Circulating Proprotein Convertase Subtilisin/kexin Type 9 Concentrations Research Articles

Relationship between Serum Proprotein Convertase Subtilisin/Kexin Type 9 Concentration and Prevalence of Coronary Artery Calcium in a Community-Based Sample of Japanese Men.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising new target for reducing low-density lipoprotein cholesterol (LDL-C) and cardiovascular events in high-risk patients. However, the influence of circulating PCSK9 concentration on atherosclerotic plaque formation in the general population remains unknown. We assessed the relationship between serum PCSK9 concentration and coronary artery calcium (CAC) prevalence in the general population. Community-dwelling Japanese men (n=622) aged 46-82 years without a history of cardiovascular disease and lipid-lowering medications were included. Serum PCSK9 concentration and CAC score were measured using the Agatston method, and the multivariable analysis was used to assess their association. CAC was defined as an Agatston score of ＞10. We conducted further analysis stratified by age (＜60, 60-69, and ≥ 70 years). The average age, LDL-C, and median serum PCSK9 concentration were 68 years, 122 mg/dL, and 240 ng/mL, respectively. After multivariable adjustment for traditional cardiovascular risk factors, no significant association was observed between serum PCSK9 concentration and CAC prevalence (adjusted relative risk [aRR] 1.05, 95% confidence interval [CI] 0.97-1.13). With age stratification, serum PCSK9 concentration was significantly associated with CAC prevalence in men aged ＜60 years (aRR 1.38, 95% CI 1.01-1.88) but not in men aged 60-69 years (aRR 0.96, 95% CI 0.85-1.10) or ≥ 70 years (aRR 1.08, 95% CI 0.99-1.19). A higher serum PCSK9 concentration was associated with a higher CAC prevalence in men aged ＜60 years, which was independent of traditional cardiovascular risk factors.

PS-BPP01-4: THE RELATIONSHIP BETWEEN SERUM PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 CONCENTRATION AND THE PREVALENCE OF CORONARY ARTERY CALCIUM

Background and aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising new target for reducing low-density lipoprotein cholesterol (LDL-C) and cardiovascular events in high-risk patients. However, the influence of circulating PCSK9 concentration on atherosclerotic plaque formation in the younger, healthy population is not fully elucidated. We assessed the relationship between serum PCSK9 concentration and coronary artery calcium (CAC) prevalence in the general population with no history of cardiovascular disease in different age group. Methods: Community-dwelling Japanese men (n = 622) aged 46–82 years, without a history of cardiovascular disease or lipid-lowering medications, were included. Serum PCSK9 concentration and CAC score were measured using the Agatston method, and CAC was defined as an Agatston score of > 10. Multivariable Poisson regression with robust error variance were used to estimate the relative risk (RR) and 95% confidence interval (CI) per 1 SD of the serum PCSK9 concentration for the presence of CAC. We conducted further analysis stratified by age (< 60, 60–69, and 70 ≦ years). Results: The average age, LDL-C, and median serum PCSK9 concentration were 68 years, 122 mg/dL, and 240 ng/mL, respectively. After multivariable adjustment for traditional cardiovascular risk factors, no significant association was observed between serum PCSK9 concentration and CAC prevalence (adjusted relative risk [aRR] 1.05, 95% CI 0.97–1.13). With age stratification, serum PCSK9 concentration was significantly associated with CAC prevalence in men aged < 60 years (aRR 1.38, 95% CI 1.01–1.88), but not in men aged 60–69 years (aRR 0.96, 95% CI 0.85–1.10) or ≧ 70 years (aRR 1.08, 95% CI 0.99–1.19). Conclusions: A higher serum PCSK9 concentration was associated with a higher CAC prevalence in men aged < 60 years, which was independent of traditional cardiovascular risk factors. The results of our study suggest that serum PCSK9 concentration might be associated with earlier-stage atherosclerosis.

Sex difference in circulating PCSK9 and its clinical implications.

Proprotein convertase subtilisin kexin type 9 (PCSK9) is a proprotein convertase that increases plasma low-density lipoprotein cholesterol (LDL-C) levels by triggering the degradation of LDL receptors (LDLRs). Beyond the regulation of circulating LDL-C, PCSK9 also has direct atherosclerotic effects on the vascular wall and is associated with coronary plaque inflammation. Interestingly, emerging data show that women have higher circulating PCSK9 concentrations than men, suggesting that the potential roles of PCSK9 may have different impacts according to sex. In this review, we summarize the studies concerning sex difference in circulating levels of PCSK9. In addition, we report on the sex differences in the relations of elevated circulating PCSK9 levels to the severity and prognosis of coronary artery disease, the incidence of type 2 diabetes mellitus, and neurological damage after cardiac arrest and liver injury, as well as inflammatory biomarkers and high-density lipoprotein cholesterol (HDL-C). Moreover, sex difference in the clinical efficacy of PCSK9 inhibitors application are reviewed. Finally, the underlying mechanisms of sex difference in circulating PCSK9 concentrations and the clinical implications are also discussed.

NAFLD fibrosis score is correlated with PCSK9 and improves outcome prediction of PCSK9 in patients with chest pain: a cohort study

BackgroundThe risk of liver fibrosis in non-alcoholic fatty liver disease (NAFLD) can be easily evaluated by noninvasive scoring systems, of which the NAFLD fibrosis score (NFS) is the most commonly used. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a new predictor of cardiovascular events, has been reported to be associated with cardiovascular outcomes and NAFLD. However, the relationship of NFS with PCSK9 and their prognostic abilities in cardiovascular risks are unknown.MethodsA total of 2008 hospitalized subjects who had chest pain without lipid-lowering therapy were consecutively included. Baseline clinical data were collected, and the NFS was calculated. The circulating PCSK9 concentration was determined by enzyme immunoassay. The major adverse cardiovascular event (MACE) occurrences were recorded in the follow-up period. Associations of PCSK9 concentration with NFS were examined. All of the participants were categorized into three groups according to NFS levels and were further stratified by PCSK9 tertiles to evaluate the MACEs.Results158 (7.87%) MACEs were observed during a mean of 3.2 years of follow-up. NFS levels were independently related to higher PCSK9 levels according to multivariable linear regression analysis. Furthermore, elevated PCSK9 and NFS concentrations were respectively associated with increased MACE incidence in multivariable Cox regression models. When combining NFS status with PCSK9 tertiles as a stratifying factor, patients with intermediate-high NFS and high PCSK9 levels had higher risks of events than those with low NFS and low PCSK9 levels.ConclusionsThis study revealed for the first time that NFS is positively related to PCSK9 and that the combination of NFS and PCSK9 greatly increased the risk of MACEs in patients with chest pain, providing a potential link between NFS and PCSK9 for predicting cardiovascular events.

Beneficial impact of epigallocatechingallate on LDL-C through PCSK9/LDLR pathway by blocking HNF1\u03b1 and activating FoxO3a

BackgroundGreen tea drinking has been proven to lower lipid and exert cardiovascular protection, while the potential mechanism has not been fully determined. This study was to investigate whether the beneficial impact of epigallocatechingallate (EGCG), a type of catechin in green tea on lipids is associated with proprotein convertase subtilisin/kexin type 9 (PCSK9) pathways.MethodsWe studied the effects and underlying molecular mechanism of EGCG or green tea on regulating cholesterol from human, animal and in vitro.ResultsIn the age- and gender-matched case control observation, we found that individuals with frequent tea consumption (n = 224) had the lower plasma PCSK9 and low density lipoprotein cholesterol (LDL-C) levels compared with ones without tea consumption (n = 224, p < 0.05). In the high fat diet (HFD) fed rats, EGCG administration significantly lowered circulating PCSK9 concentration and liver PCSK9 expression, along with up-regulated LDL receptor (LDLR) expression but decreased level of LDL-C. In hepatic cell study, similar results were obtained regarding the impact of EGCG on LDLR and PCSK9 expression. The assay transposase-accessible chromatic with high-throughput sequencing (ATAC-seq) and subsequent results suggested that two transcription factors, hepatocyte nuclear factor-1α (HNF-1α) and forkhead box class O (FoxO) 3a involved in inhibitory action of EGCG on PCSK9 expression.ConclusionsThe present study demonstrates that EGCG suppresses PCSK9 production by promoting nuclear FoxO3a, and reducing nuclear HNF1α, resulting in up-regulated LDLR expression and LDL uptake in hepatocytes. Thereby inhibiting liver and circulating PCSK9 levels, and ultimately lowering LDL-C levels.

High circulating proprotein convertase subtilisin/Kexin type 9 concentration associates with cardiovascular risk: A meta-analysis of cohort studies.

Whether the baseline circulating proprotein convertase subtilisin/Kexin type 9 (PCSK9) concentration associates with cardiovascular risk remains uncertain. This study aimed to investigate the predictive value of circulating PCSK9 in cardiovascular risk prediction.Relevant studies were searched through the MEDLINE, EMBASE, and Cochrane Library databases. The relative risk (RR) and 95% confidence interval (CI) were pooled to evaluate the association between the circulating PCSK9 concentration and cardiovascular risk. Dose-response meta-analysis was also performed in this study.A total of 11 cohort studies with 13,761 participants were included. The RR for cardiovascular risk was 1.25 (95% CI: 1.14-1.38, P < .001, I = 25%) while compared highest to lowest PCSK9 concentration. Subgroup meta-analysis, which sorted by ethnicity, base risk characteristic, and follow-up time, presented consistent results that there was a pronounced association between highest PCSK9 concentration and cardiovascular risk, such relationship was not significant in the statin-taking subjects. Seven studies were included in dose-response meta-analysis, and a nonlinear association between PCSK9 concentration and cardiovascular risk was observed [(χ test for nonlinearity = 6.7, (df = 2), P = .036].This study suggests that high circulating PCSK9 concentration associates with significantly increased cardiovascular risk, and demonstrates for the first time that it is a nonlinear dose-response association between circulating PCSK9 concentration and cardiovascular risk. These results provide the evidence that PCSK9 is an independent risk factor beyond the traditional cardiovascular risk factors and indicates a potential role of PCSK9 measurement for medical decisions. The clinical value of PCSK9 measurement and the identification of risk threshold should be confirmed in appropriately designed clinical trials.

Lipid Lowering Therapy and Circulating PCSK9 Concentration.

Hypercholesterolemia, particularly an increase in low-density lipoprotein cholesterol (LDL-C) levels, contributes substantially to the development of coronary artery disease and the risk for cardiovascular events. As the first-line pharmacotherapy, statins have been shown to reduce both LDL-C levels and cardiovascular events. However, despite intensive statin therapy, a sizable proportion of statin-treated patients are unable to achieve the recommended target LDL-C levels, and not all patients can avoid future cardiovascular events. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis by enhancing the degradation of hepatic low-density lipoprotein receptor (LDLR). Owing to its importance in lipid metabolism, PCSK9 has emerged as a novel pharmacological target for lowering LDL-C levels. In this review, the potential role of circulating PCSK9 as a new biomarker of lipid metabolism is described. Next, previous studies evaluating the effects of lipid-modifying pharmacological agents, particularly statins, on circulating PCSK9 concentrations are summarized. Statins decrease hepatic intracellular cholesterol, resulting in increased LDLRs as well as increased PCSK9 protein. There is a clear dose-response effect of statin treatment on PCSK9 level, as increasing doses of statins also increase the level of circulating PCSK9. Finally, the available therapeutic strategies to inhibit PCSK9 are present. Monoclonal antibodies against PCSK9, in combination with statins, are one of the most promising and novel approaches to achieve further reduction of LDL-C levels and reduce the risk of cardiovascular events.

Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Concentration and Risk of Cardiovascular Events - Systematic Review and Meta-Analysis of Prospective Studies.

Previous studies have not found a consistent association between circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) and the risk of cardiovascular events. The aim of this meta-analysis was to evaluate this association in prospective studies.Methods and Results:A systematic search of prospective studies published through October 2016 was carried out in order to identify studies that met pre-specified inclusion criteria. After independent data extraction, summary relative risks were calculated using random-effects models. On meta-analysis of 6 cohort and 1 nested case-control study, circulating PCSK9 concentration as a continuous variable was not significantly associated with the risk of cardiovascular events (overall RR, 1.12; 95% CI: 0.98-1.29; P=0.09), with significant heterogeneity (I2=55.1%, Pheterogeneity=0.038). The highest but not middle categories of circulating PCSK9 was significantly associated with the risk of cardiovascular events. On subgroup analysis of study design, mean age at baseline, sample size, follow-up time, and pre-existing disease, there was no significant association between PCSK9 and cardiovascular events. Sensitivity analysis with various exclusion and inclusion criteria did not materially change the results. Circulating PCSK9 concentration as a continuous variable was not significantly associated with the risk of cardiovascular events. More well-designed studies are needed to clarify the role of PCSK9 in cardiovascular risk.

Plasma PCSK9 concentrations during the course of nondiabetic chronic kidney disease: Relationship with glomerular filtration rate and lipid metabolism

The association between proprotein convertase subtilisin/kexin type 9 (PCSK9), a critical regulator of low-density lipoprotein (LDL) metabolism, and kidney function is a matter of debate. We aimed to assess the association of circulating PCSK9 concentrations with both glomerular filtration rate (eGFR) and serum lipid parameters in nondiabetic patients with chronic kidney disease (CKD). Fasting plasma PCSK9 concentrations were measured by ELISA in 94 nondiabetic nondialysis CKD (ND-CKD) patients not receiving statins, at different stages of CKD. Plasma PCSK9 levels were associated neither to eGFR (P=.770) nor to proteinuria (P=.888) at several stages of CKD. In addition, plasma PCSK9 levels did not vary significantly between the different CKD stages. Plasma PCSK9 concentrations were positively correlated with apolipoprotein B (r=0.221; P=.03) and triglycerides (r=0.211; P=.04) but not with total cholesterol, calculated LDL-cholesterol, HDL cholesterol, lipoprotein(a), or CRP. In a homogeneous population of nondiabetic subjects without lipid-lowering therapy, plasma PCSK9 concentrations are not associated to eGFR at several stages of CKD. These data suggest that kidney function per se does not impact significantly PCSK9 metabolism.

Abstract 15438: Serum Proprotein Convertase Subtilisin/Kexin Type 9 Levels Are Not Increased by Plant Stanol Ester Consumption

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in regulating cholesterol metabolism mainly by binding to LDL receptors targeting them for degradation. Statins, inhibitors of cholesterol synthesis, increase the serum PCSK9 concentration limiting the potential of statins to reduce LDL cholesterol (C) concentration, whereas ezetimibe, an inhibitor of cholesterol absorption, has ambiguous effects on circulating PCSK9 levels. Plant stanols lower LDL-C by inhibiting cholesterol absorption, but their effect on serum PCSK9 concentration is not known. Hypothesis: We assessed the hypothesis that consumption of plant stanol esters lowers LDL-C without increasing circulating PCSK9 levels. Methods: Ninety-two normo- and mildly hypercholesterolemic subjects, 35 men and 57 women (mean age 50.8±1.0 (SE) years) were randomly divided into plant stanol ester (STANOL) (n=46) and control (n=46) groups. They consumed spread enriched with (STANOL group) and without (control group) plant stanol (3g /d) ester in a double-blind intervention for six months. Serum lipids and lipoproteins were analysed enzymatically and serum PCSK9 concentration was quantitated with Quantikine Elisa Immunoassay at baseline and after the intervention. Results: At baseline, serum PCSK9 levels correlated positively with LDL-C in the whole study population. Serum total, LDL-C and non-HDL-C concentrations, similar between the study groups at baseline, declined by 7%,10%, and 11% at the end of the intervention in the STANOL group compared with the control group (p&lt; 0.001, for all). The baseline serum PCSK9 concentrations were similar between the groups (STANOL 284±16 ng/ml, controls 273±16 ng/ml, ns). At the end of the intervention, serum PCSK9 concentrations were unchanged from baseline in both groups and did not differ between the groups (STANOL 293 ±15 ng/ml, controls 309±16 ng/ml, ns). Conclusion: In conclusion, plant stanol ester consumption does not affect the circulating PCSK9 concentration. Thus, plant stanols provide an efficient dietary means to lower LDL-C concentration without interfering with the LDL receptor-mediated cellular cholesterol uptake and removal.

Circulating Levels of Proprotein Convertase Subtilisin Kexin Type 9 are Elevated by Fibrate Therapy

Proprotein convertase subtilisin kexin type 9 (PCSK9) affects lipid metabolism through modulation of low-density lipoprotein (LDL) receptor degradation. Circulating PCSK9 status is an important determinant of LDL-cholesterol levels and is thus implicated in atherogenesis. The present study aimed to resolve inconsistencies in clinical findings on the impact of fibrate therapy on circulating PCSK9 concentrations using a meta-analysis of all published studies. A comprehensive literature search in Medline and Scopus was carried out to identify clinical reports on the impact of treatment with fibrates on circulating concentrations of PCSK9. A meta-analysis of eligible studies was performed using a random-effects model. A weighed mean difference (WMD) with 95% confidence interval (CI) was used to assess the magnitude of fibrates' effect on PCSK9 concentrations. Six studies comprising 218 subjects fulfilled the eligibility criteria and were included for systematic review and quantitative data synthesis. A meta-analysis indicated a significant elevation of circulating PCSK9 concentrations following fibrate therapy (WMD: +60.37; 95% CI: 11.04-109.71; P = 0.02). The PCSK9-elevating effect of fibrates remained significant after comparison with a control group receiving either placebo or a statin (WMD: +23.97; 95% CI: 5.68-42.26; P = 0.01). Meta-regression analysis indicated that the effect size of fibrates in modulating circulating PCSK9 levels is not dependent on the duration of treatment (point estimate for slope = 0.59, SE = 4.56; 95% CI = -8.34 to 9.53; z = 0.130, P = 0.897). Fibrate therapy is associated with a significant increase in circulating PCSK9 concentrations. Such a PCSK9 elevation may partly explain the modest efficacy of fibrates on LDL-C.

Relation of circulating PCSK9 concentration to fibrinogen in patients with stable coronary artery disease.

Both proprotein convertase subtilisin/kexin type 9 (PCSK9) and fibrinogen have been established as novel markers for atherosclerotic diseases. However, no data are available regarding the relationship between circulating PCSK9 and fibrinogen concentration up to now. To explore the potential link of the circulating PCSK9 concentration to fibrinogen in patients with stable coronary artery disease (CAD). We studied 219 eligible consecutive patients with angiographically proven stable CAD. Baseline clinical and laboratory data were collected. Plasma PCSK9 concentration was measured by enzyme-linked immunosorbent assay. High-sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate, D-dimer, and albumin were also measured in all subjects as inflammatory markers. The relation of the circulating PCSK9 concentration to fibrinogen was evaluated. The data indicated that the patients with high PCSK9 concentration tended to have higher fibrinogen levels according to PCSK9 tertiles (P=.037). Spearman correlation analysis revealed a positive relation between plasma PCSK9 concentration and fibrinogen (r=0.211, P=.002). Additionally, the circulating PCSK9 concentration also correlated positively with total cholesterol, low-density lipoprotein cholesterol, and hs-CRP levels (r=0.333, P<.001; r=0.302, P<.001; r=0.153, P=.023, respectively). In the stepwise multivariate regression analysis, the association between PCSK9 and fibrinogen remained significant (β=0.168, P=.011) after adjustment for conventional cardiovascular risk factors including lipid profiles, hs-CRP, and D-dimer. The present study first demonstrated that the circulating PCSK9 concentration was positively associated with fibrinogen in patients with stable CAD, suggesting that the interactions of PCSK9 and fibrinogen in the status of atherosclerosis may need further investigation.

Evidence from a Randomized Trial That Simvastatin, but Not Ezetimibe, Upregulates Circulating PCSK9 Levels

BackgroundProprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted inhibitor of the low-density lipoprotein (LDL) receptor and an important regulator of LDL metabolism. Elevated PCSK9 levels have been associated with cardiovascular risk. The purpose of this study was to investigate how ezetimibe and simvastatin, alone and in combination, affect PCSK9 circulating concentrations.MethodsA single center, randomized, open-label parallel 3-group study in healthy men (mean age 32±9 years, body mass index 25.7±3.2 kg/m2) was performed. Each group of 24 subjects was treated for 14 days with either simvastatin 40 mg/d, ezetimibe 10 mg/d, or with both drugs. Multivariate analysis was used to investigate parameters influencing the change in PCSK9 concentrations under treatment.ResultsThe baseline plasma PCSK9 concentrations in the total cohort were 52±20 ng/mL with no statistically significant differences between the groups. They were increased by 68±85% by simvastatin (P = 0.0014), by 10±38% by ezetimibe (P = 0.51) and by 67±91% by simvastatin plus ezetimibe (P = 0.0013). The increase in PCSK9 was inversely correlated with baseline PCSK9 concentrations (Spearman’s R = –0.47, P<0.0001) and with the percent change in LDL cholesterol concentrations (Spearman’s R = –0.30, P<0.01). In multivariate analyses, only baseline PCSK9 concentrations (β = –1.68, t = –4.04, P<0.0001), percent change in LDL cholesterol from baseline (β = 1.94, t = 2.52, P = 0.014), and treatment with simvastatin (P = 0.016), but not ezetimibe (P = 0.42), significantly influenced changes in PCSK9 levels. Parameters without effect on PCSK9 concentration changes were age, body mass index, body composition, thyroid function, kidney function, glucose metabolism parameters, adipokines, markers of cholesterol synthesis and absorption, and molecular markers of cholesterol metabolism.ConclusionsEzetimibe does not increase circulating PCSK9 concentrations while simvastatin does. When added to simvastatin, ezetimibe does not cause an incremental increase in PCSK9 concentrations. Changes in PCSK9 concentrations are tightly regulated and mainly influenced by baseline PCSK9 levels and changes in LDL cholesterol.Trial RegistrationClinicalTrials.gov NCT00317993

Treadmill Exercise Training Modulates Hepatic Cholesterol Metabolism and Circulating PCSK9 Concentration in High-Fat-Fed Mice

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a novel biomarker of LDL clearance and a therapeutic target of cardiovascular disease. We examined the effects of aerobic exercise training in modulating PCSK9 abundance and hepatic sterol regulation in high-fat-fed C57BL/6 mice. Mice (n = 8) were assigned to a low-fat (LF), high-fat (HF), or an HF with exercise (HF + EX) group for 8 weeks. The HF + EX group was progressively trained 5 days/week on a motorized treadmill. The HF + EX group was protected against body weight (BW) gain and diet-induced dyslipidemia compared with the HF group. The HF + EX group demonstrated an increase in hepatic PCSK9 mRNA (1.9-fold of HF control, P < 0.05) and a reduction in plasma PCSK9 (14%) compared with the HF group. Compared with HF mice, HF + EX mice demonstrated reduced hepatic cholesterol (14%) and increased (P < 0.05) nuclear SREBP2 protein (1.8-fold of HF group) and LDLr mRNA (1.4-fold of HF group). Plasma PCSK9 concentrations correlated positively with plasma non-HDL-C (P = 0.01, r = 0.84). Results suggest that treadmill exercise reduces non-HDL cholesterol and differentially modulates hepatic and blood PCSK9 abundance in HF-fed C57BL/6 mice.

Abstract 287: Plasma PCSK9 Concentrations in Critically Ill Patients

Objective. Pro-protein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that impairs LDL clearance by promoting the LDL receptor (LDLR) degradation. Plasma lipid parameters (LDL-C and HDL-C) are related to severity of illness and survival in intensive care patients. Here, we aimed to determine whether circulating PCSK9 concentrations were correlated to the severity of illness in patients with multiple trauma. Methods/Results. Plasma PCSK9 were measured, at day 0 and 8 after admission, by ELISA in 111 patients hospitalized in ICU for severe trauma. Patients were included in the HIPOLYTE study and were randomly assigned to hydrocortisone therapy or placebo. Plasma PCSK9 levels were significantly increased by 161% at day 8 compared to day 0 (481 ± 227 vs 231 ± 117 ng/ml, P=0.0001). Hydrocortisone therapy did not alter PCSK9 concentrations at day 8 compared to placebo (451 ± 216 vs 511 ± 239ng/ml, P=0.33). In the whole population of the study, PCSK9 was positively associated with LDL-C (Pearson coefficient : 0.26, p=0.007) at day 0, but not with markers of severity illness. At day 8, an inverse correlation was found between PCSK9 and HDL-C (β =-653 ; P=0.004). Interestingly, PCSK9 concentrations at day 8 were related to markers of severity illness as injury severity score (β =6.17 ; P=0.0007), length of stay in ICU (β =6.14 ; P=0.0001), duration of both mechanical ventilation (β =8.26 ; P=0.0001) and cathecolamines infusion (β =18.57; P=0.015). Conclusion. PCSK9 appears as a late biomarker of severity illness in patients hospitalized for multiple trauma in ICU. These results open new perspectives for a role of PCSK9 in critical illness.

Serum PCSK9 is associated with multiple metabolic factors in a large Han Chinese population

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that regulates cholesterol metabolism through low-density lipoprotein receptor (LDLR) degradation. Gain-of-function and loss-of-function mutations within PCSK9 gene lead to hypercholesterolemia or hypocholesterolemia respectively. Studies in the U.S. and Canada reported a correlation between multiple metabolic factors and circulating PCSK9 concentrations. However, there is no data available on circulating PCSK9 levels in Chinese. A sandwich ELISA assay was applied to measure serum PCSK9 levels in a Chinese population of 2719 adults from Nanjing district, China, which represents a large and uniform ethnic population of Han Chinese. Serum PCSK9 levels ranged from 12.85 to 222.50 ng/ml with a mean concentration of 69.35 ng/ml in this population. Serum PCSK9 levels were slightly higher in women than in men. Compared to premenopausal women, postmenopausal women had significantly higher PCSK9 levels. Serum PCSK9 levels were correlated with multiple metabolic variables including age, BMI, total cholesterol, LDL cholesterol, triglycerides, fasting blood glucose, systolic blood pressure (SP) and diastolic blood pressure (DP) in this population. After stepwise regression analysis, there was a significant positive association between serum PCSK9 levels and total cholesterol, triglycerides and SP in men. In women, there was a positive correlation between PCSK9 levels and total cholesterol, age and DP. Our study indicates that the serum PCSK9 level may be a biomarker of metabolic status and cardiovascular disease.

Plasma PCSK9 Concentrations Correlate with LDL and Total Cholesterol in Diabetic Patients and Are Decreased by Fenofibrate Treatment

Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of the LDL receptor (LDLr) in hepatocytes, and its expression in mouse liver has been shown to decrease with fenofibrate treatment. We developed a sandwich ELISA using recombinant human PCSK9 protein and 2 affinity-purified polyclonal antibodies directed against human PCSK9. We measured circulating PCSK9 concentrations in 115 diabetic patients from the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study before and after fenofibrate treatment. We found that plasma PCSK9 concentrations correlate with total (r = 0.45, P = 0.006) and LDL (r = 0.54, P = 0.001) cholesterol but not with triglycerides or HDL cholesterol concentrations in that cohort. After 6 weeks of treatment with comicronized fenofibrate (200 mg/day), plasma PCSK9 concentrations decreased by 8.5% (P = 0.041 vs pretreatment). This decrease correlated with the efficacy of fenofibrate, as judged by a parallel reduction in plasma triglycerides (r = 0.31, P = 0.015) and LDL cholesterol concentrations (r = 0.27, P = 0.048). We conclude that this decrease in PCSK9 explains at least in part the LDL cholesterol-lowering effects of fenofibrate. Fenofibrate might be of interest to further reduce cardiovascular risk in patients already treated with a statin.

Statins Induce Plasma Levels of Proprotein Convertase Subtilisin/Kexin Type 9

LDL receptor (LDLR) number is regulated transcriptionally by sterol regulatory element‐binding protein (SREBP)‐2. Studies have shown that inhibitors of HMG‐CoA reductase (statins) used to treat hypercholesterolemia trigger a regulatory response in cells leading to elevated levels of active SREBP‐2, thereby increasing LDLR expression. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a SREBP‐2 regulated protein secreted by the liver, binds to the LDLR and mediates its degradation. Thus, induction of PCSK9 may counter‐balance the effect of statins on liver LDLR protein levels. We demonstrate that simvastatin‐fed rats exhibit elevated levels of nuclear SREBP‐2 in liver and increased transcription of SREBP‐2 target genes, including PCSK9. This was associated with a &gt;3‐fold increase in circulating PCSK9 levels compared to control rats. In human studies, 13 subjects with moderate to slightly elevated plasma LDL‐cholesterol levels (127 – 238 mg/dl) were administered a statin for 7 days (Lipitor ‐ 40 mg/day), which resulted in a 25% decrease in plasma cholesterol levels. ELISA measurements of circulating PCSK9 concentrations showed a mean increase of 35% in these subjects. These studies demonstrate that circulating PCSK9 levels are reflective of liver SREBP‐2 activity and the induction of PCSK9 by statins may partially offset their efficacy in lowering plasma LDL‐cholesterol levels. Supported by CIHR.