Proteomic, transcriptomic, and metabolic mediators of postcardiopulmonary bypass vasoplegia syndrome

Product:

Inflammation Panel 250

Topic:

Cardiovascular

Disease Area:

Post-cardiopulmonary bypass vasoplegia syndrome

Sample Type:

Plasma

Product:

Inflammation Panel 250

Topic:

Cardiovascular

Disease Area:

Post-cardiopulmonary bypass vasoplegia syndrome

Sample Type:

Plasma

Abstract

Objective

Vasoplegia syndrome (VS) after cardiopulmonary bypass (CPB) is associated with a dysregulated inflammatory response and greater rates of morbidity and mortality, but the molecular pathways involved have been incompletely identified. We used multiplexed proteomic and transcriptomic analyses and targeted biochemical assays to identify the inflammatory and metabolic mediators that characterize post-CPB VS.

Methods

Sixteen matched pairs of patients with (+) and without (–) VS were analyzed pre-CPB and post-CPB for comparative proteomic and transcriptomic differences, with Gene Ontology pathway enrichment. Circulating nitric oxide (NO) metabolites, acetylcholine (ACh), and choline acetyltransferase levels were measured and correlated with VS.

Results

Baseline proteomic analysis demonstrated elevated tumor necrosis factor-alpha, interleukin-1R1, and interleukin-17RA in patients who were VS+, with activation of inflammatory cytokine, leukocyte activation, and NO biosynthesis pathways. Analysis of temporal pre-to-post CPB proteomic changes in patients who were VS+ demonstrated post-CPB elevation of IL-17A, CXCL2, and VEGFR/FLT, and decreased immune resolving proteins. Post-CPB comparative proteomic analysis demonstrated differential activation of leukocyte trafficking, T-cell differentiation, interleukin-6, and interleukin-17 pathways in patients who were VS+. Transcriptomic analysis demonstrated post-CPB activation of cellular response to hypoxia, cellular stress response, and decreased response to angiotensin pathways. Circulating NO metabolites, ACh, and choline acetyltransferase levels were elevated pre-CPB in patients who were VS+ and increased further post-CPB. Pre-CPB ACh had a 99% area under the curve correlation with post-CPB VS+.

Conclusions

We demonstrated increased baseline cardiovascular inflammation in patients identified as VS+, which predisposed them to a dysregulated inflammatory response to CPB, and we identified CPB-induced activation of IL-17–skewed multicytokine inflammatory pathways and endothelial activation as mechanistic mediators of post-CPB VS. Circulating ACh was identified as a potential biomarker.

Authors and Affiliations

Aubrey Galloway, MDᵃ*, Caroline Magro, BSEᵃ, Chandra Goparaju, PhDᵃ, Katherine Phillips, MDᵃ, Kenneth Tokoro, PhDᵇ, Hua Zhou, PhDᵇ, Deane Smith, MDᶜ, Eugene Grossi, MDᵃ, Elias Zias, MDᵃ, Ralph Mosca, MDᵃ, Nader Moazami, MDᵃ, and Harvey Pass, MDᵃ

ᵃ Department of Cardiothoracic Surgery, NYU Langone Health, New York, NY
ᵇ Computational Biology Core Laboratory, NYU Langone Health, New York, NY
ᶜ Department of Cardiac Surgery, Northwell Health, Westbury, NY

* Corresponding author

Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition. He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.