前蛋白转化酶枯草杆菌蛋白酶/克新9型的药理学和基因下调与脓毒症存活情况

Pharmacologic and Genetic Downregulation of Proprotein Convertase Subtilisin/Kexin Type 9 and Survival From Sepsis.

作者信息

Lawler Patrick R, Manvelian Garen, Coppi Alida, Damask Amy, Cantor Michael N, Ferreira Manuel A R, Paulding Charles, Banerjee Nilanjana, Li Dadong, Jorgensen Susan, Attre Richa, Carey David J, Krebs Kristi, Milani Lili, Hveem Kristian, Damås Jan K, Solligård Erik, Stender Stefan, Tybjærg-Hansen Anne, Nordestgaard Børge G, Hernandez-Beeftink Tamara, Rogne Tormod, Flores Carlos, Villar Jesús, Walley Keith R, Liu Vincent X, Fohner Alison E, Lotta Luca A, Kyratsous Christos A, Sleeman Mark W, Scemama Michel, DelGizzi Richard, Pordy Robert, Horowitz Julie E, Baras Aris, Martin Greg S, Steg Philippe Gabriel, Schwartz Gregory G, Szarek Michael, Goodman Shaun G

机构信息

Department of Medicine, McGill University Health Centre, McGill University, Montreal, QC, Canada.

Department of Medicine, Peter Munk Cardiac Centre at University Health Network, University of Toronto, Toronto, ON, Canada.

出版信息

Crit Care Explor. 2023 Nov 8;5(11):e0997. doi: 10.1097/CCE.0000000000000997. eCollection 2023 Nov.

DOI:10.1097/CCE.0000000000000997

PMID:37954898

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10635596/

Abstract

OBJECTIVES

Treatments that prevent sepsis complications are needed. Circulating lipid and protein assemblies-lipoproteins play critical roles in clearing pathogens from the bloodstream. We investigated whether early inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) may accelerate bloodstream clearance of immunogenic bacterial lipids and improve sepsis outcomes.

DESIGN

Genetic and clinical epidemiology, and experimental models.

SETTING

Human genetics cohorts, secondary analysis of a phase 3 randomized clinical trial enrolling patients with cardiovascular disease (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]; NCT01663402), and experimental murine models of sepsis.

PATIENTS OR SUBJECTS

Nine human cohorts with sepsis (total = 12,514) were assessed for an association between sepsis mortality and loss-of-function (LOF) variants. Incident or fatal sepsis rates were evaluated among 18,884 participants in a post hoc analysis of ODYSSEY OUTCOMES. C57BI/6J mice were used in and bacteremia sepsis models, and in lipopolysaccharide-induced animal models.

INTERVENTIONS

Observational human cohort studies used genetic LOF variants as instrumental variables. ODYSSEY OUTCOMES participants were randomized to alirocumab or placebo. Mice were administered alirocumab, a PCSK9 inhibitor, at 5 mg/kg or 25 mg/kg subcutaneously, or isotype-matched control, 48 hours prior to the induction of bacterial sepsis. Mice did not receive other treatments for sepsis.

MEASUREMENTS AND MAIN RESULTS

Across human cohort studies, the effect estimate for 28-day mortality after sepsis diagnosis associated with genetic LOF was odds ratio = 0.86 (95% CI, 0.67-1.10; = 0.24). A significant association was present in antibiotic-treated patients. In ODYSSEY OUTCOMES, sepsis frequency and mortality were infrequent and did not significantly differ by group, although both were numerically lower with alirocumab vs. placebo (relative risk of death from sepsis for alirocumab vs. placebo, 0.62; 95% CI, 0.32-1.20; = 0.15). Mice treated with alirocumab had lower endotoxin levels and improved survival.

CONCLUSIONS

PCSK9 inhibition may improve clinical outcomes in sepsis in preventive, pretreatment settings.

摘要

目的

需要能够预防脓毒症并发症的治疗方法。循环中的脂质和蛋白质聚集体——脂蛋白在清除血液中的病原体方面发挥着关键作用。我们研究了早期抑制前蛋白转化酶枯草溶菌素/克新9型（PCSK9）是否能加速免疫原性细菌脂质的血液清除并改善脓毒症的预后。

设计

遗传与临床流行病学以及实验模型。

设置

人类遗传学队列、一项纳入心血管疾病患者的3期随机临床试验的二次分析（阿利西尤单抗治疗急性冠状动脉综合征后的心血管结局评估[ODYSSEY OUTCOMES]；NCT01663402）以及脓毒症的实验小鼠模型。

患者或受试者

对9个脓毒症人类队列（共12,514人）评估脓毒症死亡率与功能丧失（LOF）变异之间的关联。在ODYSSEY OUTCOMES的一项事后分析中，对18,884名参与者的脓毒症发生率或死亡率进行了评估。C57BI/6J小鼠用于菌血症脓毒症模型以及脂多糖诱导的动物模型。

干预措施

观察性人类队列研究将遗传LOF变异用作工具变量。ODYSSEY OUTCOMES的参与者被随机分配至阿利西尤单抗或安慰剂组。在诱导细菌性脓毒症前48小时，给小鼠皮下注射5 mg/kg或25 mg/kg的PCSK9抑制剂阿利西尤单抗，或同型对照。小鼠未接受其他脓毒症治疗。

测量指标和主要结果

在各项人类队列研究中，脓毒症诊断后28天死亡率与遗传LOF相关的效应估计值为比值比 = 0.86（95%置信区间，0.67 - 1.10；P = 0.24）。在接受抗生素治疗的患者中存在显著关联。在ODYSSEY OUTCOMES中，脓毒症的发生率和死亡率较低，两组之间无显著差异，尽管阿利西尤单抗组在数值上均低于安慰剂组（阿利西尤单抗与安慰剂相比，脓毒症死亡的相对风险为0.62；95%置信区间，0.32 - 1.20；P = 0.15）。接受阿利西尤单抗治疗的小鼠内毒素水平较低且生存率提高。