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Clinical and Genetic Contributors to New-Onset Atrial Fibrillation in Critically Ill Adults

Kerchberger, V. Eric MD1,2; Huang, Yi MS3; Koyama, Tatsuki PhD3; Shoemaker, M. Benjamin MD, MSCI4; Darbar, Dawood MBChB, MD5; Bastarache, Julie A. MD1,6; Ware, Lorraine B. MD1,7; Shaver, Ciara M. MD, PhD1

doi: 10.1097/CCM.0000000000004034
Clinical Investigation: PDF Only
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Objectives: New-onset atrial fibrillation during critical illness is an independent risk factor for mortality. The ability to identify patients at high risk for new-onset atrial fibrillation is limited. We hypothesized that genetic susceptibility contributes to risk of new-onset atrial fibrillation in the ICU.

Design: Retrospective sub-study of a prospective observational cohort study.

Setting: Medical and general surgical ICUs in a tertiary academic medical center.

Patients: One-thousand three-hundred sixty-nine critically ill patients admitted to the ICU for at least 2 days with no known history of atrial fibrillation who had DNA available for genotyping.

Interventions: None.

Measurements and Main Results: We genotyped 21 single-nucleotide polymorphisms associated with atrial fibrillation in ambulatory studies using a Sequenom platform (San Diego, CA). We collected demographics, medical history, and development of new-onset atrial fibrillation during the first four days of ICU admission. New-onset atrial fibrillation occurred in 98 patients (7.2%) and was associated with age, male sex, coronary artery disease, and vasopressor use. Single-nucleotide polymorphisms associated with new-onset atrial fibrillation were rs3853445 (near PITX2, p = 0.0002), rs6838973 (near PITX2, p = 0.01), and rs12415501 (in NEURL, p = 0.03) on univariate testing. When controlling for clinical factors, rs3853445 (odds ratio, 0.47; 95% CI, 0.30–0.73; p = 0.001) and rs12415501 (odds ratio, 1.72; 95% CI, 1.27–2.59; p = 0.01) remained significantly associated with new-onset atrial fibrillation. The addition of genetic variables to clinical factors improved new-onset atrial fibrillation discrimination in a multivariable logistic regression model (C-statistic 0.82 vs 0.78; p = 0.0009).

Conclusions: We identified several single-nucleotide polymorphisms associated with new-onset atrial fibrillation in a large cohort of critically ill ICU patients, suggesting there is genetic susceptibility underlying this common clinical condition. This finding may provide new targets for future mechanistic studies and additional insight into the application of genomic information to identify patients at elevated risk for a common and important condition in the ICU.

1Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.

2Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN.

3Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN.

4Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.

5Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, IL.

6Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN.

7Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN.

The contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by grants from the National Institutes of Health (NIH) T32 GM108554 (to Dr. Kerchberger), NIH HL 138737 (to Dr. Darbar), NIH HL 135849 (to Drs. Bastarache and Ware), NIH HL 103836 (to Dr. Ware), NIH HL 136888 (to Dr. Shaver), Parker B. Francis Foundation (to Dr. Shaver), and Vanderbilt Faculty Research Scholars (to Dr. Shaver). The project publication described was supported by Clinical and Translational Science Award award number UL1 TR002243 from the National Center for Advancing Translational Sciences.

Drs. Kerchberger, Koyama, Shoemaker, Darbar, Ware, and Shaver received support for article research from the National Institutes of Health (NIH). Dr. Darbar’s institution received funding from NIH R01 HL138737. Dr. Ware’s institution received funding from Boehringer Ingelheim and Global Blood Therapeutics (research grants). Dr. Shaver’s institution received funding from NIH (K08), Parker B Francis Foundation, and Vanderbilt Faculty Research Scholars. The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: vern.e.kerchberger@vumc.org

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