Impact of early pericardial fluid chymase activation after cardiac surgery

Frontiers in Cardiovascular Medicine

Cardiovascular Medicine

David McGiffin¹  Lee A. Goeddel²  James Mobley³  Jingyi Zheng⁴  James F. George⁵  James E. Davies⁵  Spencer J. Melby⁶  Carlos M. Ferrario⁷  Sarfaraz Ahmad⁷  Betty Pat⁸  Pamela Powell⁸  Louis J. Dell’Italia⁸  Brittany Butts⁹  Chad Steele^1,10 

[1] Cardiothoracic Surgery and Transplantation, The Alfred Hospital, Monash University, Melbourne, VIC, Australia;Department of Anesthesia and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States;Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL, United States;Department of Mathematics and Statistics, College of Science and Mathematics, Auburn University, Auburn, AL, United States;Department of Surgery, Division of Cardiothoracic Surgery, University of Alabama at Birmingham (UAB), Birmingham, AL, United States;Department of Surgery, Division of Cardiothoracic Surgery, Washington University, Saint Louis, MO, United States;Saint Louis VA Medical Center, Birmingham VA Health Care System, Birmingham, AL, United States;Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC, United States;Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham (UAB), Birmingham, AL, United States;Department of Veterans Affairs, Birmingham Veterans Affairs Health Care System, Birmingham, AL, United States;Nell Hodgson Woodruff School of Nursing, Emory University, Atlanta, GA, United States;School of Medicine—Microbiology and Immunology, Tulane University, New Orleans, LA, United States;

关键词: chymase;    extracellular vesicles;    exosomes;    cardiovascular surgery;    inflammation;    length of stay;    STS-PROM;    pericardial fluid;   

DOI  :  10.3389/fcvm.2023.1132786

 received in 2022-12-27, accepted in 2023-03-20,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionChymase is a highly destructive serine protease rapidly neutralized in the circulation by protease inhibitors. Here we test whether pericardial fluid (PCF) chymase activation and other inflammatory biomarkers determine intensive care unit length of stay, and explore mechanisms of chymase delivery by extracellular vesicles to the heart.MethodsPCF was collected from adult patients (17 on-pump; 13 off-pump) 4 h after cardiac surgery. Extracellular vesicles (EVs) containing chymase were injected into Sprague–Dawley rats to test for their ability to deliver chymase to the heart.ResultsThe mean intensive care unit (ICU) stay and mean total length of stay was 2.17 ± 3.8 days and 6.41 ± 1.3 days respectively. Chymase activity and 32 inflammatory markers did not differ in on-pump vs. off-pump cardiac surgery. Society of Thoracic Surgeons Predicted Risk of Morbidity and Mortality Score (STS-PROM), 4-hour post-surgery PCF chymase activity and C-X-C motif chemokine ligand 6 (CXCL6) were all independent predictors of ICU and total hospital length of stay by univariate analysis. Mass spectrometry of baseline PCF shows the presence of serine protease inhibitors that neutralize chymase activity. The compartmentalization of chymase within and on the surface of PCF EVs was visualized by immunogold labeling and transmission electron microscopy. A chymase inhibitor prevented EV chymase activity (0.28 fmol/mg/min vs. 14.14 fmol/mg/min). Intravenous injection of PCF EVs obtained 24 h after surgery into Sprague Dawley rats shows diffuse human chymase uptake in the heart with extensive cardiomyocyte damage 4 h after injection.DiscussionEarly postoperative PCF chymase activation underscores its potential role in cardiac damage soon after on- or off-pump cardiac surgery. In addition, chymase in extracellular vesicles provides a protected delivery mechanism from neutralization by circulating serine protease inhibitors.

【 授权许可】

Unknown   
© 2023 Butts, Goeddel, Zheng, Pat, Powell, Mobley, Ahmad, Steele, Mcgiffin, Davies, George, Melby, Ferrario and Dell'Italia.