Serum Proteomics of Older Patients Undergoing Major Cardiac Surgery: Identification of Biomarkers Associated With Postoperative Delirium

James Rhee; Alexandra Kuznetsov; Tina McKay; Margaret Lyons; Nicholas Houstis; Jennifer Mekkonen; Breanna Ethridge; Reine Ibala; Eunice Hahm; Jacob Gitlin; J Sawalla Guseh; Robert Kitchen; Anthony Rosenzweig; Shahzad Shaefi; Adam Flaczyk; Jason Qu; Oluwaseun Akeju

doi:10.3389/fnagi.2021.699763

Serum Proteomics of Older Patients Undergoing Major Cardiac Surgery: Identification of Biomarkers Associated With Postoperative Delirium

Front Aging Neurosci. 2021 Aug 11:13:699763. doi: 10.3389/fnagi.2021.699763. eCollection 2021.

Authors

James Rhee^{1

2}, Alexandra Kuznetsov², Tina McKay¹, Margaret Lyons^{1

2}, Nicholas Houstis², Jennifer Mekkonen¹, Breanna Ethridge¹, Reine Ibala¹, Eunice Hahm¹, Jacob Gitlin¹, J Sawalla Guseh², Robert Kitchen², Anthony Rosenzweig², Shahzad Shaefi³, Adam Flaczyk¹, Jason Qu¹, Oluwaseun Akeju¹

Affiliations

¹ Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
² Corrigan Minehan Heart Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
³ Department of Anesthesia, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.

Abstract

Background: Postoperative delirium (POD) is an acute altered mental state commonly encountered after cardiac surgery. The pathophysiological mechanisms underlying POD remain unclear. We aimed to identify circulating proteins significantly altered after major cardiac surgery with cardiopulmonary bypass (CPB). We also aimed to enable inferences on associations with POD.

Methods: Serum and whole blood samples were collected before CPB (n = 16 patients; n = 8 with POD) and again from the same patients on postoperative day 1. All patients were clinically evaluated for POD on postoperative days 1-3. An aptamer-based proteomics platform (SOMAscan) was used to quantify serum protein abundance in patients with POD compared with non-POD controls. We also performed a lipopolysaccharide (LPS)-based in vitro functional analysis (TruCulture) on whole blood samples from patients with POD and non-POD controls to approximate surgical stress. Cytokine levels were determined using a Luminex immunoassay.

Results: Cardiac surgery with CPB resulted in a significant (p_adj < 0.01) change in 48.8% (637 out of 1,305) of proteins detected by SOMAscan. Gene set enrichment showed that the most impacted biological processes involved myeloid cell activation. Specifically, activation and degranulation of neutrophils were the top five highest-scoring processes. Pathway analyses with the Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that metabolic enzymes, particularly those of glycolysis, were elevated in serum concentration after surgery. Several proteins were significantly increased postoperatively in patients diagnosed with POD relative to the non-POD controls, with interleukin-6 (IL-6) showing the greatest fold-change. LPS stimulation of whole blood samples confirmed these findings. Linear regression analysis showed a highly significant correlation between Confusion Assessment Method (CAM) scores and CPB-mediated changes in cGMP-inhibited 3',5'-cyclic phosphodiesterase A (PDE3A).

Conclusions: Cardiac surgery with CPB resulted in inflammasome changes accompanied by unexpected increases in metabolic pathways. In exploratory analyses, we found that POD was associated with changes in the expression level of various proteins, most notably IL-6 and PDE3A. This study and ongoing protein biomarker studies will likely help quantify risk or confirm the diagnosis for POD and increase understanding of its pathophysiological mechanisms.

Keywords: IL-6; PDE3A; SOMAscan; TIMP-1; TruCulture; cardiopulmonary bypass; postoperative delirium; proteomics.

Abstract

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