1. Accumulating evidence from candidate gene association studies also suggests that specific genotypes are associated with a variety of organ-specific perioperative adverse outcomes (myocardial infarction [MI], neurocognitive dysfunction, renal compromise, vein graft restenosis, postoperative thrombosis, vascular reactivity, severe sepsis, transplant rejection, death).

2. Replication of findings across different populations or related phenotypes remains the most reliable method of validating a true relationship between genetic polymorphisms and disease.

3. The year 2007 marked the publication of adequately powered and successfully replicated genome-wide association studies that identified significant genetic contributors to the risk for common polygenic diseases (coronary artery disease, MI, types I and II diabetes, atrial fibrillation, obesity, asthma, common cancers, rheumatoid arthritis, Crohn’s disease).

4. Variants in or near CDKN2A/B (cyclin-dependent kinase inhibitor 2 A/B) have been shown to confer increased risk for both type II diabetes and MI, which may lead to a mechanistic explanation for the link between the two disorders.

IV. LARGE-SCALE GENE AND PROTEIN EXPRESSION PROFILING: STATIC VERSUS DYNAMIC GENOMIC MARKERS OF PERIOPERATIVE OUTCOMES

A. Genomic approaches are anchored in the concept of transcription of messenger RNA (mRNA) from a DNA template followed by translation of RNA into protein (Fig. 6-2).

B. Transcription is a key regulatory step that may eventually signal many other cascades of events.

1. Although the human genome contains only about 25,000 genes, functional variability at the protein level is far more diverse, resulting from extensive posttranscriptional, translational, and posttranslational modifications.

2. It is believed that there are approximately 200,000 distinct proteins in humans, which are further modified posttranslationally by phosphorylation, glycosylation, oxidation, and disulfide structures.

FIGURE 6-2. Central dogma of molecular biology. Protein expression involves two main processes, RNA synthesis (transcription) and protein synthesis (translation), with many intermediate regulatory steps.

C. Increasing evidence suggests that variability in gene expression levels underlies complex diseases and is determined by regulatory DNA polymorphisms affecting transcription, splicing, and translation efficiency in a tissue- and stimulus-specific manner.

1. The main functional categories of genes identified as potentially involved in cardioprotective pathways include a host of transcription factors, proteins, and antioxidant genes.

2. Different gene programs appear to be activated in ischemic versus anesthetic preconditioning, resulting in two distinct cardioprotective phenotypes.

D. The transcriptome (the complete collection of transcribed elements of the genome) is not fully representative of the proteome (the complete complement of proteins encoded by the genome) because many transcripts are not targeted for translation, as evidenced recently by the concept of gene silencing by RNA interference.

1. Therefore, alternative splicing, a wide variety of posttranslational modifications, and protein–protein interactions responsible for biologic function would remain undetected by gene expression profiling.

2. This has led to the emergence of a new field, proteomics, which studies the sequence, modification, and function of many proteins in a biologic system at a given time. Rather than focusing on “static” DNA, proteomic studies examine dynamic protein products with the goal of identifying proteins that undergo changes in abundance, modification, or localization in response to a particular disease state, trauma, stress, or therapeutic intervention.

3. Proteomics offers a more global and integrated view of biology, complementing other functional genomic approaches.

V. GENOMICS AND PERIOPERATIVE RISK PROFILING

A. More than 40 million patients undergo surgery annually in the United States at a cost that totals $450 billion. Each year, approximately 1 million patients sustain medical complications after surgery, resulting in costs of $25 billion annually.

1. Perioperative complications are significant, costly, variably reported, and often imprecisely detected and identified. There is a critical need for accurate, comprehensive perioperative outcome databases.

2. Presurgical risk profiling is inconsistent and deserves further attention, especially for noncardiac, nonvascular surgery and older patients.

3. 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 may even occur in otherwise healthy individuals.

4. Understanding the role of allotypic variation in proinflammatory and prothrombotic pathways, the main pathophysiological 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.

B. Predictive Biomarkers for Perioperative Adverse Cardiac Events. It is commonly accepted that patients who have underlying cardiovascular disease are at risk for adverse cardiac events after surgery. However, identifying patients at the highest risk of perioperative MI remains difficult despite a strong genetic contribution to the risk of adverse cardiovascular events.

1. Inflammation Biomarkers and Perioperative Adverse Cardiac Events. Inflammatory gene polymorphisms that are independently predictive of postoperative MI after cardiac surgery with cardiopulmonary bypass have been identified.

a. C-reactive protein (CRP) is the prototypical acute-phase inflammatory marker and a robust predictor of cardiovascular risk.

b. Elevated preoperative CRP levels (>3 mg/L) have been associated with increased morbidity and mortality after coronary artery bypass graft (CABG) surgery.

c. Elevated baseline plasma CRP levels and the acute phase rise in postoperative plasma CRP levels are genetically determined.

2. Thrombosis Biomarkers and Perioperative Adverse Cardiac Events. In addition to inflammatory activation, the host response to surgery is also characterized by an increase in fibrinogen concentration, platelet adhesiveness, and plasminogen activator inhibitor-1 production.

a. Perioperative thrombotic outcomes after cardiac surgery (e.g., coronary graft thrombosis, MI, stroke, pulmonary embolism) represent one extreme on a continuum of coagulation dysfunction, with coagulopathy at the other end of the spectrum.

b. Evidence suggests genetic variability modulates the activation of each of these mechanistic pathways, reflecting a significant heritability of the prothrombotic state.

3. Natriuretic Peptides and Perioperative Adverse Cardiac Events. Circulating B-type natriuretic peptide (BNP) (produced mainly in the ventricular myocardium) is a powerful biomarker of adverse perioperative cardiovascular outcomes in many circumstances.

4. Genetic Variation in Vascular Reactivity and Perioperative Cardiac Events

a. Perioperative stress responses are also characterized by sympathetic nervous system activation, known to play a role in the pathophysiology of postoperative MI.

b. Patients with coronary artery disease and specific adrenergic receptor genetic polymorphisms may be particularly susceptible to catecholamine toxicity and cardiac complications.

5. Perioperative Atrial Fibrillation (PoAF). New-onset PoAF remains a common complication of cardiac and major noncardiac thoracic surgical procedures (incidence, 27%–40%) and is associated with increased morbidity, longer hospital lengths of stay, increased rehospitalization, increased health care costs, and reduced survival.

a. Heritable forms of PoAF occur in the ambulatory nonsurgical population.

b. A role for inflammation for PoAF is suggested by baseline CRP levels in male patients and exaggerated postoperative leukocytosis, which both predict perioperative AF; postoperative administration of nonsteroidal anti-inflammatory drugs shows a protective effect.

6. 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.

7. Predictive Biomarkers for Postoperative Event-Free Survival. Increasing evidence suggests that the ACE gene polymorphism may influence complications after CABG surgery, with carriers of the D allele having higher mortality and restenosis rates after CABG surgery than carriers of the I allele.

C. Predictive Biomarkers of Adverse Perioperative Neurologic Outcomes

1. 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, 1%–3%) to more subtle cognitive deficits (incidence, ≤69%), with a substantial impact on the risk of perioperative death, quality of life, and resource utilization.

2. The pathophysiology of perioperative neurologic injury is thought to involve complex interactions between primary pathways associated with atherosclerosis and thrombosis and secondary response pathways such as inflammation, vascular reactivity, and direct cellular injury.

a. 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. Specific pathways are associated with the development of postoperative complications such as postoperative cognitive dysfunction.

b. There is a significant association between the apolipoprotein E genotype and adverse cerebral outcomes in patients undergoing cardiac surgery. The incidence of postoperative delirium after major noncardiac surgery in elderly and critically ill patients is increased in carriers of this genotype.

c. Platelet activation may be important in the pathophysiology of adverse neurologic sequelae. The implications for perioperative medicine include identifying populations at risk that might benefit not only from an improved informed consent, stratification, and resource allocation but also from targeted anti-inflammatory strategies.

D. Predictive Biomarkers of Perioperative Acute Kidney Injury

1. Acute kidney injury is a common, serious complication of cardiac surgery. About 8% to 15% of patients develop moderate renal injury (peak creatinine increase of >1.0 mg/dL), and up to 5% of them develop renal failure requiring dialysis. Acute renal failure is independently associated with in-hospital mortality rates exceeding 60% in patients requiring dialysis.

2. Studies have demonstrated that inheritance of genetic polymorphisms is associated with acute kidney injury after CABG surgery.

E. Genetic Variants and Risk for Prolonged Postoperative Mechanical Ventilation. Genetic variants in the renin–angiotensin pathway and proinflammatory cytokine genes may be associated with respiratory complications after cardiopulmonary bypass.

FIGURE 6-3. Pharmacogenomic determinants of individual drug response operate by pharmacokinetic (A) and pharmacodynamic (B) mechanisms.