PURPOSE: We have recently shown that PCSK9 reduces the clearance of endotoxin and is therefore a critical regulator of the innate immune response during infection. However, plasma PCSK9 levels during human sepsis and their relationship to outcomes are not known. Our objective was to determine the relationship between plasma PCSK9 levels and the rate of endotoxin clearance, and then correlate PCSK9 levels with the development of acute organ failures in a cohort of patients with sepsis. METHODS: Using human hepatocyte cells, we determined the threshold at which PCSK9 is able to reduce Escherichia coli endotoxin uptake by cultured human hepatocytes. In a single-centre observational cohort at St. Paul's Hospital in Vancouver, Canada, we recruited 200 patients who activated our Emergency Department's sepsis protocol and measured plasma PCSK9 and lipid levels at triage and throughout the admission. Outcomes were the development of sepsis-induced cardiovascular or respiratory failure. RESULTS: We reviewed the literature and determined that the normal human range of PCSK9 found in plasma is 170-220 ng/ml, while levels of 250 ng/ml and above reduced E. coli endotoxin clearance in cultured human hepatocytes. In septic patients, the median levels associated with new-onset respiratory and cardiovascular failure were 370 (250-500) and 380 (270-530) ng/ml, respectively, versus 270 (220-380) ng/ml in patients who did not go on to develop any organ failure (p = 0.003 and 0.005, respectively). CONCLUSIONS: Plasma PCSK9 levels are greatly increased in sepsis. At normal levels, PCSK9 has no influence upon hepatocyte bacterial endotoxin clearance, but as levels rise, there is a progressive inhibition of clearance. During sepsis, PCSK9 levels are highly correlated with the development of subsequent multiple organ failure. Inhibition of PCSK9 activity is an attractive target for treating the spectrum of sepsis and septic shock.
PURPOSE: We have recently shown that PCSK9 reduces the clearance of endotoxin and is therefore a critical regulator of the innate immune response during infection. However, plasma PCSK9 levels during humansepsis and their relationship to outcomes are not known. Our objective was to determine the relationship between plasma PCSK9 levels and the rate of endotoxin clearance, and then correlate PCSK9 levels with the development of acute organ failures in a cohort of patients with sepsis. METHODS: Using human hepatocyte cells, we determined the threshold at which PCSK9 is able to reduce Escherichia coli endotoxin uptake by cultured human hepatocytes. In a single-centre observational cohort at St. Paul's Hospital in Vancouver, Canada, we recruited 200 patients who activated our Emergency Department's sepsis protocol and measured plasma PCSK9 and lipid levels at triage and throughout the admission. Outcomes were the development of sepsis-induced cardiovascular or respiratory failure. RESULTS: We reviewed the literature and determined that the normal human range of PCSK9 found in plasma is 170-220 ng/ml, while levels of 250 ng/ml and above reduced E. coli endotoxin clearance in cultured human hepatocytes. In septic patients, the median levels associated with new-onset respiratory and cardiovascular failure were 370 (250-500) and 380 (270-530) ng/ml, respectively, versus 270 (220-380) ng/ml in patients who did not go on to develop any organ failure (p = 0.003 and 0.005, respectively). CONCLUSIONS: Plasma PCSK9 levels are greatly increased in sepsis. At normal levels, PCSK9 has no influence upon hepatocyte bacterial endotoxin clearance, but as levels rise, there is a progressive inhibition of clearance. During sepsis, PCSK9 levels are highly correlated with the development of subsequent multiple organ failure. Inhibition of PCSK9 activity is an attractive target for treating the spectrum of sepsis and septic shock.
Authors: José Tuñón; Lina Badimón; Marie-Luce Bochaton-Piallat; Bertrand Cariou; Mat J Daemen; Jesus Egido; Paul C Evans; Imo E Hoefer; Daniel F J Ketelhuth; Esther Lutgens; Christian M Matter; Claudia Monaco; Sabine Steffens; Erik Stroes; Cécile Vindis; Christian Weber; Magnus Bäck Journal: Cardiovasc Res Date: 2019-01-01 Impact factor: 10.787
Authors: Auguste Dargent; Jean-Paul Pais de Barros; Samir Saheb; Randa Bittar; Wilfried Le Goff; Alain Carrié; Thomas Gautier; Isabelle Fournel; Anne Laure Rerole; Hélène Choubley; David Masson; Laurent Lagrost; Jean-Pierre Quenot Journal: J Lipid Res Date: 2020-10-09 Impact factor: 5.922
Authors: Faheem W Guirgis; Christiaan Leeuwenburgh; Lyle Moldawer; Gabriela Ghita; Lauren Page Black; Morgan Henson; Elizabeth DeVos; David Holden; Phil Efron; Srinivasa T Reddy; Frederick A Moore Journal: Ann Intensive Care Date: 2021-05-20 Impact factor: 6.925
Authors: Sokratis A Apostolidis; Amrita Sarkar; Heather M Giannini; Rishi R Goel; Divij Mathew; Aae Suzuki; Amy E Baxter; Allison R Greenplate; Cécile Alanio; Mohamed Abdel-Hakeem; Derek A Oldridge; Josephine Giles; Jennifer E Wu; Zeyu Chen; Yinghui Jane Huang; Ajinkya Pattekar; Sasikanth Manne; Oliva Kuthuru; Jeanette Dougherty; Brittany Weiderhold; Ariel R Weisman; Caroline A G Ittner; Sigrid Gouma; Debora Dunbar; Ian Frank; Alexander C Huang; Laura A Vella; John P Reilly; Scott E Hensley; Lubica Rauova; Liang Zhao; Nuala J Meyer; Mortimer Poncz; Charles S Abrams; E John Wherry Journal: bioRxiv Date: 2021-05-03