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Lipoproteins in Sepsis
Keith R. Walley, MDSt. Paul’s Hospital
University of British Columbia
Vancouver, Canada
Disclosure / Conflict of Interest
• UBC has filed a patent application based on PCSK9 data.
Keith Walley, Jim Russell, John Boyd are inventors.
2
Sepsis drugs
3
Clearing the pathogen works (e.g. antibiotics)
Kumar A et al Crit Care Med, 34:1589-1596, 2006
Delayed antibiotic
administration after
onset of hypotension
increases mortality by
~7% per hour.
Late modulation of host response doesn’t work (e.g. rhAPC, anti-TNF)
Deans KJ et al. J Trauma, 58:867-874, 2005
4Levels et al. Infection and Immun. 69 (5); 2821–2828, 2001
Flu
ore
sce
nt
L
PS
Chole
ste
rol
200 40 60200 40 60
How are pathogens cleared?Lipopolysaccharide, Lipoteichoic acid, phospholipomannan
VLDL, LDL, HDL
Plasma LPS distribution
5
Non–lipoprotein-bound residual 4%
Levels et al. Crit Care Med. 31:1647–1653, 2003
Lipoproteins in sepsis(Non-survivors filled circles)
6Chien J-Y et al. Crit Care Med 33:1688–1693, 2005.
200
100
150
60
Low LDL / HDL levels in sepsis
7Boyd JH, et al. J Innate Immunity. 8(2):211-20, 2016
Low HDL is bad
8
Percen
t su
rviv
al
0 15 30 45 60 75 900
6070
80
90
100
HDL < 25.1 mg/dL
HDL> 25.1 mg/dL
At-risk patients:HDL > 25.1mg/dL 132 131 130 125 124 123 121HDL < 25.1mg/dL 68 62 57 54 52 52 51
Days
Cirstea M, et al. J Crit Care. 38:289-294, 2017
CETP genetic variants confirm functional
effect of low HDL (CETP decreases HDL)
9Trinder M, et al. Am J Respir Crit Care Med. 2018 [Epub ahead of print]. PMID 30321485
CETP gain-of-function decreases HDL(rs1800777 A allele)
10
Trinder M, et al. Am J Respir Crit Care Med. 2018 [Epub ahead of print]. PMID 30321485
Why is low HDL bad?
HDL binding is the first
step in LPS clearance
Low LDL drives PCSK9 in sepsis
11
Elevated PCSK9 is Bad
12Boyd JH et al. Journal of Innate Immunity. 8(2):211-20, 2016
Why is ↑ PCSK9 bad?
Start with PCSK9 and LDL clearance
Image from caltagmedsystems.blogspot.com13
• Sanofi/Regeneron: alirocumab (Praluent)
• Amgen: evolocumab (Repatha)
14
PCSK9 decreases
hepatic LDL receptor
numbers.
PCSK9 decreases
pathogen lipid
clearance.
PCSK9 worsens
sepsis.
Hypothesis
Lipopolysaccharide (LPS) gram–, Lipoteichoic acid (LTA) gram+, Phospholipomannan fungal
PCSK9 reduces hepatocyte LPS clearance
15Walley KR et al. Science Trans Med. 6(258):258ra143, 2014
PCSK9 antibody: CLP survival
16
*
*
PCSK9 AntibodyIsotype Control
*
*
PCSK9 AntibodyIsotype Control
p=0.034
TNF (p=0.027), IL-6 (p=0.051), IL-10 (p=0.068), JE (p=0.0085) and MIP-2 (p=0.040)
PCSK9 Loss-of-Function (LOF)
Human septic shock survival
17
VASST
p=0.0054SPH
p=0.022
Replication and extension
18Dwivedi DJ, et al. Shock. 2016
Was it via the LDL receptor?
19Topchiy E, et al. PLoS One. 11(5):e0155030, 2016
Blood Liver
LPS uptake by hepatocytes
20Topchiy E, et al. PLoS One. 11(5):e0155030, 2016
Role of VLDL?LPS is sequestered in adipose tissue via VLDLR
21
↑ VLDLR increases septic shock survival
(VLDLR rs7852409 C allele is gain-of-function)
22
1.0
0.9
0.8
0.7
0.6
0.5
Days
28211470
Surv
ival
*
GG (n=305)
CG (n=171)
CC (n=43)
Lipoproteins in Sepsis
23
Adipose
tissue
VLDLR
UBC co-investigators
John Boyd
Jim Russell
U Penn co-investigators
Muredach Reilly
Nuala Meyer
Jason Christie
Jane Ferguson
Databases
VASST Investigators
People
Taka Nakada
Katherine Thain
Simone Thair
Lynda Lazosky
Funding
CIHR
NIH
