title: Increased Plasma PCSK9 Levels Are Associated with Reduced Endotoxin Clearance and the Development of Acute Organ Failures during Sepsis.
abstract: OBJECTIVE
  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.
authors.affiliation: Centre for Heart Lung Innovation, University of British Columbia, Vancouver, B.C., Canada.
authors.forename: John H
authors.initials: JH
authors.lastname: Boyd
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Fjell
authors.forename: James A
authors.initials: JA
authors.lastname: Russell
authors.forename: Demetrios
authors.initials: D
authors.lastname: Sirounis
authors.forename: Mihai S
authors.initials: MS
authors.lastname: Cirstea
authors.forename: Keith R
authors.initials: KR
authors.lastname: Walley
mesh_terms: D002460:Cell Line; D004731:Endotoxins / Q000097:blood* / Q000276:immunology; D005260:Female; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008297:Male; D009102:Multiple Organ Failure / Q000097:blood* / Q000276:immunology / Q000628:therapy; D000071449:Proprotein Convertase 9 / Q000097:blood* / Q000276:immunology; D018805:Sepsis / Q000097:blood* / Q000276:immunology / Q000628:therapy
chemical_list: D004731:Endotoxins; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9