perioperative period.