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J Am Coll Cardiol, 2005; 46:1965-1977, doi:10.1016/j.jacc.2005.08.040 (Published online 8 November 2005).
© 2005 by the American College of Cardiology Foundation
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CARDIOVASCULAR GENOMIC MEDICINE

New Paradigms in Cardiovascular Medicine

Emerging Technologies and Practices: Perioperative Genomics

Mihai V. Podgoreanu, MD*,* and Debra A. Schwinn, MD*,{dagger},{ddagger},§

* Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina
{dagger} Department of Pharmacology/Cancer Biology, Duke University Medical Center, Durham, North Carolina
{ddagger} Department of Surgery, Duke University Medical Center, Durham, North Carolina
§ Center for Genomic Medicine, Duke Institute for Genome Science and Policy, Durham, North Carolina.

Manuscript received June 21, 2005; revised manuscript received August 5, 2005, accepted August 17, 2005.

* Reprint requests and correspondence: Dr. Mihai V. Podgoreanu, Box 3094, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710 (Email: mihai.podgoreanu{at}duke.edu).


   Abstract
Top
 Abstract
Genetic variability and...
 Why perioperative genomics?
 Perioperative genomics studies:...
 Perioperative clinical genomics:...
 References
 
Considerable progress has been made in understanding the pathophysiology of perioperative stress responses and their impact on the cardiovascular system; however, researchers are just beginning to unravel genetic and molecular determinants that predispose to increased risk for postoperative cardiovascular adverse events. A new field, coined perioperative genomics, aims to apply functional genomic approaches to uncover the biological reasons why similar patients can have dramatically different clinical outcomes after surgery. For the perioperative physician, such findings may soon translate into prospective risk assessment incorporating genomic profiling of markers important in inflammatory, thrombotic, vascular, and neurologic responses to perioperative stress, with implications ranging from individualized additional pre-operative testing and physiological optimization, to perioperative decision-making, choice of monitoring strategies, and critical care resource utilization. We review current knowledge regarding genomic technologies in perioperative cardiovascular disease characterization and outcome prediction, as well as discuss future trends/challenges for translating integrated "omic" information into daily clinical management of the surgical patient.

Abbreviations and Acronyms
  ACE = angiotensin-converting enzyme
  AF = atrial fibrillation
  APOE = apolipoprotein E
  AR = adrenergic receptor
  CABG = coronary artery bypass grafting
  CAD = coronary artery disease
  CPB = cardiopulmonary bypass
  FVL = factor V Leiden
  HSP = heat shock protein
  IL = interleukin
  MACE = major adverse cardiac events
  PAI-1 = plasminogen activator inhibitor-1
  PMI = perioperative myocardial infarction
  PoAF = postoperative atrial fibrillation
  SNP = single nucleotide polymorphism

Perioperative care of surgical patients remains a critical component of modern medicine, requiring comprehensive and increasingly multidisciplinary approaches. Cardiologists are intimately involved in estimating risk for patients with cardiovascular disease of developing postoperative complications such as myocardial infarction, arrhythmias, stroke, or sudden death. This review discusses unique characteristics of perioperative injury and highlights current and future applications of genomic technologies in perioperative cardiovascular disease characterization, risk assessment, and outcome prediction, as well as identification and validation of novel therapeutic targets and strategies.


   Genetic variability and perioperative cardiovascular risk assessment
Top
 Abstract
 Genetic variability and...
Why perioperative genomics?
 Perioperative genomics studies:...
 Perioperative clinical genomics:...
 References
 
Several pre-operative cardiac risk assessment tools have been developed to guide perioperative management of patients at high risk for cardiovascular morbidity. For noncardiac surgery, historical risk indexes proposed by Goldman, Detsky, and Lee were found to have only modest positive predictive value. Current standards for pre-operative cardiac evaluation support the use of noninvasive cardiac tests to improve perioperative risk stratification (1), but predictive value remains <25% (2). Similarly, a variety of risk stratification systems have been proposed for cardiac surgical patients linked to mortality, serious nonfatal morbidity, resource utilization, and patient satisfaction (3). Prospective evaluation of such severity-adjusted models reveal marked discrepancies in predicting individual outcomes, as well as systematic biases in over/under-prediction for subgroups of patients (4). Due to lack of precision in individual classification, the search for novel risk factors predicting perioperative cardiovascular adverse events is important.

The need for improved perioperative risk profiling is further justified by a worrisome growing surgical burden, owing to accelerated population aging and increased reliance on surgery for disease treatment. Over 40 million patients undergo surgery annually in the U.S., resulting in costs of $450 billion per year (5). With approximately one-third of surgical patients ≥65 years of age and 40% having atherosclerosis risk factors (5), ~1.25 million perioperative cardiovascular complications occur annually, resulting in an additional $25 billion in health care expenditures (6). It is projected that by 2020 the number of surgeries will increase by 25%, associated costs by 50%, and likelihood of atherosclerotic-related cardiac, cerebral, and renal complications by 100% (6).

One hallmark of perioperative medicine is striking variability in patient response(s) to surgical stress, anesthetic agents, hemodynamic challenges, and the pharmacopoeia used in the perioperative period. Current risk stratification based on patient demographics, comorbidities, physiologic reserve, and procedural variables explains only a small part of observed variability in incidence of perioperative complications. Evidence is accumulating that genetic variations, or polymorphisms, can significantly affect an individual’s susceptibility to adverse postoperative events (7–9). A new field, coined perioperative genomics, aims to apply functional genomic approaches to uncover the biological mechanisms underlying why similar patients have dramatically different outcomes after surgery (10).


   Why perioperative genomics?
Top
 Abstract
 Genetic variability and...
 Why perioperative genomics?
Perioperative genomics studies:...
 Perioperative clinical genomics:...
 References
 
Common chronic diseases like atherosclerosis, coronary artery disease (CAD), hypertension, and diabetes, as well as responses to injury, drugs, and non-pharmacological therapies, are genetically complex, characteristically involving interplay of many susceptibility genes and environmental exposures (Fig. 1). In the perioperative period, patients with various burdens of complex comorbid conditions are exposed to "controlled trauma" in the operating room environment, consisting of surgical injury, anesthesia, pharmacologic interventions, and, in the case of cardiac surgery, extracorporeal circulation. As an environmental stimulus, perioperative injury can be characterized as: 1) robust and extreme; 2) multifactorial (i.e., outcomes are the cumulative result of both direct initial operative injury and the host’s responses to injury, both interacting with an individual’s genetic background); 3) quantifiable (e.g., for cardiac surgery, duration of cardiopulmonary bypass [CPB] and aortic cross-clamping, number of coronary bypass grafts, volume, type and route of cardioplegia, perioperative medications, and so on); 4) defined onset of exposure; and 5) defined time course, usually shorter than for common chronic diseases, although in some cases predictive of future natural history of disease (e.g., cognitive decline).



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  		Figure 1 Perioperative outcomes are complex traits, characteristically involving multiple gene-gene interactions and gene-environment interactions to produce a final clinical phenotype (presence/absence and severity of an adverse event). CPB = cardiopulmonary bypass; OR = operating room.

 
Characteristic phenotypes studied by perioperative genomics include immediate postoperative adverse events (incidence/severity of organ dysfunction), as well as long-term outcomes (Table 1). Overall, an individual’s genetic susceptibility to adverse perioperative events stems not only from genetic contributions to the development of comorbid risk factors (like CAD) during the patient’s lifetime, but also from genetic variability in specific biological pathways participating in pathophysiological events during and after surgery. Thus, the term perioperative genomics is justified by a combination of unique environmental insults and postoperative phenotypes that characterize surgical and critically ill patient populations.


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  		Table 1. Categories of Perioperative Phenotypes
 

   Perioperative genomics studies: Major findings
Top
 Abstract
 Genetic variability and...
 Why perioperative genomics?
 Perioperative genomics studies:...
Perioperative clinical genomics:...
 References
 
Although several important genetic determinants of complex cardiovascular outcomes like myocardial infarction (11) and stroke (12) have been identified using genome-wide linkage analysis, such studies rely on data from multigeneration families, something impractical in studies investigating perioperative outcomes. Furthermore, perioperative adverse events likely involve multiple susceptibility markers, each of modest importance, thereby limiting application of linkage analysis. Thus, most discoveries in perioperative genomics derive from association studies examining specific genetic polymorphisms in population-based samples of unrelated diseased individuals and appropriately matched unaffected controls. Candidate genes are first selected based on a priori hypotheses about potential etiological roles in adverse outcomes, current understanding of pathophysiologic processes from literature reviews, biochemical/physiologic pathway analysis, and expert opinion (13). Further candidate genes are identified in more unbiased ways using microarray gene expression profiling in human tissues and surgical animal models. Growing evidence suggests that variability in gene expression levels underlies susceptibility to complex disease and is determined by regulatory polymorphisms affecting transcription, splicing, and translation efficiency in a tissue- and stimulus-specific manner (14). Thus, in the current conceptual framework, identification of disease-modifying genes involves integrating data on DNA sequence variation and gene expression variation in well-phenotyped surgical patient populations.

Several reciprocally interactive complex biological systems are involved in perioperative organ injury (Fig. 2). Specific genetic variants in these pathways have been associated with various organ-specific adverse outcomes, including myocardial ischemia (15), postoperative arrhythmias (16), vein graft restenosis (17), transplant rejection (18), renal compromise (19,20), neurocognitive dysfunction (21,22), stroke (23), and death (24,25), as well as broader systemic abnormalities mechanistically involved in perioperative complications like bleeding (26,27), thrombosis (28), inflammatory responses and severe sepsis (29), and alterations in vascular reactivity (30). To increase clinical relevance for the practicing cardiologist, we summarized these studies by specific outcome while highlighting candidate genes in relevant mechanistic pathways (Tables 2 and 3).Go



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  		Figure 2 Biological systems and mechanistic pathways genetically associated with perioperative adverse events.

 

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  		Table 2. Representative Genetic Polymorphisms Associated With Adverse Perioperative Cardiovascular Events
 

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  		Table 3. Representative Genetic Polymorphisms Associated With Other Adverse Perioperative Outcomes
 
Perioperative myocardial injury.   Adverse cardiovascular events persist as serious complications after anesthesia and surgery, with mortality after perioperative myocardial infarction (PMI) of 40% to 50% (31). Similarly, despite advances in surgical, cardioprotective, and anesthetic techniques, incidence of PMI after cardiac surgery ranges from 7% to 15% (32) and alters long-term survival. Reports from animal models, linkage, twin, and population association studies reveal genetic influences in incidence and progression of CAD; heritability of death from CAD is as high as 0.57 (33), and hazardous patterns of angiographic CAD (left main and proximal disease), known major risk factors for perioperative cardiovascular complications, are also highly heritable (34). Similarly, genetic susceptibility to myocardial infarction is established (11,35). Although these studies do not directly address heritability of adverse perioperative myocardial events, they suggest a strong genetic contribution to risk of adverse cardiovascular outcomes in general.

A paucity of studies exists directly relating genetic risk factors to adverse perioperative myocardial outcomes, mainly after coronary artery bypass grafting (CABG) (17,36,37). In the setting of cardiac surgery, PMI involves three major converging pathophysiologic processes (Fig. 3). In non-cardiac surgery, pathophysiology of PMI is not so clearly understood, but a combination of two mechanisms appears predominant: 1) plaque rupture and coronary thrombosis triggered by perioperative endothelial injury from catecholamine surges, proinflammatory and prothrombotic states; and 2) prolonged stress-induced ischemia and tachycardia in the context of compromised perfusion. Extensive genetic variability exists in each of these mechanistic pathways, which may combine to modulate magnitude of myocardial injury.



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  		Figure 3 The degree of perioperative myocardial injury is a result of the balance between injurious and cardioprotective (endogenous and exogenous) biological mechanisms, mediated via a wide array of biochemical pathways with extensive genetic variability. AR = adrenergic receptor; CPB = cardiopulmonary bypass; EC = endothelial cells; PMN = polymorphonuclear neutrophils; RNS = reactive nitrogen species; ROS = reactive oxygen species.

 
Inflammatory gene polymorphisms and postoperative myocardial outcomes
Genetic variants affecting inflammatory responses have been identified. Polymorphisms in the interleukin-6 (IL6) gene promoter significantly increase inflammatory response to cardiac surgery with CPB (38) and are associated with length of hospitalization after CABG (39). Both apolipoprotein E (APOE) genotype (40) and several single nucleotide polymorphisms (SNP) in tumor necrosis factor genes have been associated with proinflammatory effects in patients undergoing CPB (41). Conversely, an SNP-modulating expression of anti-inflammatory cytokine IL10 in response to CPB has been associated with postoperative cardiovascular dysfunction (42). Recently, Shaw et al. (43) reported an association between SNPs in two inflammatory genes (IL6 and tumor necrosis factor-alpha [TNFA]) and incidence of postoperative complications (a composite outcome that included PMI) after non-cardiac surgery (lung resection for cancer). Taken together, an exaggerated proinflammatory response to surgical stress appears to correlate with enhanced adverse postoperative events.

Coagulation variability and perioperative myocardial outcomes
The acute-phase response to surgery is characterized by increased fibrinogen concentration, platelet adhesiveness, and plasminogen activator inhibitor-1 (PAI-1) production. Cardiac surgery induces additional complex hemostatic alterations, triggered by hypothermia, hemodilution, and CPB-induced activation of coagulation, fibrinolytic, and inflammatory pathways. Thrombotic outcomes after cardiac surgery (coronary graft thrombosis, PMI, stroke, pulmonary embolism) represent one extreme on a continuum of coagulation dysfunction, with coagulopathy and bleeding at the other end. Pathophysiologically, the balance between bleeding, normal hemostasis, and thrombosis is markedly influenced by rate of thrombin formation and platelet activation. Genetic variants modulate activity of each of these mechanistic pathways (44), suggesting heritability of a prothrombotic state.

Several prothrombotic genotypes are associated with risk of coronary graft thrombosis and myocardial injury after CABG. A common prothrombotic point mutation in coagulation factor V (factor V Leiden [FVL]) results in resistance to activated protein C and increased risk of myocardial infarction (45). In a prospective study of CABG patients with routine three-month post-operative angiographic follow-up, a higher proportion of FVL carriers had graft occlusion compared to non-carriers (46).

A platelet glycoprotein IIIa gene (ITGB3) polymorphism, resulting in increased platelet aggregation, is associated with higher postoperative troponin I levels (47) and increased risk for one-year thrombotic coronary graft occlusion, myocardial infarction, and death after CABG (25). In patients undergoing major vascular surgery, two SNPs in platelet glycoprotein receptors (ITGB3 and GP1BA) are independent risk factors for PMI and result in an improved predictive model when added to historic and procedural risk factors (15).

Plasminogen activator inhibitor-1 is an important negative regulator of fibrinolytic activity; an insertion/deletion polymorphism in the PAI-1 promoter has been consistently associated with higher plasma levels of PAI-1. A high correlation has been reported between PAI-1 levels and risk of angiographically detected early graft thrombosis after CABG (48), and a meta-analysis showed significant effect of PAI-1 genotype on incidence of myocardial infarction (49).

Genetic polymorphisms and perioperative vascular reactivity
With robust sympathetic nervous system activation characteristic of perioperative stress responses, and known to play an important role in the pathophysiology of PMI, patients with CAD and specific adrenergic receptor (AR) genetic polymorphisms may be particularly susceptible to catecholamine toxicity and cardiac complications. Significantly increased perioperative vascular responsiveness to alpha-AR stimulation (phenylephrine) is found in carriers of an endothelial nitric oxide synthase (NOS3) SNP (50) and angiotensin-converting enzyme (ACE) insertion/deletion polymorphism (30,51) undergoing cardiac surgery with CPB. A common ß2AR variant (ADRB2) is associated with increased blood pressure in response to endotracheal intubation (52). Several other functionally important polymorphisms modulating AR pathways have been characterized (for review, see Zaugg and Schaub [53]).

Three functionally important SNPs are specifically associated with variations in coronary tone (54). A polymorphism in GNB3, encoding the G protein ß3 subunit, is associated with exaggerated coronary vasoconstrictor response to {alpha}-AR agonists, and a paraoxonase-1 (PON1) SNP is associated with increased coronary vasomotor tone at rest. Conversely, a NOS3 SNP is associated with reduced endothelium-dependent coronary vasodilation and coronary spasm. Although some of these associations have not been directly validated in the perioperative setting, identification of polymorphisms modulating interindividual variability in coronary vasomotor response may have important implications for prediction of perioperative myocardial ischemic events, given the intrinsic catecholamine surges and prevalent use of alpha-AR agonists during this period.

Gene expression studies of myocardial pre-conditioning
Microarray technology has revolutionized gene expression analysis in complex disease by simultaneously examining genome-wide changes of many thousands of mRNA transcripts in a single experiment. Several studies have reported gene expression patterns in ischemic (55) and stunned myocardium (56). In perioperative medicine, microarrays have been applied to evaluate organ-specific responses to surgical stress, endotoxemia, and CPB with cardioplegic arrest (57), which are age-related (58). Importantly, microarray profiling is being used to search for novel cardioprotective genes, with a goal of designing strategies to activate beneficial pathways and prevent myocardial injury. Pre-conditioning is one such well-studied model of cardioprotection, induced by triggers like intermittent ischemia, heat shock, and, interestingly, inhaled anesthetics. Different transcriptional programs are activated in ischemic versus anesthetic pre-conditioning, resulting in distinct cardioprotective phenotypes (59,60). Development of molecular signatures defining magnitude of myocardial injury and response to various cardioprotective strategies may ultimately contribute to improved outcome prediction in patients undergoing coronary revascularization (Table 4).


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  		Table 4. Summary of Gene Expression Studies With Implications for Perioperative Cardiovascular Outcomes
 
Postoperative atrial fibrillation (AF).   With a reported incidence of 27% to 40%, new-onset postoperative AF (PoAF) remains a common complication of cardiac and major non-cardiac thoracic surgical procedures, associated with increased morbidity, hospital length of stay, rehospitalization, health care costs, and reduced survival (61,62). Several large prospective multicenter trials have identified and validated comprehensive risk indexes for development of PoAF based on demographic, clinical, electrocardiographic, and procedural risk factors, but their predictive accuracy remains at best moderate (63), suggesting an inherent genetic pre-operative risk. Heritability of AF has been reported, with genome-wide linkage scans successfully mapping genetic loci for familial AF (64) and gain-of-function mutations in cardiac potassium channel genes associated with AF (65). It appears that AF is genetically heterogeneous (66), with both rare monogenic forms, like "lone" AF, and polygenic predisposition to more common acquired forms (67), like PoAF. Such genetic modifiers interact with additional environmental stressors to determine abnormal cardiac electrical activity and modulate long-term remodeling of cardiac structural and electrical substrates. Candidate susceptibility genes for PoAF include those determining action potential duration (voltage-gated ion channels, ion transporters), magnitude of inflammatory and oxidative stress, responses to extracellular factors (adrenergic and other hormone receptors, signal transduction mechanisms, heat shock response), and remodeling processes (68).

Accumulating evidence suggests a role for inflammation in the pathogenesis of AF in general (69) and after cardiac surgery; PoAF is predicted by baseline C-reactive protein levels (70) and exaggerated postoperative leukocytosis (71), and prevented by administration of non-steroidal anti-inflammatory drugs (63). The robust inflammatory insult elicited by cardiac surgery with CPB, as well as pericarditis, alters atrial coupling with transient structural and electrical changes that predispose to PoAF (72). Complement activation and C-reactive protein have been mechanistically associated with PoAF after cardiac surgery (73). A single study has directly examined inflammation gene variants in relation to PoAF, with a functional SNP in the IL6 promoter independently predicting PoAF after CABG (16). This polymorphism has consistently shown a strong relationship with IL6 plasma levels (38), postoperative inflammatory complications (74), and hospital length of stay after cardiac surgery (39). In a preliminary report, this IL6 variant and a chemokine, RANTES (Regulated upon Activation, Normally T-Expressed, and presumably Secreted), SNP were shown to be independent risk factors for failure of beta-blockers in preventing PoAF (75). Additionally, polymorphisms in two inflammatory genes (IL6 and TNFA) were associated with composite postoperative morbidity (including new-onset arrhythmias) after lung resection procedures (43).

An important modulator of myocardial fibrosis and remodeling, the renin-angiotensin system, is involved in AF, evidenced by increased atrial expression of ACE in patients with AF and beneficial effects of ACE inhibitor therapy in reducing AF occurrence associated with myocardial infarction, left ventricular dysfunction, and relapse rates after cardioversion. Perioperative ACE inhibitor therapy in cardiac surgical patients also reduces risk of PoAF, whereas withdrawal from therapy increases risk (63). Several associations between non-familial structural AF and genetic variants in the renin-angiotensin system have been reported, including the ACE insertion/deletion (76), and several angiotensinogen (AGT) polymorphisms (77), but none so far directly related to PoAF.

Other mechanisms may also be important in AF. Although associated with altered inward rectifier and acetylcholine-activated K+ currents in cultured atrial myocytes, a SNP in ß3-subunit of G-proteins (GNB3) shows no genotypic differences between atrial myocardial tissues from patients with or without PoAF and no association with incidence of PoAF (78). Age-dependent atrial accumulation of a mitochondrial DNA deletion mutation (mtDNA-4977) is associated with AF (79), providing a possible explanation for increased incidence of AF with age. Furthermore, a recent study reported association between mitochondrial dysfunction in response to ischemia-reperfusion injury and PoAF (80). Heat shock proteins (HSP) are molecular chaperones that protect during cardiac-surgery-induced ischemia-reperfusion myocardial injury. Pre-operative atrial HSP70 expression levels inversely correlate with incidence of PoAF (81), and anti-HSP65 antibodies are associated with occurrence of PoAF after cardiac surgery (82). Oxidative stress has been implicated as a pathophysiologic mechanism in PoAF, with CABG patients demonstrating increased plasma lipid peroxidation and decreased cardiac glutathione levels after aortic cross clamp release, persisting for ≥24 h postoperatively. Transcriptional profiling of human atrial myocardium identifies a shift in balance of pro-oxidation and antioxidation toward oxidative stress that occurs in AF (83), suggesting antioxidants may prove to be interesting therapeutic targets for AF.

In a porcine model of pacing-induced AF, integrated genomic and proteomic analysis of characteristic early myocardial gene expression changes demonstrate increased ratios of ventricular to atrial isoforms in fibrillating atrial tissue, suggesting dedifferentiation (84). These findings were recently replicated in humans, with a similar ventricular-like genomic signature observed in fibrillating atrium (85). However, it remains unclear whether "ventricularization" of atrial gene expression reflects cause or effect of AF. Human right atrial microarray studies have identified gene expression signatures highly predictive of PoAF following cardiac surgery (86). Initial human proteomic studies also identify specific PoAF signatures (87), as well as overall down-regulation of protein expression, which may represent adaptive energy-saving processes to the high metabolic demand of fibrillating atrial myocardium, akin to chronic hibernation. Elucidating which changes are required for initiation of AF, or diseases that predispose to AF, is important in identifying novel therapeutic targets (88) (Table 4).

Studies summarized in the preceding text illustrate the comprehensive approaches required to "tackle" complex phenotypes like AF. Future efforts will also need to capture gene-gene and gene-environment interactions, as well as various endophenotypes (electrocardiographic P-wave abnormalities, biomarkers) that co-segregate with AF.

Perioperative event-free survival.   Several large randomized clinical trials have identified subgroups of patients who benefit from surgical revascularization, yet this group still demonstrates substantial variability in long-term survival after CABG, implicating genetic influences. Increasing evidence suggests that ACE insertion/deletion polymorphism influences post-CABG complications, including higher mortality and graft restenosis rates (37). Similarly, a functionally important glycoprotein IIb/IIIa platelet receptor (ITGB3) SNP is associated with risk for major adverse cardiac events (MACE), a composite of myocardial infarction, coronary bypass graft occlusion, or death after CABG surgery (25). Mechanistically, this may be related to a genetically modulated prothrombotic tendency, as this SNP results in increased fibrinogen binding and epinephrine-induced platelet aggregation (89) and is associated with acute coronary thrombosis (90). Hyperhomocysteinemia is another important risk factor for coronary, cerebrovascular, and peripheral vascular atherosclerotic disease, and a strong predictor of mortality among patients with CAD. Plasma homocysteine levels are influenced by both environmental and genetic factors, with a methylenetetrahydrofolate reductase gene (MTHFR) SNP influencing enzyme activity, resulting in elevated plasma homocysteine levels (91). In a study of patients undergoing myocardial revascularization (both percutaneous and surgical), the MTHFR genotype predicts MACE (92). Our group recently found preliminary evidence for association between two functional SNPs modulating ß2AR activity and death/MACE after cardiac surgery (24). We also reported association between a non-synonymous P-selectin (SELP) SNP and risk of MACE after combined CABG-valve surgery in women only; this may explain some observed gender-based disparities in cardiac surgery outcomes (93).

Genomic profiling and risk of cardiac allograft rejection.   Despite increased success of heart/lung transplantation, severe complications (acute rejection, transplant CAD, post-transplant malignancies, infections) continue to result in morbidity and mortality. A central phenomenon in graft rejection is a shift of proinflammatory and anti-inflammatory cytokines away from a graft-tolerant state toward a proinflammatory milieu (7); several cytokine gene polymorphisms have been associated with allograft outcome (7,18). A hypersecretor genotype in the TNFA promoter and a hyposecretor genotype in the anti-inflammatory cytokine IL10 promoter increase risk of acute cardiac graft rejection (18). A functional polymorphism in interleukin-1 receptor antagonist (IL1RN), an endogenous anti-inflammatory molecule, is associated with increased frequency of chronic thoracic allograft rejection when combined with specific IL-1ß genotypes, particularly when IL1 region haplotypes and multiple rejection episodes were investigated (94). Conversely, presence of an intercellular adhesion molecule-1 (ICAM1) SNP in either donor or recipient is protective against transplant vasculopathy (95).

Currently, serial right ventricular endomyocardial biopsies are the mainstay for monitoring heart transplant rejection; biopsies are invasive and limited by patient discomfort, risk of complications, poor reproducibility, and cost. A noninvasive strategy, peripheral blood gene expression profiling in circulating leukocytes, has been correlated with biopsy-proven allograft rejection (96). Using oligonucleotide microarrays, a characteristic genomic signature of acute cellular rejection has been identified that can reveal persistent immune activation despite normalization of biopsy in response to treatment. This suggests expression profiling may provide more sensitive screening for rejection (96). The prospective multicenter Cardiac Allograft Rejection Gene Expression Observational (CARGO) study was designed to develop and validate a gene expression test for detection and monitoring of acute rejection and quiescence in cardiac transplant recipients using peripheral blood mononuclear cells. After an exploratory phase (candidate gene identification using microarray analysis) (97), in the development phase (98) a 20-gene real-time quantitative polymerase chain reaction assay (AlloMap, XDx, South San Francisco, California) was used in conjunction with an algorithm to yield a score (AlloMap score) that reliably and reproducibly distinguishes quiescence from acute rejection (99); these findings have been subsequently validated in an independent patient population. Such technology may help tailor steroid therapy to avoid over-immunosuppression, thus minimizing infectious and malignant long-term complications (100) and resulting in significant health care savings (101). Another technology that has been used to investigate cell-based inflammatory responses in heart transplantation is the leukocyte antibody array. Increased expression of specific leukocyte cluster of differentiation antigens has been reported during CPB in patients undergoing heart transplantation (102). Furthermore, using a proteomic approach, two myocardial proteins ({alpha}B-crystallin and tropomyosin) have been identified as significantly increased in sera of patients showing histological signs of rejection (103). However, it is likely that a panel of protein markers will be required to provide enough sensitivity to detect all rejection episodes.

Adverse perioperative neurologic outcomes.   Despite advances in surgical and anesthetic techniques, significant neurologic morbidity continues to occur after cardiac surgery, ranging in severity from coma and focal stroke (incidence up to 6%) to more subtle cognitive deficits (incidence up to 69%), with substantial impact on risk of perioperative death, quality of life, and resource utilization. Cardiac surgery represents a unique clinical paradigm where, in addition to genetic predispositions, certain procedural events (such as aortic manipulation) may lead to embolization of material to the brain and perioperative neurological injury, the pathophysiology of which involves complex interactions between primary pathways associated with atherosclerosis and thrombosis, and secondary response pathways like inflammation, oxidative stress, vascular reactivity, and direct cellular injury. Functional genetic variants have been described in each of these mechanistic pathways. Our group reported an association of APOE genotype with adverse cerebral outcomes in cardiac surgery patients (22), consistent with other studies suggesting a role for APOE variants in recovery from acute brain injury such as intracranial hemorrhage, closed head injury, stroke, and experimental models of cerebral ischemia-reperfusion injury (for review, see Newman et al. [104]). Unlike adult patients, infants carrying a different APOE isoform are at risk for developing adverse neurodevelopmental sequelae after cardiac surgery (105). Mechanistically, the role of APOE genotypes in modulating inflammatory response (40), extent of aortic atheroma burden (106), risk for coronary atherosclerosis (107), and autoregulation of cerebral blood flow may explain the observed associations with altered neurological outcomes.

Platelet activation is a centerpiece in the pathophysiology of adverse neurological sequelae. Genetic variants in surface platelet membrane glycoproteins, important mediators of platelet adhesion and platelet-platelet interactions, increase susceptibility to prothrombotic events. Among these an ITGB3 polymorphism related to various adverse thrombotic outcomes, including acute coronary thrombosis (90) and atherothrombotic stroke (108), is also correlated with neurocognitive decline after CPB (21), potentially representing exacerbation of platelet-dependent thrombotic processes associated with plaque embolism. We identified two common SNPs in the promoter region of IL6 and 3'-untranslated region of C-reactive protein (CRP) genes as independent predictors of stroke risk after cardiac surgery, suggesting a pivotal role of inflammation in the pathogenesis of perioperative stroke (23), and consistent with an increasing body of literature identifying proinflammatory genetic profiles as susceptibility factors in stroke (109).

Implications of identifying novel predictors for risk of perioperative neurological dysfunction and the molecular mechanisms underlying such risk are several-fold. Patient-informed consent process will be improved, and resource allocation can be optimized based on risk stratification. Second, development of neuroprotective agents, and application of therapeutic modalities tailored to an individual’s molecular risk profile, will be facilitated.

Integrating "omic" information.   Integrated genomic and proteomic analysis have been applied to characterize tissue-specific adaptive and maladaptive programs of gene expression in animal models of surgical stress (110) and myocardial ischemia-reperfusion injury (111), and to predict outcome in patients undergoing thoracoabdominal aortic aneurysm repair. Gene expression patterns from peripheral blood leukocytes and circulating plasma proteins discriminated between patients who developed multiple organ dysfunction syndrome and those who did not (112).

The metabolic consequences of surgery and anesthesia are complex. Surgical trauma triggers an integrated neuroendocrine reaction, with increased secretion of stress hormones, antidiuretic hormone, and activation of the renin-angiotensin system. The magnitude of the ensuing counter-regulatory response depends on the severity of surgery and postoperative complications, such as sepsis, but perioperative hyperglycemia-insulin resistance appears to be related to various postoperative adverse events, especially after cardiac surgery. Thus, perioperative assessment of an individual’s metabolic state using metabolomic techniques (the global study of all molecules produced in the human body) can help clinicians understand complex metabolic derangements associated with surgical stress. One principal advantage metabolomics offers over other "omic" technologies such as transcriptomics and proteomics is that metabolic information is readily transferable between species. Preliminary studies have reported using metabolic signatures to characterize overall effects of stress (113), impact of ischemia-reperfusion injury on allograft function (114), and effectiveness of cytoprotective therapy in preventing lung injury in models of surgical sepsis (115) or myocardial ischemia-reperfusion injury (116).


   Perioperative clinical genomics: Pipe dream or near reality?
Top
 Abstract
 Genetic variability and...
 Why perioperative genomics?
 Perioperative genomics studies:...
 Perioperative clinical genomics:...
References
 
In this review, opportunities to use the unique operating room environment to answer potentially important and clinically relevant physiologic questions have been presented. Indeed, this process gives new meaning to the operating room as the "last human physiology laboratory in medicine." Perioperative physicians have long recognized that a bell-shaped curve of responses occurs to various environmental perturbations (inflammatory response to stress of surgery, hemodynamic challenge, drug administration, and so on) demonstrating that although most patients respond in predictable patterns, others respond either more or less vigorously. Astute clinicians appreciate that an individual patient’s response to stress may alter perioperative outcomes such as incidence of PMI, arrhythmias, respiratory distress syndrome, survival, and response to pain management. But what are the mechanisms underlying physiologic and pharmacodynamic variability to stress? The answer to this complex question includes understanding how the unique genetic background an individual brings to the operating room affects his or her perioperative outcome. It is becoming increasingly clear that although proinflammatory pathways are important in wound healing in the perioperative and intensive care unit environment, too robust of a response may be detrimental, resulting in poorer patient outcome. Robust activation of proinflammatory pathways appears to augment organ injury by providing a milieu that goes beyond normal healing of a surgical incision, trauma, or severe illness, to induce injury. Thus, in the context of the extreme acute perioperative (environmental) stressors, genetically modulated deficiencies in homeostatic mechanisms are unmasked and may contribute to adverse postoperative cardiovascular outcomes.

As studies are now published suggesting perioperative organ injury can be predicted by examining genetic variability, how can this information be translated to the clinic once validated? Is it possible to stratify patients so that increased risk for myocardial injury, stroke, bleeding, renal complications, sepsis, and neurocognitive deficits can be determined before surgery? The answer to this question is—yes. The ability to rapidly genotype large numbers of patients for validated genetic variants is becoming reality. However, before being considered in clinical perioperative risk management, genomic-based tests will need to have additional predictive power over and above accepted risk factors (117). We, and others, have already identified genetic variants that, when evaluated simultaneously, improve the predictability of existing models of perioperative adverse events (20,23,26). Because the effect size of any single genetic variant on the clinical end points is relatively modest, it is the multilocus interaction of several genotypes that will likely be large enough to be of clinical relevance. Thus, further progress in analysis of complex traits, including perioperative cardiovascular complications, will require simultaneous analysis of increasingly larger numbers of genetic variants in a highly systematic and unbiased fashion, while balancing the increased informativity of such an approach against costs and the challenges it imposes on genetic epidemiology and computational biology. Furthermore, the turn-around time from taking a blood sample and having a genetic "fingerprint" should be <12 h in order to be clinically useful, ideally just a few hours (much like clinical chemistries are analyzed now). This will become reality over the next few years using many genotyping platforms. A panel of SNPs replicated in different independent patient populations and validated by functional genomics approaches will likely be used in the near future as a "perioperative chip" to predict risks of adverse events and drug responses in patients undergoing major surgery.

The operating room is very receptive to new technologies, being the incubator of many patient-monitoring modalities and surgical devices. Hence, it is no surprise that several genomic-based tests have already been implemented clinically and have the potential to impact perioperative management. We have already described the AlloMap (XDx), used to diagnose cardiac allograft rejection and to help tailor immunosuppressive therapy postoperatively. The AmpliChip CYP450 (Roche Diagnostics, Basel, Switzerland) is a microarray-based pharmacogenomics test designed to identify genetic variants in two major drug metabolizing enzymes (CYP2D6 and CYP2C19) and to predict associated enzyme activities. Because several drugs routinely used in the perioperative period are metabolized through these enzymes (beta-blockers, benzodiazepines, anti-emetics), such information can aid perioperative physicians to individualize treatment doses and reduce variability or toxicity in response to these drugs.

But determining a genetic profile is only the first part of the equation for clinical utility. The interpretation of specific combinations of SNPs or gene expression patterns will be equally important. It is difficult for the average clinician to stay abreast of all important genetic variants, so interpretations of genetic panels should be simple and suggest specific possible interventions (updated regularly) if a patient is found to be high risk. This will not only facilitate movement of genetics into the clinical setting, but should help standardize interventions designed to lower risk. It is also important to communicate to a patient that just because they are determined to be in a low-risk group this does not mean they will not have an adverse event, just a lower risk for that event. The introduction of sequence-based information into daily clinical practice will lead to an exquisite pre-operative identification of the vulnerable patient, and such subtle distinctions will become important in all aspects of perioperative care, from disclosing perioperative or periprocedure risks between physicians and patients, to pre-operative optimization and postoperative monitoring, thus optimizing the allocation of finite resources to prioritized clinical needs. Such "omic"-based decision tools could be applied for instance in the individualized selection of procedure type (e.g., percutaneous vs. surgical on-pump/off-pump coronary revascularization, catheter-based vs. Maze procedure for arrhythmia ablation), intraoperative decisions (e.g., choice of coronary bypass conduit), and postoperative follow-up (e.g., anticoagulation management, frequency of coronary graft surveillance).

A strong need remains for prospective, well-powered genetic studies in highly phenotyped surgical populations, which mandate the development of multidimensional perioperative databases and establishing perioperative research consortia and standardized protocols for biological specimen collection and processing as well as phenotype definition. Existing animal models of perioperative stress and injury will continue to be improved, and comparative genomics approaches will be used to identify evolutionarily conserved stress-specific genes and pathways, as well as tissue-specific orthologous markers that may facilitate early detection of perioperative organ dysfunction. Molecular profiling will also be used in translational drug development and to identify patients that respond better to a treatment arm than the other, providing the scientific basis for improved clinical trial design and analysis. Furthermore, characterizing the genomic determinants of drug resistance (e.g., beta-blockers and PoAF, aspirin, and vein graft failure) and monitoring drug responses according to pharmacogenomic principles will likely result in individualized drug selection and dosing for each patient to minimize adverse effects. New anti-inflammatory, antithrombotic, antioxidant, and cytoprotective therapeutics will be delivered in the acute setting using cell-based and genomic-based (e.g., ribonucleic acid interference, antisense nucleotides) technologies, in addition to the traditional pharmacological agents.

Conclusions.   Sequencing of the human genome represents the pinnacle of a reductionist era in molecular medicine. The great challenge in coming years is reintegrating this information using systems biology approaches to provide a better understanding of the intact organism, its responses to various environmental stimuli, and translating the knowledge into daily clinical practice. For the perioperative physician, this will soon translate into prospective risk assessment based on genomic profiling of markers important in inflammatory, thrombotic, neurologic, and vascular responses to perioperative stress, allowing the development of more comprehensive cross-disciplinary treatment paradigms for stress-induced organ dysfunction in each individual patient.


   Footnotes
 
Supported in part by grants AG17556 and HL075273 (to Dr. Schwinn) from the National Institutes of Health and grant 0120492U (to Dr. Podgoreanu) from the American Heart Association.


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