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.

© 2016 S. Karger AG, Basel.

Figures

Fig. 1

Meta-analysis of 15 studies with a total of 3,556 subjects not on statins or fibrates. Studies were weighted according to the number of subjects, and the final pooled 95% confidence interval for plasma PCSK9 levels was 170-220 ng/ml.

Fig. 2

PCSK9 level is positively correlated with the inhibition of hepatocyte endotoxin uptake. The elimination and detoxification of bacterial endotoxin (LPS) is done almost exclusively via the liver. We used genetically identical human liver cells to evaluate the threshold and dose-response characteristics of the PCSK9 level compared to the rate of LPS uptake into the liver and, thus, clearance from the circulation. A total of 20,000 cells were pooled for each data point and the data are representative of three separate experiments. Compared to no PCSK9 (0 ng/ml), at 250 ng/ml, there is a statistically significant but biologically small (4%) reduction in LPS uptake. Saturation of the dose-response occurs at 3,000 ng/ml with a 60% reduction in endotoxin uptake. The steepest portion of the PCSK9 dose-response slope occurs between 250 and 1,000 ng/ml. All doses of PCSK9 tested in this curve were significantly different to 0 ng/ml (p

Fig. 3

Lipid and PCSK9 profile at triage in patients assessed for sepsis. Two hundred patients who presented with sepsis and abnormal vital signs triggered the local sepsis protocol and had plasma drawn with the first blood culture. Histogram plots of total cholesterol, HDL, LDL, triglycerides and PCSK9 plasma levels are shown along with normal reference ranges. There is a clear and profound shift towards low cholesterol of all types and high PCSK9. Triglycerides remain largely unaffected early in sepsis.

Fig. 4

The odds of developing more than one acute sepsis-related organ failure increase as PCSK9 levels exceed the normal range. The upper section displays the fraction of patients not on statins whose triage PCSK9 levels exceed the x-axis threshold. The lower panel plots the odds ratio of developing more than one organ failure in those whose triage PCSK9 levels exceed the x-axis threshold versus those at or below it. Standard error estimates are plotted in grey.

Fig. 5

PCSK9 levels according to the development of cardiovascular or respiratory failure due to sepsis. A total of 143 patients not on statins who triggered the sepsis protocol were followed during their admission for the development of organ failure(s). a PCSK9 plasma levels according to whether the patient developed cardiovascular failure. b PCSK9 plasma levels according to whether the patient developed respiratory failure. * p < 0.05.