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Inhibition of Cholesteryl Ester Transfer Protein Preserves High-Density Lipoprotein Cholesterol and Improves Survival in Sepsis

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Trinder, M, Wang, Y, Madsen, CM, Ponomarev, T, Bohunek, L, Daisley, BA, Kong, HJ, Blauw, LL, Nordestgaard, BG, Tybjærg-Hansen, A, Wurfel, MM, Russell, JA, Walley, KR, Rensen, PCN, Boyd, JH & Brunham, LR 2021, 'Inhibition of Cholesteryl Ester Transfer Protein Preserves High-Density Lipoprotein Cholesterol and Improves Survival in Sepsis', Circulation, bind 143, nr. 9, s. 921-934. https://doi.org/10.1161/CIRCULATIONAHA.120.048568

APA

Trinder, M., Wang, Y., Madsen, C. M., Ponomarev, T., Bohunek, L., Daisley, B. A., Kong, H. J., Blauw, L. L., Nordestgaard, B. G., Tybjærg-Hansen, A., Wurfel, M. M., Russell, J. A., Walley, K. R., Rensen, P. C. N., Boyd, J. H., & Brunham, L. R. (2021). Inhibition of Cholesteryl Ester Transfer Protein Preserves High-Density Lipoprotein Cholesterol and Improves Survival in Sepsis. Circulation, 143(9), 921-934. https://doi.org/10.1161/CIRCULATIONAHA.120.048568

CBE

Trinder M, Wang Y, Madsen CM, Ponomarev T, Bohunek L, Daisley BA, Kong HJ, Blauw LL, Nordestgaard BG, Tybjærg-Hansen A, Wurfel MM, Russell JA, Walley KR, Rensen PCN, Boyd JH, Brunham LR. 2021. Inhibition of Cholesteryl Ester Transfer Protein Preserves High-Density Lipoprotein Cholesterol and Improves Survival in Sepsis. Circulation. 143(9):921-934. https://doi.org/10.1161/CIRCULATIONAHA.120.048568

MLA

Vancouver

Author

Trinder, Mark ; Wang, Yanan ; Madsen, Christian M ; Ponomarev, Tatjana ; Bohunek, Lubos ; Daisley, Brendan A ; Kong, HyeJin Julia ; Blauw, Lisanne L ; Nordestgaard, Børge G ; Tybjærg-Hansen, Anne ; Wurfel, Mark M ; Russell, James A ; Walley, Keith R ; Rensen, Patrick C N ; Boyd, John H ; Brunham, Liam R. / Inhibition of Cholesteryl Ester Transfer Protein Preserves High-Density Lipoprotein Cholesterol and Improves Survival in Sepsis. I: Circulation. 2021 ; Bind 143, Nr. 9. s. 921-934.

Bibtex

@article{94b908eb9eb346efa78c6c10cf06289f,
title = "Inhibition of Cholesteryl Ester Transfer Protein Preserves High-Density Lipoprotein Cholesterol and Improves Survival in Sepsis",
abstract = "BACKGROUND: The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis.METHODS: We examined the effect of a gain-of-function variant in CETP (rs1800777, p.Arg468Gln) and a genetic score for decreased CETP function on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5949), iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk; n=882), Copenhagen General Population Study (n=2068), Copenhagen City Heart Study (n=493), Early Infection (n=200), St Paul's Intensive Care Unit 2 (n=203), and Vasopressin Versus Norepinephrine Infusion in Patients With Septic Shock studies (n=632). We then studied the effect of the CETP inhibitor, anacetrapib, in adult female APOE*3-Leiden mice with or without human CETP expression using the cecal-ligation and puncture model of sepsis. RESULTS: A fixed-effect meta-analysis of all 7 cohorts found that the CETP gain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio, 1.44 [95% CI, 1.22-1.70]; P<0.0001). In addition, a genetic score for decreased CETP function was associated with significantly decreased sepsis mortality in the UK Biobank (hazard ratio, 0.77 [95% CI, 0.59-1.00] per 1 mmol/L increase in HDL-C) and iSPAAR cohorts (hazard ratio, 0.60 [95% CI, 0.37-0.98] per 1 mmol/L increase in HDL-C). APOE*3-Leiden.CETP mice treated with anacetrapib had preserved levels of HDL-C and apolipoprotein-AI and increased survival relative to placebo treatment (70.6% versus 35.3%, Log-rank P=0.03), whereas there was no effect of anacetrapib on the survival of APOE*3-Leiden mice that did not express CETP (50.0% versus 42.9%, Log-rank P=0.87). CONCLUSIONS: Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis.",
author = "Mark Trinder and Yanan Wang and Madsen, {Christian M} and Tatjana Ponomarev and Lubos Bohunek and Daisley, {Brendan A} and Kong, {HyeJin Julia} and Blauw, {Lisanne L} and Nordestgaard, {B{\o}rge G} and Anne Tybj{\ae}rg-Hansen and Wurfel, {Mark M} and Russell, {James A} and Walley, {Keith R} and Rensen, {Patrick C N} and Boyd, {John H} and Brunham, {Liam R}",
year = "2021",
month = mar,
day = "2",
doi = "10.1161/CIRCULATIONAHA.120.048568",
language = "English",
volume = "143",
pages = "921--934",
journal = "Circulation (Baltimore)",
issn = "0009-7322",
publisher = "Lippincott Williams & Wilkins",
number = "9",

}

RIS

TY - JOUR

T1 - Inhibition of Cholesteryl Ester Transfer Protein Preserves High-Density Lipoprotein Cholesterol and Improves Survival in Sepsis

AU - Trinder, Mark

AU - Wang, Yanan

AU - Madsen, Christian M

AU - Ponomarev, Tatjana

AU - Bohunek, Lubos

AU - Daisley, Brendan A

AU - Kong, HyeJin Julia

AU - Blauw, Lisanne L

AU - Nordestgaard, Børge G

AU - Tybjærg-Hansen, Anne

AU - Wurfel, Mark M

AU - Russell, James A

AU - Walley, Keith R

AU - Rensen, Patrick C N

AU - Boyd, John H

AU - Brunham, Liam R

PY - 2021/3/2

Y1 - 2021/3/2

N2 - BACKGROUND: The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis.METHODS: We examined the effect of a gain-of-function variant in CETP (rs1800777, p.Arg468Gln) and a genetic score for decreased CETP function on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5949), iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk; n=882), Copenhagen General Population Study (n=2068), Copenhagen City Heart Study (n=493), Early Infection (n=200), St Paul's Intensive Care Unit 2 (n=203), and Vasopressin Versus Norepinephrine Infusion in Patients With Septic Shock studies (n=632). We then studied the effect of the CETP inhibitor, anacetrapib, in adult female APOE*3-Leiden mice with or without human CETP expression using the cecal-ligation and puncture model of sepsis. RESULTS: A fixed-effect meta-analysis of all 7 cohorts found that the CETP gain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio, 1.44 [95% CI, 1.22-1.70]; P<0.0001). In addition, a genetic score for decreased CETP function was associated with significantly decreased sepsis mortality in the UK Biobank (hazard ratio, 0.77 [95% CI, 0.59-1.00] per 1 mmol/L increase in HDL-C) and iSPAAR cohorts (hazard ratio, 0.60 [95% CI, 0.37-0.98] per 1 mmol/L increase in HDL-C). APOE*3-Leiden.CETP mice treated with anacetrapib had preserved levels of HDL-C and apolipoprotein-AI and increased survival relative to placebo treatment (70.6% versus 35.3%, Log-rank P=0.03), whereas there was no effect of anacetrapib on the survival of APOE*3-Leiden mice that did not express CETP (50.0% versus 42.9%, Log-rank P=0.87). CONCLUSIONS: Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis.

AB - BACKGROUND: The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis.METHODS: We examined the effect of a gain-of-function variant in CETP (rs1800777, p.Arg468Gln) and a genetic score for decreased CETP function on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5949), iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk; n=882), Copenhagen General Population Study (n=2068), Copenhagen City Heart Study (n=493), Early Infection (n=200), St Paul's Intensive Care Unit 2 (n=203), and Vasopressin Versus Norepinephrine Infusion in Patients With Septic Shock studies (n=632). We then studied the effect of the CETP inhibitor, anacetrapib, in adult female APOE*3-Leiden mice with or without human CETP expression using the cecal-ligation and puncture model of sepsis. RESULTS: A fixed-effect meta-analysis of all 7 cohorts found that the CETP gain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio, 1.44 [95% CI, 1.22-1.70]; P<0.0001). In addition, a genetic score for decreased CETP function was associated with significantly decreased sepsis mortality in the UK Biobank (hazard ratio, 0.77 [95% CI, 0.59-1.00] per 1 mmol/L increase in HDL-C) and iSPAAR cohorts (hazard ratio, 0.60 [95% CI, 0.37-0.98] per 1 mmol/L increase in HDL-C). APOE*3-Leiden.CETP mice treated with anacetrapib had preserved levels of HDL-C and apolipoprotein-AI and increased survival relative to placebo treatment (70.6% versus 35.3%, Log-rank P=0.03), whereas there was no effect of anacetrapib on the survival of APOE*3-Leiden mice that did not express CETP (50.0% versus 42.9%, Log-rank P=0.87). CONCLUSIONS: Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis.

U2 - 10.1161/CIRCULATIONAHA.120.048568

DO - 10.1161/CIRCULATIONAHA.120.048568

M3 - Journal article

C2 - 33228395

VL - 143

SP - 921

EP - 934

JO - Circulation (Baltimore)

JF - Circulation (Baltimore)

SN - 0009-7322

IS - 9

ER -

ID: 61929671