Pharmacogenomics and end-organ susceptibility to injury in the perioperative period

Genomic medicine has provided new mechanistic understanding for many complex diseases over the last 5–10 years. More recently genomic approaches have been applied to the perioperative paradigm, facilitating identification of patients at high risk for adverse events, as well as those who will respond better/worse to specific pharmacologic therapies. The consistent biological theme emerging is that while inflammation is important in healing from surgical trauma, patients who are too robustly proinflammatory appear to be at higher risk for adverse perioperative events. Precise predictors of each adverse event are being elucidated so that corrective therapeutics can be instituted to improve outcomes in high-risk patients. While the field of perioperative genomics could be considered in its infancy, such approaches are the wave of the future.

Introduction

The ability to identify patients at high risk for perioperative and peri-procedure adverse events is critical so that interventions can be identified that optimize outcome. Over 40 million patients undergo surgery annually in the U.S., resulting in costs of $450 billion per year¹, a number which continues to rise with the aging population world-wide. The operating room is a unique setting where acute, robust, and generalized proinflammatory cascades are initiated on a reproducible basis (see perioperative physiology discussion below). An advantage of using a robust surgical perturbation to elucidate novel mechanisms underlying perioperative adverse events is that the surgical stressor is usually elective, predictable (occurs on the day of surgery), graded (magnitude of insult increases with length of surgery, cardiopulmonary bypass [CPB] and/or aortic cross-clamp or other ischemia/reperfusion injury), adverse cardiovascular outcomes peak within days (e.g. perioperative myocardial ischemia/infarction peaks on postoperative day 1–2), sufficiently common to be studied (e.g. 7–15% of cardiac surgery patients have perioperative myocardial ischemia/injury*2, *3), and patients are routinely invasively monitored and treated using routes that facilitate obtaining unique human specimens (e.g. arterial and coronary sinus blood, human atrium, adipose tissue, etc.). These characteristics make the surgical environmental a unique perturbation capable of revealing latent phenotypes and mechanisms underlying acute perioperative adverse events.

Despite advances in surgical, anesthetic, and cardioprotective strategies, the incidence of perioperative adverse events continues to be significant, and is associated with reduced short and long-term survival.⁴ Since all surgical patients are exposed to perturbations that potentially activate inflammation, coagulation, and other stress-related pathways, but only a subset experience adverse perioperative events (even after controlling for co-existent disease), a genetic component is likely involved. To explore this further, the next sections will review general genetic/genomic concepts, complex physiologic pathways activated during surgery, generalizability of the perioperative physiology paradigm, effects of genetic variability on such physiology, and finally data associating genetic variants related to adverse perioperative events.