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When the Usual Suspects Turn Up in the ICU: Searching for Genetic Clues to Atrial Fibrillation.

128 www.ccmjournal.org January 2020 • Volume 48 • Number 1 The development of new-onset atrial fibrillation (AF) is a common complication that alters the course of critical illness. New-onset AF occurs in at least 8% of patients in the ICU and is associated with adverse outcomes (1–4). Patients with new-onset AF demonstrate higher vasopressor and inotrope requirements, higher net positive fluid balance, and a higher rate of diastolic dysfunction (5), and had longer lengths of stay in the ICU and hospital (4). In the long term, new-onset AF during critical illness has been associated with an increased risk of heart failure, ischemic stroke, and death (1, 6). Since newonset AF represents a significant complication of critical illness, it is imperative to characterize and understand the risk factors for the disease. Identifying patients at risk for new-onset AF might allow interventions targeting AF prevention, a goal which has been proposed (7). Although predictive models based on known risk factors for new-onset AF exist (8), such models have imperfect performance and do not account for the strong genetic predisposition reported in studies of ambulatory patients (7). Parental AF increases the future odds for an individual’s AF by 1.8 to three-fold (7). New-onset AF likely represents a complex gene-environment interaction in which an underlying susceptible substrate and the profound physiologic derangements of critical illness interact to produce the arrhythmia. In order to evaluate a gene-by-environment interaction, environmental risk factors must be understood. Studies using data from prospective cohorts (5, 6), claims data (2), and retrospective cohorts (4) have identified risks for new-onset AF specific to the critical illness context: acute organ failures, immunocompromise, presence of sepsis, and use of inotropic medications. In addition, factors common to ambulatory AF have been identified, such as age, sex, obesity, Caucasian race, and cardiac disease (2, 4–6), although studies restricted to critically ill populations do not uniformly identify traditional risk factors of diabetes mellitus, hypertension, or congestive heart failure during the ICU setting (2, 5). Although genetic factors conferring risk of new-onset AF in the ambulatory patient population are replicated and well characterized, the genetics of new-onset AF during critical illness is relatively unexplored. The physiologic stresses encountered during critical illness, including systemic inflammation and increased adrenergic activity, may be unique compared with new-onset AF developed in the ambulatory setting. Human experimental studies with endotoxin prove the existence of differential genetic regulation between quiescent states and stress-evoked inflammation (8). Uncovering the genetic risk factors for new-onset AF during critical illness might advance our understanding of the disease and the targeting of at-risk patients in a precision medicine paradigm. In a this issue of Critical Care Medicine, Kerchberger et al (9) assess the significance of genetic variation as a risk factor for new-onset AF during critical illness. In a candidate gene approach, the authors tested well-validated AF-associated single-nucleotide polymorphisms (SNPs) from prior genomewide association studies in ambulatory populations. To identify new-onset AF in critically ill patients, they leveraged a substudy from the Validating Acute Lung Injury markers for Diagnosis (VALID) cohort, a prospective observational cohort study of critically ill adults admitted to medical or surgical ICUs in whom AF was determined by manual screening of the medical record (5). Genotyping was performed using a customized multi-SNP platform (9). The authors identified three SNPs—rs3853445, rs6838973, and rs12415501—previously identified as genome-wide ambulatory AF variants as also being associated with new-onset AF during critical illness. The associations between AF and two SNPs (rs3853445 and rs12415501) were robust to adjustment for statistically significant clinical variables. The authors also report that both rs3853445 and rs12415501 may have biological significance in new-onset AF. Rs3853445 is within a noncoding intergenic region near PITX2, paired like homeodomain 2. A homeobox transcription factor, PITX2 has been implicated in cardiac electrical and structural remodeling (10). The gene within which rs12415501 resides, NEURL (neuralized E3 ubiquitin protein ligase 1), has been linked to atrial action potential duration (11). To study the effect of genetic variation in concert with environmental stresses, Kerchberger et al (9) used clinical predictors for new-onset AF previously identified in the VALID population (5) and then applied a least absolute shrinkage and selection operator (LASSO) regression model to select the most informative AF predictors while avoiding selection of co-linear variables. The LASSO model retained age, sex, history of previously diagnosed coronary artery disease, and use of vasopressor as the leading clinical variables associated with new-onset AF. Both rs3853445 and rs12415501 were also retained by the LASSO regression as AF predictors. Finally, the authors tested a combined clinical and genetic risk model 0090-3493