Proprotein Convertase Subtilisin/kexin Type 9 Concentrations Research Articles

Proprotein convertase subtilisin/kexin type 9 levels and the risk of cardiovascular events in statin-treated patients with cardiovascular disease

Abstract Background Previous studies have not found a consistent association between circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and the risk of cardiovascular events. Although PCSK9 is cleaved by furin and becomes biologically inactive, previous studies have employed measurement methods which cannot distinguish furin-cleaved and uncleaved form of PCSK9. Methods This study is a prespecified sub-study of the REAL-CAD study which is a prospective, multicenter, randomized trial to compare high- versus low-dose statin in patients with stable coronary artery disease (CAD). The substudy primary endpoint was a composite of major adverse cerebrovascular and cardiovascular events (MACCE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. In a case-cohort study, sub-cohort was randomly selected samples from the total cohort as tripling the number of cases with MACCE. Serum mature (uncleaved) and furin-cleaved PCSK9 levels obtained at 6 months after randomization were measured among participants who subsequently developed MACCE and among randomly selected participants. Their relationships with cardiovascular events were assessed according to the quartiles. Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence intervals (CI). Results From 1,478 patients in the sub-cohort, the Cox proportional hazards models with a pseudolikelihood method for case-cohort design revealed that the risk of primary endpoint in patients in the highest quartile of mature PCSK9 concentrations was similar to the lowest quartile (HR 0.809; 95%CI, 0.541-1.209). Similarly, HRs for the highest to lowest quartiles of furin-cleaved PCSK9s was 0.948 [95%CI, 0.645-1.392] (P=0.784). As compared to the lowest quartile, both serum mature and furin-cleaved PCSK9 levels did not predict the cardiovascular events. Conclusions Serum mature and furin-cleaved PCSK9 levels did not provide useful information in the assessment of future cardiovascular events in statin-treated patients with stable CAD.Study FlowThe weighted Kaplan-Meier cueves

Maternal Obesity Modulates Cord Blood Concentrations of Proprotein Convertase Subtilisin/Kexin-type 9 Levels.

In utero exposure to maternal obesity or diabetes is considered a pro-inflammatory state. To evaluate whether cord blood proprotein convertase subtilisin/kexin-type 9 (PCSK9), which is regulated by inflammation and metabolic derangements, is elevated in neonates born to overweight, obese, or diabetic mothers. A retrospective study in full-term neonates born between 2010 and 2023, at Brigham and Women's Hospital. There were 116 neonates included in our study, of which 74 (64%) were born to overweight/obese mothers and 42 (36%) were born to nonoverweight/nonobese mothers. Neonates born to overweight/obese mothers had significantly higher cord blood concentrations of PCSK9 compared with neonates born to nonoverweight/nonobese group (323 [253-442] ng/mL compared with 270 [244-382] ng/mL, P = .041). We found no significant difference in cord blood concentrations of PCSK9 between neonates of diabetic mothers compared with neonates of nondiabetic mothers. In multivariate linear regression analysis, higher cord plasma PCSK9 concentration was significantly associated with maternal overweight/obesity status (b = 50.12; 95% CI, 4.02-96.22; P = .033), after adjusting for gestational age, birth weight, male sex, and intrauterine growth restriction. Neonates born to mothers with overweight/obesity have higher cord blood PCSK9 concentrations compared with the nonoverweight/nonobese group, and higher cord blood PCSK9 concentrations were significantly associated with maternal overweight/obesity status, after adjusting for perinatal factors. Larger longitudinal studies are needed to examine the role of PCSK9 in the development of metabolic syndrome in high-risk neonates born to overweight, obese, or diabetic mothers.

Lipoprotein(a) and Low-Molecular-Weight Apo(a) Phenotype as Determinants of New Cardiovascular Events in Patients with Premature Coronary Heart Disease.

Lipoprotein(a) (Lp(a)) is a genetic risk factor of atherosclerotic cardiovascular diseases (ASCVDs). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is related to vascular inflammation and detected in atherosclerotic plaques. A temporary increase in the circulating concentration of PCSK9 and Lp(a) was shown in patients with myocardial infarction (MI). The aim of this study was to evaluate the role of the apo(a) phenotype and the Lp(a) concentration as well as its complex with PCSK9 in the development of cardiac events and MI in patients with a premature manifestation of coronary heart disease (CHD). In a prospective study with retrospective data collection, we included 116 patients with premature CHD who were followed for a median of 14 years. The medical history and information on cardiovascular events after an initial exam as well as data on the levels of lipids, Lp(a), PCSK9, PCSK9-Lp(a) complex, and apo(a) phenotype were obtained. The patients were divided into two groups depending on the presence of a low- (LMW, n = 52) or high-molecular weight (HMW, n = 64) apo(a) phenotype. LMW apo(a) phenotype (odds ratio 2.3 (1.1 to 4.8), p = 0.03), but not elevated Lp(a) (1.9 (0.8-4.6), p = 0.13), was an independent predictor for the development of MI after adjustment for sex, age of CHD debut, initial lipids levels, and lipid-lowering treatment. The apo(a) phenotype also determined the relationship between Lp(a) and PCSK9 concentrations. The level of the PCSK9-Lp(a) complex was higher in LMW apo(a) patients. The LMW apo(a) phenotype is a risk factor for non-fatal MI in a long-term prospective follow-up of patients with premature CHD, and this link could be mediated via PCSK9.

Significance of Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) for the Monitoring of Treatment Response to Cyclosporine in Patients with Psoriasis.

Serum samples were obtained before and after three months cyclosporine therapy. Patients were grouped into responders and non-responders to cyclosporine depending on whether they achieved at least 50% reduction of Psoriatic Activity Score Index (PASI), or not. Serum levels of PCSK9 and NGAL were assayed using commercially available ELISA tests. Lipid levels were measured with an enzymatic method. There were 40 patients enrolled. A significant decrease in serum NGAL level was seen in cyclosporine responders. No similar dependance was found for PCSK9. Serum PCSK9 concentration correlated with total cholesterol (TChol) and LDL at baseline and after three month treatment. Cyclosporine therapy contributes to the reduction of the NGAL serum but not the PCSK9 concentration. Correlation between the PCSK9 serum level and TChol as well as LDL concentration may help to understand drug induced dyslipidemia after cyclosporine.

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.

Association between plasma PCSK9 levels and lipid profile in patients with Parkinson's disease and comparison with healthy subjects.

Background: Up to know, limited and contradictory results have been published about the role of prognostic values of lipid profile and proprotein convertase subtilisin/kexin type 9 (PCSK9) in Parkinson's disease (PD). The aim of the present study is to investigate the role of lipid profile and PCSK9 in patients with PD and compare it with healthy individuals. Methods: In this case-control study, 31 individuals diagnosed with PD were compared with 31 healthy individuals. The lipid profile and PCSK9 of research participants were measured and the resulting data were analyzed using SPSS software. The P-values smaller than 0.05 were considered significant. Results: The mean age of participants in the PD and control group was 56.9 ± 8.8 and 53.7 ± 10.1 years, respectively (P > 0.050). 27 individuals (87.1%) in the PD group and 13 individuals (41.9%) in the control group were men. Low-density lipoprotein (LDL) level (84.2 ± 24.9 ml/dl vs. 105.5 ± 16.8, P < 0.001), high-density lipoprotein (HDL) level (45.5 ± 8.7 ml/dl vs. 51.1 ± 9.5 ml/dl, P < 0.001), and total cholesterol (155.3 ± 31.2 ml/dl vs. 192.8 ± 32.5 ml/dl, P < 0.001) were lower and triglyceride (TG) level was higher in the PD group (133.3 ± 79.3 ml/dl vs. 131.2 ± 58.6 ml/dl, P = 0.900) compared with the control group. PCSK9 level was higher in the PD group, but no significant difference was found (141.6 ± 70.0 vs. 129.7 ± 51.0 ng/ml, P = 0.500) compared to healthy subjects. Moreover, there was no relation between PCSK9 and severity of PD. Conclusion: Our findings showed that individuals with PD had lower levels of HDL, LDL, and total cholesterol compared with the control group. However, higher concentrations of PCSK9 were observed in patients with PD compared with healthy volunteers.

Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial

Whether long-term treatment with the twice-yearly, siRNA therapeutic inclisiran, which reduces hepatic production of proprotein convertase subtilisin/kexin type 9 (PCSK9), results in sustained reductions in LDL cholesterol with an acceptable safety profile is not known. The aim of this study was to assess the effect of long-term dosing of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol. ORION-3 was a 4-year open-label extension study of the placebo-controlled, phase 2 ORION-1 trial, conducted at 52 sites across five countries. Patients with prevalent atherosclerotic cardiovascular disease or high-risk primary prevention and elevated LDL cholesterol despite maximally tolerated statins or other LDL-lowering treatments, or with documented statin intolerance, who had completed the ORION-1 trial were eligible. Patients receiving inclisiran in ORION-1 received twice-yearly 300 mg subcutaneous inclisiran sodium throughout ORION-3 (inclisiran-only arm), whereas patients receiving placebo in ORION-1 first received subcutaneous evolocumab 140 mg every 2 weeks until day 360 thereafter transitioning to inclisiran twice-yearly for the remainder of ORION-3 study (switching arm). The primary efficacy endpoint was the percentage change in LDL cholesterol with inclisiran from the start of ORION-1 through to day 210 of the open label extension phase in the inclisiran-only arm (approximately 570 days of total inclisiran exposure in the modified intention-to-treat population). Secondary and exploratory endpoints included changes in LDL-C cholesterol and PCSK9 concentrations levels up to day 1440 (4 years) in each arm, and safety. ORION-3 is registered with ClinicalTrials.gov, NCT03060577. Of the original ORION-1 cohort of 497 patients, 290 of 370 patients allocated to drug continued into the inclisiran-only arm and 92 of 127 patients allocated to placebo entered the switching-arm in the ORION-3 extension study conducted between March 24, 2017, and Dec 17, 2021. In the inclisiran-only arm, LDL cholesterol was reduced by 47·5% (95% CI 50·7-44·3) at day 210 and sustained over 1440 days. The 4-year averaged mean reduction of LDL-C cholesterol was 44·2% (95% CI: 47·1-41·4), with reductions in PCSK9 ranging from 62·2% to 77·8%. Adverse events at the injection site were reported in 39 (14%) of 284 patients in the inclisiran-only arm and 12 (14%) of 87 patients in the switching arm. The incidence of treatment-emergent serious adverse events possibly related to the study drug was 1% (three of 284) in the inclisiran-only arm and 1% (one of 87) in the switching arm. Twice-yearly inclisiran provided sustained reductions in LDL cholesterol and PCSK9 concentrations and was well tolerated over 4 years in the extension study. This is the first prospective long-term study to assess repeat hepatic exposure to inclisiran. Novartis Pharma.

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 &gt; 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 (&lt; 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 &lt; 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 &lt; 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.

Heparin Does Not Regulate Circulating Human PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) in a General Population-Brief Report.

PCSK9 (proprotein convertase subtilisin-kexin type 9) chaperones the hepatic LDLR (low-density lipoprotein receptor) for lysosomal degradation, elevating serum LDL (low-density lipoprotein) cholesterol and promoting atherosclerotic heart disease. Though the major effect on the hepatic LDLR comes from secreted PCSK9, the details of PCSK9 reuptake into the hepatocyte remain unclear. In both tissue culture and animal models, HSPGs (heparan sulfate proteoglycans) on hepatocytes act as co-receptors to promote PCSK9 reuptake. We hypothesized that if this PCSK9:HSPG interaction is important in humans, disrupting it with unfractionated heparin (UFH) would acutely displace PCSK9 from the liver and increase plasma PCSK9. We obtained remnant plasma samples from 160 subjects undergoing cardiac catheterization before and after administration of intravenous UFH. PCSK9 levels were determined using a commercial enzyme-linked immunosorbent assay. Median plasma PCSK9 was 113 ng/mL prior to UFH and 119 ng/mL afterward. This difference was not significant (P=0.83 [95% CI, -6.23 to 6.31 ng/mL]). Equivalence testing provided 95% confidence that UFH would not raise plasma PCSK9 by > 4.7%. Among all subgroups, only subjects with the lowest baseline PCSK9 concentrations exhibited a response to UFH (8.8% increase, adj. P=0.044). A modest correlation was observed between baseline plasma PCSK9 and the change in plasma PCSK9 due to UFH (RS=-0.3634; P<0.0001). Administration of UFH does not result in a clinically meaningful effect on circulating PCSK9 among an unselected population of humans. The results cast doubt on the clinical utility of disrupting the PCSK9:HSPG interaction as a general therapeutic strategy for PCSK9 inhibition. However, the observations suggest that in selected populations, disrupting the PCSK9:HSPG interaction could still affect PCSK9 reuptake and offer a therapeutic benefit.

Abstract 9318: The Safety, Pharmacokinetics, Pharmacodynamics and Immunogenicity of Ebronucimab in Healthy Volunteers: Result From a Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Dose-Escalation Study

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have demonstrated to be effective therapeutic agents for lowing low-density lipoprotein cholesterol (LDL-C). Ebronucimab (AK102) is a novel fully human immunoglobulin G1 (IgG1) monoclonal antibody against PCSK9. The objective of this study is to investigate the safety and tolerability of ebronucimab in healthy subjects. Methods: A total of 32 healthy adult subjects were planned to be enrolled and treated in a dose escalation manner. In each cohort, 8 subjects were randomized in a 3:1 ratio to receive a single dose of ebronucimab (75, 150, 300 or 500 mg) or matching placebo via subcutaneous injection (Figure 1). Blood was drawn at pre-selected timepoints to evaluate the pharmacokinetic parameters, free PCSK9 concentration and anti-drug antibody (ADA). Safety assessment was carried out up to day 85 ± 3 or early termination visit. Results: Safety Among the 32 subjects recruited, 87.5% (21/24) subjects administrated ebronucimab and 75% (6/8) subjects treated with placebo reported treatment emergent adverse events (TEAEs). The majority of adverse events were mild and moderate in severity. No relationship was identified between the dose of ebronucimab and the incidence of TEAEs. No TEAEs leading to study discontinuation and death were reported. Pharmacokinetics (PK)/Pharmacodynamics (PD) Following a single subcutaneous injection of 75 mg to 500 mg ebronucimab in healthy subjects, the median of T max ranged from 2.0 to 6.0 days and t 1/2 was within 4.11 to 5.01 days across cohorts. C max, AUC 0-t , and AUC 0-∞ increased approximately in a dose-proportional manner, see Table 1 and Figure 2. Serum free PCSK9 was almost completely inhibited after ebronucimab injection. The lowest level of free PCSK9 was observed around 2 days post administration and maintained at a low level 14-22 days post injection, see Figure 3. Immunogenicity A total of 3 subjects were tested ADA positive at least once during the study (75 mg, 1 subject; 500 mg, 2 subjects). The incidence of ADAs in subjects treated with ebronucimab was 12.5 % (3/24). Conclusions: Ebronucimab was well tolerated in healthy subjects and no special safety signal was identified during the study.

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.

Combined Semi-mechanistic Target-Mediated Drug Disposition and Pharmacokinetic-Pharmacodynamic Models of Alirocumab, PCSK9, and Low-Density Lipoprotein Cholesterol in a Pooled Analysis of Randomized Phase I/II/III Studies.

Alirocumab is a cholesterol-lowering monoclonal antibody targeting proprotein convertase subtilisin kexin type 9 (PCSK9) indicated in the prevention of cardiovascular risk and exhibiting target-mediated drug disposition (TMDD). The aim of this work was to develop an integrated pharmacokinetic-pharmacodynamic model to describe the interaction of alirocumab with PCSK9 and its impact on the evolution of low-density lipoprotein cholesterol (LDL-C) levels and explore labeling specification for subpopulations. Using data collected from nine phase I/II/III clinical studies (n=527, subcutaneous or intravenous administration), a TMDD model considering the quasi-steady-state approximation was developed to characterize the interaction dynamics of alirocumab and PCSK9, combined with an indirect pharmacodynamic model describing the inhibition of LDL-C by PCSK9 in a one-step approach using nonlinear-mixed effects modeling. A "full fixed effects modeling" strategy was implemented to quantify parameter-covariate relationships. The model captures the interaction between alirocumab and its target PCSK9 and how this mechanism drives LDL-C depletion, with an estimation of the associated between-subject variability of model parameters and the quantification of clinically relevant parameter-covariate relationships. Co-administration of statins was found to increase the central volume of distribution of alirocumab by 1.75-fold (5.6L versus 3.2L) and allow for a 14% greater maximum lipid-lowering effect (88% versus 74%), highlighting the synergy of action between anti-PCSK9 therapeutic antibodies and statins toward lowering LDL-C plasma levels. Baseline levels of PCSK9 were found to be related to the amplitude of LDL-C variations by increasing the concentration of free PCSK9 necessary to reach half its capacity of inhibition of LDL-C degradation. The maximum effect of alirocumab is achieved when free PCSK9 concentration is close to zero, as seen mostly after 150mg every 2weeks (Q2W) or 300 mg every 4weeks (Q4W), indicating that there would be no additional clinical benefit of increasing the dose higher than these recommended dosing regimens.

Proteomic Profiling of Cryoglobulinemia.

ObjectiveWe aimed to explore and identify candidate protein biomarkers of cryoglobulinemia (CGE) in disease control patients with negative cryoglobulin (DC) or healthy controls (HCs).MethodsThe tandem mass tag (TMT)-labeled serum quantitative proteomics approach was used to identify differentially expressed proteins between the CGE and DC groups. Ingenuity pathway analysis was used for functional annotation of differentially expressed proteins. Biomarker candidates were validated in another cohort using the parallel reaction monitoring (PRM) method. Apolipoprotein A1 (APOA1), apolipoprotein CIII (APOC3), adiponectin, and proprotein convertase subtilisin/kexin type-9 (PCSK9), which represent key proteins involved in the cholesterol metabolism pathway, were further verified in an increased number of samples by enzyme-linked immunosorbent assay (ELISA).ResultsA total of 1004 proteins were identified, of which 109 proteins were differentially expressed between the CGE and DC groups. These differentially expressed proteins were primarily involved in hepatic fibrosis/hepatic stellate cell activation and immune/inflammation-related pathways. In the disease and biofunction analysis, these proteins were mainly associated with the adhesion of blood cells, leukocyte migration, cholesterol transport, and transport of lipids. Twelve candidate biomarkers were validated by PRM-based proteomics, and proteins involved in the cholesterol metabolism pathway were further verified. APOA1, APOC3, adiponectin and PCSK9 concentrations were increased in CGE patients compared with healthy controls (P=0.0123, 0.1136, 0.5760, and 0.0019, respectively).ConclusionThis report describes the first application of a TMT-PRM-ELISA workflow to identify and validate CGE-specific biomarkers in serum. APOA1 and PCSK9 have been confirmed to be increased in CGE patients, demonstrating that proteins involved in cholesterol metabolism are also implicated in the development of CGE. These findings contribute to pathogenesis research and biomarker discovery in CGE.

Ramadan Intermittent Fasting Is Associated with Changes in Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Metabolically Healthy Obese Subjects.

Background and Objectives: Dietary modification is the principal approach to the management of hyperlipidemia in adults. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of plasma cholesterol and a target for novel lipid-lowering pharmacotherapies. This study aimed to explore how circulating levels of PCSK9 changed during Ramadan intermittent fasting in metabolically healthy obese subjects. Materials and Methods: This cross-sectional study used convenience sampling to recruit 55 overweight and obese participants (22 females and 33 males) who observed Ramadan fasting. Body weight and composition, glucoregulatory factors, serum PCSK9 concentration, dietary intake, and physical activity were assessed 1 week before and at the end of Ramadan fasting. Results: The median (interquartile range) age was 35 (22) years, and body mass index was 30.2 (5.4). We found significant (p < 0.05) increases in serum levels of PCSK9, serum insulin, insulin resistance, and leptin at the end of Ramadan compared with pre-fasting levels. Significant (p < 0.05) reductions in body weight, waist circumference, systolic and diastolic blood pressure, total cholesterol, triglycerides, high-density lipoprotein cholesterol, and adiponectin were also observed at the end of Ramadan. Conclusions: Observing Ramadan fasting was associated with increased PCSK9 levels in metabolically healthy obese subjects. The complex relationships between PCSK9 and insulin resistance and dysregulation of adipokine secretion in relation to dietary and lifestyle modifications during Ramadan warrant further research.

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.

Serum PCSK9 Correlates with PTX3 and Apolipoproteins B, A1, and C3 Concentrations in Patients with Type 2 Diabetes.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in the regulation of LDL metabolism. There is evidence that circulating PCSK9 is a cardiovascular risk factor. In this study, we determined factors associated with circulating PCSK9 in a group of patients with type 2 diabetes mellitus (DM2). Material included 116 consecutive patients with DM2 from outpatient diabetes clinic. Circulating PCSK9, PTX3, apolipoprotein (apo) B100, apo B48, and apo C3 levels were determined by ELISA, apo A1 by immunoturbidimetry. The mean (sd) age of patients was 59.1 (11.1) years, the mean (sd) values of serum PCSK9 were 255.4 (106.97) ng/ml. Circulating PCSK9 correlated negatively with age (r = −0.21, p < 0.05) and HbA1c (r = −0.21, p < 0.05) and positively with BMI (r = 0.21, p < 0.05), total cholesterol (r = 0.59), LDL-cholesterol (r = 0.50), triglyceride (r = 0.35), apo B100 (r = 0.43), apo A1 (r = 0.43) (p < 0.001 for all), apo C3 (r = 0.29, p < 0.01), and apo B48 (r = 0.25, p < 0.01) concentration and FLI (r = 0.26, p < 0.01). Strong correlation between PTX3 and PCSK9 levels was observed (r = 0.47, p < 0.001). Multiple stepwise backward regression analysis with PCSK9 as dependent variable revealed that PTX3, apo B100, apo A1, apo B48, and BMI were significantly positive and the presence of NAFLD and HbA1c negatively associated with PCSK9 concentrations. These variables together explain 57% of PCSK9 variability; the strongest relationship was observed between PCSK9 and PTX3 and apo B100. Our results indicate that circulating PCSK9 is significantly associated with inflammation marker PTX3 as well as atherogenic lipids and apolipoproteins C3, B100, and B48, which might be of value in understanding interactions between development of atherosclerosis and inflammatory state in DM2 patients.

Prognostic value of PCSK9 Levels in Non-ST elevation myocardial infarction patients undergoing percutaneous coronary intervention

Abstract Background The role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in predicting major adverse cardiovascular events (MACEs) in Non-ST elevation myocardial infarction (NSTEMI) patients is still an open question and the PCSK9 concentration of clinical usefulness remains unknown in guiding treatment. Purpose To explore the role of PCSK9 in predicting major adverse cardiovascular events (MACEs) in Non-ST elevation myocardial infarction patients. Methods 272 patients with NSTEMI were included in our study, all patients received PCI therapy after admission. Patients were followed up for 1 year and MACEs were recored. Their baseline plasma PCSK9 levels were determined by ELISA. Patients were divided into high, medium and low PCSK9 groups and the associations of PCSK9 with other biomarkers and MACEs were evaluated. Results The results showed that PCSK9 levels was related to levels of lipoproteins, high-sensitivity C-reactive protein (r=0.162, P=0.008), platelet volume distribution width (r=0.299, P&amp;lt;0.001) and D-dimer (r=0.285, P&amp;lt;0.001). And the concentrations of PCSK9 was greater higher in people with MACEs (137.2ng/ml vs 243.6ng/ml) (Fig. 1A). The Kaplan-Meier curves showed patients with high PCSK9 level had lower event-free survival rate (Fig. 1B). Survival analysis indicated high level of PCSK9 predicted MACEs independently after adjusted for traditional cardiovascular risk factors and GRACE score (HR=2.646, 95CI%: 1.047–6.686, P=0.027) (Fig. 1C, Fig. 2). Subgroup analysis demonstrated the prognostic value of high PCSK9 level was greater for patients classified by the GRACE score as high risk (Fig. 1D). Conclusions In a NSTEMI setting, the concentration of PCSK9 is associated with hypercoagulability and hyper-inflammation. High levels of PCSK9 independently predict future MACEs in NSTEMI patients, particularly those classified by the GRACE score as high risk. Funding Acknowledgement Type of funding sources: None.

Association of physical signs with genotype, lipid- and inflammation-related markers, coronary stenosis or calcification, and outcomes in patients with heterozygous familial hypercholesterolemia

Abstract Background Although several previous studies indicated that the existence of physical signs [tendon xanthomas or corneal arcus (TX/CA)] was associated with the risk of coronary artery disease (CAD) in patients with heterozygous familial hypercholesterolemia (HeFH), its relations to genotypes and clinical characteristics have not been fully determined. The present study aims to examine the association of TX/CA with genetic mutation, lipid and inflammation-related markers, coronary calcification, coronary severity and cardiovascular events (CVE) in Chinese patients with HeFH. Methods A total of 489 HeFH patients diagnosed with Dutch Lipid Clinic Network (DLCN) criteria and/or genetic testing were consecutively recruited. To compare the patients with TX/CA versus those without, propensity score matching (1:4 matched) was performed to adjust for age and sex. Patients were finally divided into the TX/CA group (n=50) and non-TA/CA group (n=200). Data including genetic mutation [low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9)] and laboratory analysis including lipoprotein(a), PCSK9, high-sensitivity C-reactive protein (hsCRP), computed tomography angiography, coronary angiography, and follow up CVEs were compared. Results Patients with physical signs presented significantly higher LDL cholesterol levels (8.65±2.53 vs. 7.70±2.18 mmol/L, p=0.025), more LDLR (+) mutations (OR 2.896, 95% CI 1.295–6.473, p=0.010), higher prevalence of high tertiles of Gensini, SYNTAX and Jeopardy score, and coronary artery calcium scores compared to those without. In addition, patients in the TX/CA group had a higher prevalence of high PCSK9 and hsCRP tertiles compared with those without signs. Over an average of 3.7 years of follow-up, patients with TX/CA were at a significantly greater risk of CVE (multivariate adjusted hazard ratio [HR] 2.81, 95% confidence interval [CI] 1.14–6.90, p=0.024). Conclusions The physical signs were associated with positive genetic mutation, higher PCSK9 or hsCRP concentration and worse outcomes in patients with HeFH, suggesting that these signs may help to risk stratification in patients with HeFH. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Capital Health Development Fund (201614035) and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2016-I2M-1-011)

Increased serum PCSK9 in patients with idiopathic pulmonary arterial hypertension: insights from inflammatory cytokines.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important and major player in the pathophysiology of hypercholesterolemia and atherosclerosis. Recently, PCSK9 has been implicated in the pathogenesis of inflammatory diseases. Whether PCSK9 is involved in idiopathic pulmonary arterial hypertension (IPAH) remains unclear. This study aimed to investigate the relationship between PCSK9 and IPAH. Serum PCSK9, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 β (IL-1β), and monocyte chemotactic protein-1 (MCP-1) were measured by enzyme linked immunosorbent assay. Transthoracic echocardiography was performed among 40 IPAH patients and 20 control subjects. Hemodynamic data were collected via right heart catheterization in patients with IPAH. Serum PCSK9, TNF-α, IL-6, IL-1β, and MCP-1 levels were significantly higher in IPAH patients than in control subjects (p < 0.001). Among enrolled IPAH patients, PCSK9 levels were higher in WHO-FC III/IV patients compared with those in WHO-FC I/II (p < 0.05), and were positively correlated with TNF-α, IL-6, MCP-1, N-Terminal pro-brain natriuretic peptide, pulmonary arterial systolic pressure (r = 0.653, p < 0.001), pulmonary arterial diastolic pressure (r = 0.466, p = 0.002), mean pulmonary arterial pressure (mPAP, r = 0.730, <0.001), pulmonary vascular resistance (r = 0.488, p = 0.001), and right ventricle diameter (r = 0.563, p < 0.001). In multiple regression analysis, mPAP was strongly associated with serum PCSK9 (β = 0.694, p < 0.001), independent of other variables. Receiver operating characteristic curve analysis showed the optimal cutoff value of serum PCSK9 concentration for predicting IPAH was 90.67 ng/ml, with a sensitivity of 90.0% and a specificity of 85.0%. In conclusion, IPAH patients had elevated serum PCSK9 levels which correlated the presence and severity of pulmonary hypertension. PCSK9 may be a novel potential therapeutic target.

Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease

Development of cholesteryl ester transfer protein (CETP) inhibitors for coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and drug target Mendelian randomization of CETP protein concentration, comparing this to Mendelian randomization of proprotein convertase subtilisin/kexin type 9 (PCSK9). We show that previous failures of CETP inhibitors are likely compound related, as illustrated by significant degrees of between-compound heterogeneity in effects on lipids, blood pressure, and clinical outcomes observed in trials. On-target CETP inhibition, assessed through Mendelian randomization, is expected to reduce the risk of CHD, heart failure, diabetes, and chronic kidney disease, while increasing the risk of age-related macular degeneration. In contrast, lower PCSK9 concentration is anticipated to decrease the risk of CHD, heart failure, atrial fibrillation, chronic kidney disease, multiple sclerosis, and stroke, while potentially increasing the risk of Alzheimer’s disease and asthma. Due to distinct effects on lipoprotein metabolite profiles, joint inhibition of CETP and PCSK9 may provide added benefit. In conclusion, we provide genetic evidence that CETP is an effective target for CHD prevention but with a potential on-target adverse effect on age-related macular degeneration.