Longitudinal profiling in patients undergoing cardiac surgery reveals postoperative changes in DNA methylation

Matthew A Fischer; Douglas J Chapski; Elizabeth Soehalim; Dennis J Montoya; Tristan Grogan; Matteo Pellegrini; Hua Cai; Richard J Shemin; Thomas M Vondriska

doi:10.1186/s13148-022-01414-4

Longitudinal profiling in patients undergoing cardiac surgery reveals postoperative changes in DNA methylation

Clin Epigenetics. 2022 Dec 30;14(1):195. doi: 10.1186/s13148-022-01414-4.

Authors

Affiliations

¹ Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine, UCLA, CHS 37-100, 650 Charles Young Dr, Los Angeles, CA, 90095, USA. mfischer@mednet.ucla.edu.
² Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine, UCLA, CHS 37-100, 650 Charles Young Dr, Los Angeles, CA, 90095, USA.
³ Department of Molecular, Cellular & Developmental Biology, David Geffen School of Medicine, UCLA, Los Angeles, USA.
⁴ Department of Surgery, David Geffen School of Medicine, UCLA, Los Angeles, USA.
⁵ Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, USA.
⁶ Department of Physiology, David Geffen School of Medicine, UCLA, Los Angeles, USA.

Abstract

Background: Cardiac surgery and cardiopulmonary bypass induce a substantial immune and inflammatory response, the overactivation of which is associated with significant pulmonary, cardiovascular, and neurologic complications. Commensurate with the immune and inflammatory response are changes in the heart and vasculature itself, which together drive postoperative complications through mechanisms that are poorly understood. Longitudinal DNA methylation profiling has the potential to identify changes in gene regulatory mechanisms that are secondary to surgery and to identify molecular processes that predict and/or cause postoperative complications. In this study, we measure DNA methylation in preoperative and postoperative whole blood samples from 96 patients undergoing cardiac surgery on cardiopulmonary bypass.

Results: While the vast majority of DNA methylation is unchanged by surgery after accounting for changes in cell-type composition, we identify several loci with statistically significant postoperative changes in methylation. Additionally, two of these loci are associated with new-onset postoperative atrial fibrillation, a significant complication after cardiac surgery. Paired statistical analysis, use of FACS data to support sufficient control of cell-type heterogeneity, and measurement of IL6 levels in a subset of patients add rigor to this analysis, allowing us to distinguish cell-type variability from actual changes in methylation.

Conclusions: This study identifies significant changes in DNA methylation that occur immediately after cardiac surgery and demonstrates that these acute alterations in DNA methylation have the granularity to identify processes associated with major postoperative complications. This research also establishes methods for controlling for cell-type variability in a large human cohort that may be useful to deploy in other longitudinal studies of epigenetic marks in the setting of acute and chronic disease.

Keywords: Atrial fibrillation; Cardiac surgery; DNA methylation; Precision medicine.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Cardiac Surgical Procedures* / adverse effects
DNA Methylation*
Gene Expression Regulation
Humans
Longitudinal Studies
Postoperative Complications / genetics

Abstract

Publication types

MeSH terms

Grants and funding