Search

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulates as mature and furin-cleaved forms, which differ in their properties to degrade low-density lipoprotein (LDL) receptors., Objectives: In this study, we sought to investigate whether PCSK9 subtypes associate with atherosclerotic cardiovascular events., Methods: We investigated 1,436 statin-naive Japanese subjects without any cardiovascular disease in the Suita Study, an epidemiologic Japanese cohort study. Total, mature, and furin-cleaved PCSK9 levels were measured by means of enzyme-linked immunosorbent assay. The occurrence of coronary and stroke events were compared in subjects stratified by PCSK9 level tertile., Results: Total, mature, and furin-cleaved PCSK9 levels were associated with non-high-density lipoprotein cholesterol (all P  < 0.001) and systolic blood pressure ( P  = 0.001, P  = 0.004, and P  < 0.001, respectively). Furthermore, only furin-cleaved PCSK9 level was correlated to high-sensitivity C-reactive protein (hs-CRP) ( P  < 0.001). During the 13.6-year observational period, furin-cleaved PCSK9 level predicted a greater likelihood of experiencing coronary events (tertile 2: hazard ratio [HR]: 2.84 [95% confidence interval [CI]: 1.21-6.65; P  = 0.01]; tertile 3: HR: 2.81 [95% CI: 1.17-6.74; P  = 0.02]), but not stroke (tertile 2: HR: 1.31 [95% CI: 0.72-2.40; P  = 0.36]; tertile 3: HR: 1.27 [95% CI: 0.68-2.38; P  = 0.44]). Total and mature PCSK9 levels were not associated with coronary events (total PCSK9: tertile 2: HR: 1.35 [95% CI: 0.68-2.68; P  = 0.39]; tertile 3: HR: 1.13 [95% CI: 0.54-2.34; P  = 0.73]; mature PCSK9: tertile 2: HR: 1.02 [95% CI: 0.52-2.02; P  = 0.93]; tertile 3: HR: 0.96 [95% CI: 0.47-1.95; P  = 0.92]) and stroke events (total PCSK9: tertile 2: HR: 0.90 [95% CI: 0.50-1.61; P  = 0.72]; tertile 3: HR: 0.99 [95% CI:0.54-1.80; P  = 0.97]; mature PCSK9: tertile 2: HR: 0.86 [95% CI: 0.47-1.57; P  = 0.63]; tertile 3: HR: 1.11 [95% CI: 0.61-1.99; P  = 0.72]), respectively., Conclusions: Furin-cleaved but not total and mature PCSK9 was associated with both LDL cholesterol and hs-CRP and predicted future coronary events in the primary prevention settings. Our findings provide pathophysiological insights into the properties of PCSK9 subtypes in association with coronary events., Competing Interests: Dr Kataoka has received research support from Nipro and Abbott; and honoraria from Nipro, Abbott, Kowa, Amgen, Sanofi, Astellas, Takeda, and Daiichi-Sankyo. Dr Miyamoto has research funding from Tokyo Marine and Nichido Fire Insurance Co, Fujitsu Co, Softbank Co, Meiji Yasuda Life Insurance Co, and Sara Ya Co. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

The aim of the studies was to evaluate the safety, tolerability, and efficacy of tafolecimab, a novel proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody, in Chinese healthy volunteers and patients with hypercholesterolemia. Fifty-eight healthy volunteers (phase 1a) were randomized to receive a single dose of 25, 75, 150, 300, 450, or 600 mg tafolecimab subcutaneously, 75 or 450 mg intravenously, or placebo. Sixty patients with hypercholesterolemia (phase 1b) were randomized to receive 75 or 140 mg tafolecimab every 2 weeks, 300 or 420 mg every 4 weeks, or 450 or 600 mg every 6 weeks subcutaneously or placebo for 12 weeks. Tafolecimab was well tolerated. Adverse events in both studies were either mild or moderate. In the phase 1a study, a single dose of tafolecimab reduced low-density lipoprotein-cholesterol (LDL-C) levels up to 72% in healthy volunteers. In the phase 1b study, tafolecimab reduced LDL-C levels up to 71.6% and by more than 50% consistently to week 12 for all tafolecimab dose regimens. Tafolecimab is a safe PCSK9 monoclonal antibody with significant and potential long-acting LDL-C-lowering effect. (Single Ascending Dose Study of PCSK-9 Inhibitor [IBI306] in Healthy Subjects; NCT03366688) (Multiple Ascending Dose Study of PCSK-9 Inhibitor [IBI306] in Chinese Patients With Hypercholesterolemia; NCT03815812)., Competing Interests: This study was sponsored by Innovent Biologics and funded by National Science and Technology Major Projects (2019ZX09732-001). Drs Qian, Deng, and H. Li are employees of Innovent Biologics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

Background: The International Atherosclerosis Society (IAS) has proposed "severe familial hypercholesterolemia" (FH) as a phenotype with the highest cardiovascular risk. However, whether this criteria could appropriately stratify a high-risk Japanese patient with FH remains unknown., Objectives: This study sought to characterize atherosclerotic cardiovascular diseases in IAS-defined Japanese subjects with severe FH., Methods: This study analyzed 380 clinically diagnosed subjects with heterozygous FH without any history of atherosclerotic cardiovascular diseases. Severe FH was defined as untreated low-density lipoprotein cholesterol >400 mg/dL, >310 mg/dL plus 1 high-risk feature, or >190 mg/dL plus 2 high-risk features according to IAS-proposed statement. The occurrence of first and subsequent composite outcomes (cardiac [cardiac death + coronary artery disease + coronary revascularization] and noncardiac events [stroke + peripheral artery disease] was compared between subjects with severe (n = 135) and non-severe (n = 227) FH., Results: Severe FH was identified in 40.3% of study population. They had higher low-density lipoprotein cholesterol ( P < 0.001) and lipoprotein(a) ( P = 0.03) levels. Moreover, they more frequently received high-intensity statin ( P < 0.001), PCSK9 inhibitor ( P < 0.001), and lipoprotein apheresis ( P = 0.01) than nonsevere FH subjects did, which resulted in a lower on-treatment low-density lipoprotein cholesterol level of subjects with severe FH (113 ± 47.2 vs 130 ± 53.9 mg/dL; P = 0.007). However, during the 7.4-year observational period, subjects with severe FH exhibited a 9.3-, 15.4-, and 5.9-fold greater risk for first composite ( P < 0.001), cardiac ( P < 0.001), and noncardiac outcomes (P = 0.02), respectively. Multivariate Cox proportional hazard model consistently revealed the 7.8- and 7.9-fold elevated risks of first ( P < 0.001) and of subsequent ( P < 0.001) composite outcomes in subjects with severe FH., Conclusions: Japanese subjects with severe FH present profound risks of both first and subsequent atherosclerotic cardiovascular diseases in the primary prevention settings. These findings support the clinical applicability of IAS-defined severe FH in Japanese patients, which identifies those who require further stringent antiatherosclerotic management., Competing Interests: Dr Kataoka has received research support from Nipro and Abbott; and honoraria from Nipro, Abbott, Kowa, Amgen, Sanofi, Astellas, Takeda, and Daiichi-Sankyo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

Objective: Oncostatin M (OSM) is an inflammatory cytokine of the interleukin-6 family which plays a crucial role in the pathogenesis of atherosclerosis. Therefore, we tested our hypothesis that serum OSM levels are increased in patients with coronary artery diseases (CAD)., Methods and Results: Serum OSM level was measured by sandwich technique immunoassay in 315 consecutive patients and who underwent coronary angiography at the International University of Health and Welfare Hospital from April 2019 to March 2021. A diagnosis of CAD was made in 169 patients. Serum OSM levels were significantly higher in patients with significant coronary stenosis compared to those without it. [123.0 ± 46.7 pg/mL (n = 169) vs. 98.3 ± 47.9 pg/mL (n = 146), p < 0.001]. A positive correlation was noted between serum OSM levels and severity and complexity of coronary stenosis. Importantly, the coronary revascularization significantly decreased the serum OSM levels. We furthermore detected a positive correlation between serum OSM levels and HbA1c levels. Finally, our data suggested that 120 pg/mL of serum OSM was the potential cutoff value for screening of silent myocardial ischemia related with diabetic mellitus (DM)., Conclusion: Serum OSM can be a novel biomarker for CAD and may be useful for the screening of asymptomatic CAD in patients with DM., (© 2021 The Authors.)

Objectives: In 2009, the Japan Society of Clinical Chemistry (JSCC) recommended a reference method for the measurement of serum high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels. This automated method uses cholesterol esterase-cholesterol dehydrogenase to measure cholesterol levels in fractions obtained after ultracentrifugation and dextran sulfate/magnesium chloride precipitation. In the present study, using fresh samples, we compared the LDL-C and HDL-C levels measured using this method with those measured using the traditional Centers for Disease Control and Prevention (CDC)-beta-quantification (BQ) method., Design: and methods: Using both the JSCC and CDC-BQ methods, LDL-C/HDL-C levels were measured in 47 non-diseased and 126 diseased subjects, whose triglyceride levels were lower than 11.29 ​mmol/L (1000 ​mg/dL)., Results: For LDL-C, the equation of the line representing the correlation between the two methods was y ​= ​0.991x + 0.009 ​mmol/L; r ​= ​0.999; and Sy/x ​= ​0.025 ​mmol/L, where x is the mean LDL-C level measured using the CDC-BQ method. Similarly, for HDL-C, the equation of the line representing the correlation between the two methods was y ​= ​0.988x + 0.041 ​mmol/L, r ​= ​0.999, and Sy/x ​= ​0.019 ​mmol/L, where x is the mean HDL-C level measured using the CDC-BQ method., Conclusions: The JSCC method agreed with the CDC-BQ method in cases of both non-diseased and diseased subjects, including those with dyslipidemia., Competing Interests: The authors have declared that no conflict of interest exists., (© 2021 The Author(s).)

Background: The deeper understanding of the complex hereditary basis of familial hypercholesterolemia (FH) has raised the rationale of genetic testing, which has been underutilized in clinical practice., Objectives: The present study aimed to explore the variant spectrum of FH in an expanding manner and compare its diagnostic performance., Methods: A total of 169 Chinese individuals (124 index cases and 45 relatives) with clinical definite/probable FH were consecutively enrolled. Next-generation sequencing was performed for genetic analysis of 9 genes associated with hypercholesterolemia (major genes: LDLR, APOB, and PCSK9; minor genes: LDLRAP1, LIPA, STAP1, APOE, ABCG5, and ABCG8 ) including the evaluations of small-scale variants and large-scale copy number variants (CNVs)., Results: Among the 169 clinical FH patients included, 98 (58.0%) were men. A total of 85 (68.5%) index cases carried FH-associated variants. The proportion of FH caused by small-scale variants in LDLR , APOB, and PCSK9 genes was 62.1% and then increased by 6.5% when other genes and CNVs were further included. Furthermore, the variants in LDLR , APOB , and PCSK9 genes occupied 75% of all FH-associated variants. Of note, there were 8 non- LDLR CNVs detected in the present study., Conclusions: LDLR , APOB , and PCSK9 genes should be tested in the initial genetic screening, although variants in minor genes also could explain phenotypic FH, suggesting that an expanding genetic testing may be considered to further explain phenotypic FH., Competing Interests: This work was supported by the Capital Health Development Fund (201614035), CAMS Major Collaborative Innovation Project (2016-I2M-1-011). The authors have reported that theyhave no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

Metabolic syndrome comprises a cluster of metabolic disorders related to the development of cardiovascular disease and type 2 diabetes mellitus. In latter years, plant secondary metabolites have become of special interest because of their potential role in preventing and managing metabolic syndrome. Sesquiterpene lactones constitute a large and diverse group of biologically active compounds widely distributed in several medicinal plants used for the treatment of metabolic disorders. The structural diversity and the broad spectrum of biological activities of these compounds drew significant interests in the pharmacological applications. This review describes selected sesquiterpene lactones that have been experimentally validated for their biological activities related to risk factors of metabolic syndrome, together with their mechanisms of action. The potential beneficial effects of sesquiterpene lactones discussed in this review demonstrate that these substances represent remarkable compounds with a diversity of molecular structure and high biological activity, providing new insights into the possible role in metabolic syndrome management., Competing Interests: The authors declare no conflict of interest., (© 2020 SAAB. Published by Elsevier B.V. All rights reserved.)

Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators may attenuate PCSK9-induced low-density lipoprotein receptor (LDLR) degradation in lysosome and promote the clearance of circulating low-density lipoprotein cholesterol (LDL-C). A novel series of tetrahydroprotoberberine derivatives (THPBs) were designed, synthesized, and evaluated as PCSK9 modulators for the treatment of hyperlipidemia. Among them, eight compounds exhibited excellent activities in downregulating hepatic PCSK9 expression better than berberine in HepG2 cells. In addition, five compounds 15 , 18 , 22 , ( R )- 22 , and ( S )- 22 showed better performance in the low-density lipoprotein, labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate (DiI-LDL) uptake assay, compared with berberine at the same concentration. Compound 22 , selected for in vivo evaluation, demonstrated significant reductions of total cholesterol (TC) and LDL-C in hyperlipidemic hamsters with a good pharmacokinetic profile. Further exploring of the lipid-lowering mechanism showed that compound 22 promoted hepatic LDLR expression in a dose-dependent manner in HepG2 cells. Additional results of human ether-à-go-go related gene (hERG) inhibition assay indicated the potential druggability for compound 22 , which is a promising lead compound for the development of PCSK9 modulator for the treatment of hyperlipidemia., (© 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

To assess the efficacy and short-term outcomes of adherence to statin therapy among coronary heart disease (CHD) patients following their hospital discharge, we enrolled 615 CHD patients who were prescribed statins from The First Affiliated Hospital of Chongqing Medical University in China between February 1st and October 31st of 2013. Statin adherence was evaluated by identifying the proportion of patients who remained adherent or became non-adherent to statin therapy over 4-8 months post-discharge from the hospital. The composite outcomes included all-cause mortality and re-hospitalization with cardiovascular disease. We found that 15.9% patients were non-adherent to their statin therapies and that coronary artery stenosis<75% (OR = 3.433, 95% CI: 2.191-5.380, p < 0.001) and adverse effects (OR = 2.542, 95% CI: 1.327-4.869, p = 0.005) both clearly contributed to poor adherence. The primary self-reported reasons for non-adherence included a lack of knowledge about the benefits of statin therapy (36.7%), the treatment being halted at the advice of their doctor (19.4%), and the difficulty in obtaining statins (12.2%). Non-adherence to statin therapy was significantly associated with an increased risk of cardiovascular events (OR = 1.741, 95% CI: 1.035-2.929, p = 0.037). In conclusion, CHD patients with moderate stenosis or adverse effects tended to have poor statin adherence, and this was significantly associated with increased cardiovascular events. We should strengthen education of the importance of statin therapy for both patients and doctors and facilitate the ability of patients to obtain their statin medication. Clinical Study Register Code: ChiCTR-EPC-16007839.

Background: There is increasing interest in the non-skeletal effects of vitamin D and the relationship between vitamin D deficiency and chronic conditions such as diabetes mellitus. We aimed to investigate the relationship between surrogate indices of insulin resistance (IR), and vitamin D deficiency/insufficiency in postmenopausal Saudi women with and without metabolic syndrome., Methods: The study population consisted of 300 postmenopausal women aged 46-88 years enrolled consecutively from women attending the Outpatient Clinics of King Abdulaziz University Hospital. Demographic, anthropometric, and biochemical parameters were recorded. Data were analyzed for women with and without metabolic syndrome., Results: Abdominal obesity, IR, and hypovitaminosis D were highly prevalent within our population sample. Of the components used to define metabolic syndrome; waist circumference, serum triglycerides (TG), high density lipoprotein-cholesterol, and fasting blood glucose (FBG) were significantly related with all surrogate measures of IR. Significant inverse correlations were found between serum vitamin D and serum TG, FBG, and diastolic blood pressure, within the study cohort., Conclusions: These observations suggest that hypovitaminosis D may be associated with the risk of developing metabolic syndrome. Interrelationships between IR, metabolic syndrome, and hypovitaminosis D are of particular interest in Saudi population, given the high prevalence of these conditions in this region.

Low-density lipoprotein receptor (LDLR) mediates hepatic clearance of plasma cholesterol; proprotein convertase subtilisin/kexin 9 (PCSK9) opposes this clearance by promoting LDLR degradation. The plant flavonoid quercetin-3-β-d-glucoside (Q3G) has been shown to reduce hypercholesterolemia in experimental animals. Here, we examined how it affects LDLR and PCSK9 expression as well as LDL uptake by human Huh7 hepatocytes. At low micromolar concentrations, Q3G increased LDLR expression, reduced PCSK9 secretion, and stimulated LDL uptake. It also diminished intracellular sortilin, a sorting receptor known to facilitate PCSK9 secretion. Thus, as an LDLR inducer and a PCSK9 anti-secretagogue, Q3G may represent an effective anti-cholesterolemic agent.