Increased Plasma PCSK9 Levels Are Associated with Reduced Endotoxin Clearance and the Development of Acute Organ Failures during Sepsis

Abstract

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.

PCSK9 and infection: A potentially useful or dangerous association?

“…Similar results have been reported by Boyd et al () who found elevated plasma levels of PCSK9 and increased systemic inflammation during human sepsis. They evaluated the effect of PCSK9 on Escherichia coli endotoxin uptake by the human hepatocyte cells and indicated that hepatic PCSK9 concentrations above physiological plasma levels gradually mitigate bacterial endotoxin clearance of the blood and the development of subsequent organ failure.…”

Cholesterol levels and long-term rates of community-acquired sepsis

“…PCSK9 inhibitors are currently under investigation as lipid-lowering agents because they promote LDL clearance and thus reduce LDL levels, but they may also have an application in clearance of lipid-based pathogens in sepsis. PCSK9 inhibition results in decreased inflammatory cytokine production and physiological responses to endotoxin in septic mice and increased PCSK9 levels are associated with reduced endotoxin clearance and organ failure in sepsis [45, 46]. Although this is a new area of research, it demonstrates that modulation of cholesterol metabolism may have potential as a future application of these findings.…”

Update of Sepsis in the Intensive Care Unit

“…Subsequently, PCSK9 knockout and PCSK9 inhibition decrease mortality and markers of inflammation such as plasma cytokines. Furthermore, plasma PCSK9 levels are increased in sepsis and correlated with the development of subsequent cardiovascular and respiratory failure [103] . Additionally, anti-PCSK9 therapy is associated with increased pathogen clearance and decreased inflammatory responses in a murine model of sepsis [104] .…”