Dataset Information

Impact of PCSK9 loss-of-function genotype on 1-year mortality and recurrent infection in sepsis survivors.

ABSTRACT:

Background

Reduced activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been associated with decreased short-term death in patients with septic shock. Whether PCSK9 genotype influences long-term outcomes in sepsis survivors is unknown.

Methods

We evaluated the impact of PCSK9 loss-of-function (LOF) genotype on both 1-year mortality and infection-related readmission (IRR) after an index sepsis admission. The Derivation cohort included 342 patients who survived 28 days after a sepsis admission in a tertiary hospital (Vancouver/Canada, 2004-2014), while an independent Validation cohort included 1079 septic shock patients admitted at the same hospital (2000-2006). All patients were genotyped for three common missense PCSK9 LOF variants rs11591147, rs11583680, rs562556 and were classified in 3 groups: Wildtype, single PCSK9 LOF, and multiple PCSK9 LOF, according to the number of LOF alleles per patient. We also performed a meta-analysis using both cohorts to investigate the effects of PCSK9 genotype on 90-day survival.

Findings

In the Derivation cohort, patients carrying multiple PCSK9 LOF alleles showed lower risk for the composite outcome 1-year death or IRR (HR: 0.40, P = 0.006), accelerated reduction on neutrophil counts (P = 0.010), and decreased levels of PCSK9 (P = 0.037) compared with WT/single LOF groups. Our meta-analysis revealed that the presence of multiple LOF alleles was associated with lower 90-day mortality risk (OR = 0.69, P = 0.020).

Interpretation

The presence of multiple PCSK9 LOF alleles decreased the risk of 1-year death or IRR in sepsis survivors. Biological measures suggest this may be related to an enhanced resolution of the initial infection.

Funding

Canadian Institutes of Health Research (PJT-156056).

SUBMITTER: Genga KR

PROVIDER: S-EPMC6306489 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Publications

Impact of PCSK9 loss-of-function genotype on 1-year mortality and recurrent infection in sepsis survivors.

Genga Kelly Roveran KR Lo Cody C Cirstea Mihai S MS Leitao Filho Fernando Sergio FS Walley Keith R KR Russell James A JA Linder Adam A Francis Gordon A GA Boyd John H JH

EBioMedicine 20181123

<h4>Background</h4>Reduced activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been associated with decreased short-term death in patients with septic shock. Whether PCSK9 genotype influences long-term outcomes in sepsis survivors is unknown.<h4>Methods</h4>We evaluated the impact of PCSK9 loss-of-function (LOF) genotype on both 1-year mortality and infection-related readmission (IRR) after an index sepsis admission. The Derivation cohort included 342 patients who survived 28 d ...[more]

PMID: 30473376

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Project description:BackgroundSepsis is associated with significant mortality. Yet, there are no efficacious therapies beyond antibiotics. PCSK9 loss-of-function (LOF) and inhibition, through enhanced low-density lipoprotein receptor (LDLR) mediated endotoxin clearance, holds promise as a potential therapeutic approach among adults. In contrast, we have previously demonstrated higher mortality in the juvenile host. Given the potential pleiotropic effects of PCSK9 on the endothelium, beyond canonical effects on serum lipoproteins, both of which may influence sepsis outcomes, we sought to test the influence of PCSK9 LOF genotype on endothelial dysfunction.MethodsSecondary analyses of a prospective observational cohort of pediatric septic shock. Genetic variants of PCSK9 and LDLR genes, serum PCSK9, and lipoprotein concentrations were determined previously. Endothelial dysfunction markers were measured in day 1 serum. We conducted multivariable linear regression to test the influence of PCSK9 LOF genotype on endothelial markers, adjusted for age, complicated course, and low- and high-density lipoproteins (LDL and HDL). Causal mediation analyses to test impact of select endothelial markers on the association between PCSK9 LOF genotype and mortality. Juvenile Pcsk9 null and wildtype mice were subject to cecal slurry sepsis and endothelial markers were quantified.ResultsA total of 474 patients were included. PCSK9 LOF was associated with several markers of endothelial dysfunction, with strengthening of associations after exclusion of those homozygous for the rs688 LDLR variant that renders it insensitive to PCSK9. Serum PCSK9 was not correlated with endothelial dysfunction. PCSK9 LOF influenced concentrations of Angiopoietin-1 (Angpt-1) upon adjusting for potential confounders including lipoprotein concentrations, with false discovery adjusted p value of 0.042 and 0.013 for models that included LDL and HDL, respectively. Causal mediation analysis demonstrated that the effect of PCSK9 LOF on mortality was mediated by Angpt-1 (p = 0.0008). Murine data corroborated these results with lower Angpt-1 and higher soluble thrombomodulin among knockout mice with sepsis relative to the wildtype.ConclusionsWe present genetic and biomarker association data that suggest a potential direct role of the PCSK9-LDLR pathway on Angpt-1 in the developing host with septic shock and warrant external validation. Further, mechanistic studies on the role of PCSK9-LDLR pathway on vascular homeostasis may lead to the development of pediatric-specific sepsis therapies.

Project description:Background: Sepsis is associated with significant mortality, yet there are no efficacious therapies beyond antibiotics and supportive care. In adult sepsis studies, PCSK9 loss-of-function (LOF) and inhibition has shown therapeutic promise, likely through enhanced low-density lipoprotein receptor (LDLR) mediated endotoxin clearance. In contrast, we previously demonstrated higher mortality in septic juvenile hosts with PCSK9 LOF. In addition to direct influence on serum lipoprotein levels, PCSK9 likely exerts pleiotropic effects on vascular endothelium. Both mechanisms may influence sepsis outcomes. We sought to test the influence of PCSK9 LOF genotype on endothelial dysfunction in pediatric sepsis. Methods: Secondary analyses of a prospective observational cohort of pediatric septic shock. Single nucleotide polymorphisms of PCSK9 and LDLR genes were assessed. Serum PCSK9, lipoprotein, and endothelial marker concentrations were measured. Multivariable linear regression tested the influence of PCSK9 LOF genotype on endothelial markers, adjusted for age, complicated course, and low- and high-density lipoproteins (LDL and HDL). Causal mediation analyses assessed impact of select endothelial markers on the association between PCSK9 LOF genotype and mortality. Juvenile Pcsk9 null and wildtype mice were subject to cecal slurry sepsis and endothelial markers were quantified. Results: 474 patients were included. PCSK9 LOF was associated with several markers of endothelial dysfunction, with strengthening of associations after exclusion of patients homozygous for the rs688 LDLR variant that renders it insensitive to PCSK9. Serum PCSK9 levels did not correlate with endothelial dysfunction. PCSK9 LOF significantly influenced concentrations of Angiopoietin-1 (Angpt-1) and Vascular Cell Adhesion Molecule-1 (VCAM-1). However, upon adjusting for LDL and HDL, PCSK9 LOF remained significantly associated with low Angpt-1 alone. Causal Mediation Analysis demonstrated that the effect of PCSK9 LOF on mortality was partially mediated by Angpt-1 (p=0.0008). Murine data corroborated these results with lower Angpt-1 and higher soluble thrombomodulin among knockout mice with sepsis relative to the wildtype. Conclusions: PCSK9 LOF independently influences serum Angpt-1 levels in pediatric septic shock. Angpt-1 likely contributes mechanistically to the effect of PCSK9 LOF on mortality in juvenile hosts. Mechanistic studies on the role of PCSK9-LDLR pathway on vascular homeostasis may lead to the development of novel pediatric-specific sepsis therapies.

Project description:OBJECTIVES:Sepsis hospitalizations are frequently followed by hospital readmissions, often for recurrent sepsis. However, it is unclear how often sepsis readmissions are for relapsed/recrudescent versus new infections. The aim of this study was to assess the extent to which 90-day readmissions for recurrent sepsis are due to infection of the same site and same pathogen as the initial episode. DESIGN:Retrospective cohort study. SETTING:University of Michigan Health System. PATIENTS:All hospitalizations (May 15, 2013 to May 14, 2015) with a principal International Classification of Diseases, Ninth revision, Clinical Modification diagnosis of septicemia (038.x), severe sepsis (995.92), or septic shock (785.52), as well as all subsequent hospitalizations and sepsis readmissions within 90 days. We determined organism and site of sepsis through manual chart abstraction. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:We identified 472 readmissions within 90 days of sepsis, of which 137 (29.1%) were for sepsis. In sepsis readmissions, the site and organisms were most commonly urinary (29.2%), gastrointestinal (20.4%), Gram negative (29.9%), Gram positive (16.8%), and culture negative (30.7%). Ninety-four readmissions (68.6%) were for infection at the same site as initial sepsis hospitalization. Nineteen percent of readmissions were confirmed to be same site and same organism. However, accounting for the uncertainty from culture-negative sepsis, as many as 53.2% of readmissions could plausibly due to infections with both the same organism and same site. CONCLUSIONS:Of the patients readmitted with sepsis within 90 days, two thirds had infection at the same site as their initial admission. Just 19% had infection confirmed to be from the same site and organism as the initial sepsis hospitalization. Half of readmissions were definitively for new infections, whereas an additional 34% were unclear since cultures were negative in one of the hospitalizations.

Project description:BackgroundIt remains unclear whether sepsis-related cardiovascular complications have an adverse impact on survival independent of pre-existing comorbidities. To investigate the survival impact of post-sepsis cardiovascular complications among sepsis survivors, we conducted a population-based study using the National Health Insurance Database of Taiwan.MethodsWe identified sepsis patients from the National Health Insurance Research Database of Taiwan using ICD-9-CM codes involving infection and organ dysfunction between 2000 and 2011. Post-sepsis incident myocardial infarction (MI) and stroke were ascertained by ICD-9-CM codes and antiplatelet treatment. We constructed a non-sepsis comparison cohort using propensity score matching to ascertain the association between sepsis and cardiovascular complications. Furthermore, we compared the 180-day mortality and 365-day mortality between patients surviving sepsis with or without post-sepsis MI or stroke within 70 days of hospital discharge. We constructed Cox regression models adjusting for pre-existing comorbidities to evaluate the independent survival impact of post-sepsis MI or stroke among sepsis survivors.ResultsWe identified 42,316 patients hospitalized for sepsis, from which we matched 42,151 patients 1:1 with 42,151 patients hospitalized without sepsis. Compared to patients hospitalized without sepsis, patients hospitalized with sepsis had an increased risk of MI or stroke (adjusted odds ratio 1.72, 95% CI 1.60-1.85). Among 42,316 patients hospitalized for sepsis, 486 (1.15%) patients developed incident stroke and 108 (0.26%) developed incident MI within 70 days of hospital discharge. Compared to sepsis survivors without cardiovascular complications, sepsis survivors with incident MI or stroke had a higher mortality rate at 180 days (11.68% vs. 4.44%, P = 0.003) and at 365 days (16.75% vs. 7.11%, P = 0.005). Adjusting for age, sex, and comorbidities, post-sepsis MI or stroke was independently associated with increased 180-day (adjusted hazard ratio [HR] 2.16, 95% CI 1.69-2.76) and 365-day (adjusted HR 1.90, 95% CI 1.54-2.32) mortality.ConclusionsCompared to sepsis patients without incident MI or stroke, sepsis patients with incident MI or stroke following hospital discharge had an increased risk of mortality for up to 365 days of follow-up. This increased risk cannot be explained by pre-sepsis comorbidities.

Project description:BackgroundSepsis is a frequent reason for ICU admission and a leading cause of death. Its incidence has been increasing over the past decades. While hospital mortality is decreasing, it is recognized that the sequelae of sepsis extend well beyond hospitalization and are associated with a high mortality rate that persists years after hospitalization. The aim of this study was to disentangle the relative contribution of sepsis (infection with multi-organ failure), of infection and of inflammation, as reasons for ICU admission to long-term survival. This was done as infection and inflammation are both cardinal features of sepsis. We assessed the 3-year mortality of ICU patients admitted with sepsis, with individually matched ICU patients with an infection but not sepsis, and with an inflammatory illness not caused by infection, discharged alive from hospital.MethodsA multicenter cohort study of adult ICU survivors admitted between January 1st 2007 and January 1st 2019, with sepsis, an infection or an inflammatory illness. Patients were classified within the first 24 h of ICU admission according to APACHE IV admission diagnoses. Dutch ICUs (n = 78) prospectively recorded demographic and clinical data of all admissions in the NICE registry. These data were linked to a health care insurance claims database to obtain 3-year mortality data. To better understand and distinct the sepsis cohort from the non-sepsis infection and inflammatory condition cohorts, we performed several sensitivity analyses with varying definitions of the infection and inflammatory illness cohort.ResultsThree-year mortality after discharge was 32.7% in the sepsis (N = 10,000), 33.6% in the infectious (N = 10,000), and 23.8% in the inflammatory illness cohort (N = 9997). Compared with sepsis patients, the adjusted HR for death within 3 years after hospital discharge was 1.00 (95% CI 0.95-1.05) for patients with an infection and 0.88 (95% CI 0.83-0.94) for patients with an inflammatory illness.ConclusionsBoth sepsis and non-sepsis infection patients had a significantly increased hazard rate of death in the 3 years after hospital discharge compared with patients with an inflammatory illness. Among sepsis and infection patients, one third died in the next 3 years, approximately 10% more than patients with an inflammatory illness. The fact that we did not find a difference between patients with sepsis or an infection suggests that the necessity for an ICU admission with an infection increases the risk of long-term mortality. This result emphasizes the need for greater attention to the post-ICU management of sepsis, infection, and severe inflammatory illness survivors.

Project description:ImportanceAn animal (mouse) study indicated that deficiency of proprotein convertase subtilisin/kexin type 9 (PCSK9) causes cardiac remodeling and heart failure (HF). Cardiac remodeling after PCSK9-inhibitor treatment is a concern for patients and for development of treatment directed against PCSK9.ObjectiveTo determine whether genetic variants in the PCSK9 gene are associated with altered cardiac structure, cardiac function, and HF in humans.Design, setting, participantsThis was a nested case-control study within the UK Biobank. Between March 13, 2006, and October 1, 2010, the UK Biobank enrolled 502 480 individuals aged 40 to 69 years. This study focused on a subset of those individuals, who completed cardiac magnetic resonance (CMR) imaging and had available genetic data. Analyses were conducted between November 2, 2021, and October 28, 2022.ExposuresCarrier status of predicted loss-of-function (pLoF) PCSK9 variants, R46L missense variant, and a genetic risk score (GRS).Main outcomes and measuresA total of 11 CMR imaging measurements, generated using a machine learning algorithm, and HF diagnosis.ResultsIn up to 35 135 individuals with CMR images, 18 252 (52%) were female individuals, and mean (SD) age was 55.0 (7.4) years. No significant association between PCSK9 carrier status and CMR indices were found for left ventricular mass (pLoF: β = -1.01; 95% CI, -2.99 to 0.98; P = .32; R46L: β = -0.18; 95% CI, -0.55 to 0.19; P = .35; GRS: β = -0.19; 95% CI, -0.50 to 0.11; P = .22) and left ventricular ejection fraction (pLoF: β = 0.43; 95% CI, -1.32 to 2.18; P = .63; R46L: β = -0.19; 95% CI, -0.52 to 0.14; P = .26; GRS: β = -0.08; 95% CI, -0.35 to 0.20; P = .58) or HF (pLoF: odds ratio [OR], 1.14; 95% CI, 0.56-2.05; P = .69; R46L: OR, 0.99; 95% CI, 0.90-1.10; P = .91; GRS: OR, 1.04; 95% CI, 0.96-1.13; P = .32).Conclusions and relevanceResults of this case-control study suggest that there was no association between PCSK9 genetic variants and altered cardiac structure, cardiac function, or HF in humans.

Dataset Information

Impact of PCSK9 loss-of-function genotype on 1-year mortality and recurrent infection in sepsis survivors.

Background

Methods

Findings

Interpretation

Funding

Publications

Impact of PCSK9 loss-of-function genotype on 1-year mortality and recurrent infection in sepsis survivors.

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