Bench to Bedside PCSK9 Children are Different
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1 Bench to Bedside PCSK9 Children are Different Hector R. Wong, MD Division of Critical Care Medicine Cincinnati Children s Hospital Medical Center Cincinnati Children s Research Foundation Critical Care Canada Forum October 2016
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5 Genetic ablation or pharmacologic inhibition of PCSK9 protects against experimental sepsis (mice). Adults with sepsis and PCSK9 loss of function variants have better outcomes. Effects lost in LDRL null mice and in humans homozygous for an LDLR variant that is resistant to the effects of PCSK9. Other experiments linking PCSK9 activity, lipid clearance via the LDLR, and the response to sepsis. PCSK9 inhibition as a novel strategy in sepsis?
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7 Is the PCSK9-LDLR pathway operative in children with septic shock? 430 children with septic shock. Genotyped for the same PCSK9 variants as Walley et al. Loss of function (LOS): rs , rs , and rs Gain of function (GOF): rs Genotyped for the LDRL variant resistant to PCSK9 activity: rs688 Primary outcome variable: complicated course Secondary outcome variable: 28 day mortality Excluded patients with both LOF and GOF variants (n=17)
8 Allele Distribution and Clinical Characteristics Homozygous for wild type alleles: 219 (51%). At least one LOF variant: 175 (40%). At least one GOF allele: 39 (9%). Equal distribution based on gender, co-morbidity burden, corticosteroid exposure, infecting organism, and illness severity (PRISM score). LOF alleles more prevalent among Caucasian children, GOF alleles more prevalent among African-American children.
9 Allele Distribution and Outcomes Wild type LOF allele GOF allele P value N Complicated Course, n (%) 48 (22) 58 (33) 11 (28) 0.031
10 Allele Distribution and Outcomes Wild type LOF allele GOF allele P value N Complicated Course, n (%) 48 (22) 58 (33) 11 (28) day mortality, n (%) 14 (6) 25 (14) 5 (13) 0.044
11 Multiple logistic regression: association between LOF & outcome Any PCSK9 LOF allele vs. wild type or GOF. Adjusted for age and illness severity (PRISM). Complicated course: LOF allele independently associated with increased odds of complicated course. O.R. 1.7 (1.1 to 2.7, p= 0.025) 28 day mortality: LOF allele independently associated with increased odds of mortality. O.R. 2.2 (1.1 to 4.2), p = Effect sizes increased when excluding those with LDLR variant resistant to PCSK9.
12 PCSK9 loss of function and septic shock outcomes Adults with septic shock Better outcomes Children with septic shock Worse outcomes
13 Biological Paradox PCSK9 inhibition Enhanced clearance of bacterial lipids via the LDLR Better outcomes (adults) Worse outcomes (children)????
14 The PCSK9-LDLR Pathway in Children with Sepsis PCSK9 inhibition (loss of function) Enhanced clearance of bacterial lipids via the LDLR Exaggerated/enhanced inflammation in the immature liver
15 IL8 concentrations in children with septic shock PCSK9 LOF vs. no LOF IL8 pg/ml PCSK9 LOF PCSK9 No LOF
16 The PCSK9-LDLR Pathway in Children with Sepsis PCSK9 inhibition Enhanced clearance of bacterial lipids via the LDLR Exaggerated/enhanced inflammation in the immature liver
17 Immature Model of Sepsis Adult Mice Juvenile mice 12 to 14 days old i.p. injection of a standardized cecal slurry
18 Immature Model of Sepsis Genetic or pharmacologic inhibition of MMP8 Genetic or pharmacologic inhibition of MMP8 Beneficial in sepsis Solan et al. Crit Care Med Detrimental in sepsis Atkinson et al. Mol Med. 2016
19 Immature Model of Sepsis Genetic or pharmacologic inhibition of PCSK9 Genetic or pharmacologic inhibition of PCSK9 Beneficial in sepsis Detrimental in sepsis??
20 Preliminary observations Administration of a PCSK9 neutralizing antibody does not improve or worsen mortality in juvenile mice challenged with sepsis.
21 Summary PCSK9 loss of function is associated with improved outcomes among adults with septic shock. The biology of this association is very well corroborated in experimental models of adult murine sepsis. This association is not evident among children with septic shock. Clinical validation pending. Experimental validation pending using a juvenile model of sepsis.
22 Take home message Novel sepsis therapies developed based on adult data and adult experimental models might not be biologically appropriate for children.
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24 Thank You
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