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The Proprotein Convertase Subtilisin Kexin of type 9 (PCSK9) has been identified in 2003 as the third gene involved in familial hypercholesterolemia. PCSK9 binds to the membrane low-density lipoprotein receptor (LDLR) and promotes its cellular internalization and lysosomal degradation. Beyond this canonical role, PCSK9 was recently described to be involved in several immune responses. However, to date, the contribution of PCSK9 in food allergy remains unknown. Here, we showed that Pcsk9 deficiency or pharmacological inhibition of circulating PCSK9 with a specific monoclonal antibody (m-Ab) protected mice against symptoms of gliadin-induced-food allergy, such as increased intestinal transit time and ear oedema. Furthermore, specific PCSK9 inhibition during the elicitation steps of allergic process was sufficient to ensure anti-allergic effects in mice. Interestingly, the protective effect of PCSK9 inhibition against food allergy symptoms was independent of the LDLR as PCSK9 inhibitors remained effective in Ldlr deficient mice. In vitro , we showed that recombinant gain of function PCSK9 (PCSK9 D374Y) increased the percentage of mature bone marrow derived dendritic cells (BMDCs), promoted naïve T cell proliferation and potentiated the gliadin induced basophils degranulation. Altogether, our data demonstrate that PCSK9 inhibition is protective against gliadin induced food allergy in a LDLR-independent manner. [ABSTRACT FROM AUTHOR]

[Display omitted] • PCSK9 exacerbates atrial structural remodeling and promotes AF in collagen-induced arthritis rats by enhancing M1 macrophages polarization. • The PCSK9 is increased in RA patients complicated with AF and the level of PCSK9 is independently associated with AF risk in RA patients. • Evolocumab (a monoclonal antibody of PCSK9) reduces AF susceptibility of rheumatoid arthritis rats. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is implicated in the pathogenesis and progression of autoimmune disease. Patients with rheumatoid arthritis (RA) are at high risk of developing atrial fibrillation (AF), while whether PCSK9 is involved in the onset of AF among RA patients remains unclear. To explore the role of PCSK9 in the occurrence of AF in RA patients and decipher the underlying mechanism. We established a rat model of collagen-induced arthritis (CIA) by immunization with type II collagen in Freund's incomplete adjuvant. Atrial electrophysiological test was used to evaluate AF susceptibility. We performed a clinical study to examine the correlation between PCSK9 level and AF, which recruited healthy control, RA patients and RA patients complicated with AF. Evolocumab (a monoclonal antibody of PCSK9) is administered via intraperitoneal injection in CIA rats to assess the role of PCSK9 in RA-related AF. LPS-RS (LPS inhibitor), clodronate liposomes (depletion of macrophages), and cell co-culture model were used to dissect the mechanism underlying PCSK9 promotes AF. AF inducibility and duration were higher in CIA rats, accompanied by elevated plasma and atrial PCSK9. Interestingly, compared with healthy control subjects, patients with RA showed an increase in PCSK9, and the PCSK9 is much higher in RA patients complicated with AF. The level of PCSK9 was independently associated with AF risk in RA patients. In the in vivo experiment, evolocumab reduced AF susceptibility, and ameliorated atrial structural remodeling of CIA rats. Mechanistically, augmented LPS in CIA rats led to an increase in PCSK9, which exacerbated fibrosis of cardiac fibroblasts and apoptosis of cardiac myocytes by enhancement of M1 macrophages polarization and inflammation, thereby contributing to AF. This study suggests that elevated PCSK9 causes atrial structural remodeling by enhancement of M1 macrophages polarization in atria, and evolocumab can effectively protects CIA rats from AF. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely tied to obesity. The degree ranges from steatosis (MASL) and steatohepatitis (MASH) to liver cirrhosis. PCSK9 controls cholesterol and lipid particle transport to the liver. PCSK9 might interfere with the pathophysiology of MASLD and bariatric surgery (BS) outcomes of patients with MASLD. Evaluate the relationship between serum and hepatic PCSK9 levels with the degree of MASLD and the metabolic outcome of BS. University Hospital, Spain. A total of 110 patients with obesity undergoing BS were classified according to liver histology as controls, MAS, and MASH. PCSK9 levels in serum were measured before and 6 months after BS using enzyme-linked immunosorbent assay. PCSK9 protein and mRNA levels in liver tissue were analyzed by immunohistochemistry and reverse transcriptase-polymerase chain reaction, respectively. Hepatic PCSK9 protein levels were diminished in MASL and MASH compared with patients without MASLD and showed a strong negative association with MASLD severity scores. Liver PCSK9 mRNA was higher in MASH compared with controls and MASL and showed positive associations with MASLD severity scores. There were no differences in serum PCSK9 pre or postBS between the groups. Pre- and postsurgery serum PCSK9 positively correlated with cholesterol fold-changes and body mass index (BMI), cholesterol, and low-density lipoprotein -cholesterol fold-changes, respectively. PCSK9 fold-change positively correlated with BMI changes and was the sole variable explaining BMI fold changes in a regression model. PCSK9 mRNA and protein in the liver might be associated with the degree of MASLD. Serum PCSK9 may be associated with cholesterol and/or BMI fold changes. Serum changes of PCSK9 after BS could explain BMI loss outcome. • PCSK9 mRNA and protein levels in liver associated with the degree of MASLD. • Pre-surgery serum PCSK9 linked to changes in total cholesterol after BS. • Post-surgery serum PCSK9 linked to changes in total cholesterol, LDL-cho and BMI after BS. • Serum PCSK9 changes upon surgery correlated with BMI changes. • PCSK9 could play a role in explaining BMI loss following BS. [ABSTRACT FROM AUTHOR]

The impact of the loss-of-function (LOF) genetic variant PCSK9 R46L on glucose homeostasis and cardiovascular disease (CVD) remains uncertain, despite its established correlation with diminished blood cholesterol levels. This meta-analysis aimed at exploring the effect of the PCSK9 R46L genetic variant on plasma insulin and glucose levels, risk of diabetes mellitus and CVD. PubMed, Embase, and the Cochrane Library were searched for cohort and case–control studies published until October 1, 2023. The studies should report the association of the PCSK9 R46L genetic variant with one of the following: fasting plasma insulin, blood glucose levels, diabetes mellitus, and CVD risk. A dominant model of the PCSK9 R46L genetic variant was employed to statistical analysis. The meta-analyses were performed for continuous variables with standard mean difference (SMD), categorical variables with odds ratio (OR) using a random-effects model. A total of 17 articles with 20 studies engaging 1,186,861 population were identified and mobilized for these analyses. The overall results indicated that, compared with non-carriers of the PCSK9 R46L genetic variant, carriers of the PCSK9 R46L genetic variant did not increase or decrease the levels of fasting plasma insulin (3 studies with 7277 population; SMD, 0.08; 95% CI, −0.04 to 0.19; P = 0.270), and the levels of fasting plasma glucose (7 studies with 9331 population; SMD, 0.03; 95% CI, −0.08 to 0.13; P = 0.610). However, carriers of the PCSK9 R46L genetic variant indeed had 17% reduction in the risk of CVD (11 studies with 558,263 population; OR, 0.83; 95% CI, 0.71 to 0.98; P = 0.030), and 9% increase in the risk of diabetes mellitus (10 studies with 744,466 population; OR, 1.09; 95% CI, 1.04 to 1.14; P < 0.01). Meta-regression analyses indicated that the increased risk of diabetes mellitus and the reduced risk of CVD were positively correlated with reduction in LDL-C (P = 0.004 and 0.033, respectively). PCSK9 R46L genetic variant exhibited an elevated susceptibility to diabetes mellitus alongside a reduced vulnerability to CVD. • The PCSK9 R46L genetic variant was not associated with fasting plasma insulin and glucose levels. • The PCSK9 R46L genetic variant increased the risk of diabetes mellitus, but reduced the risk of cardiovascular disease (CVD). • The elevated risk of diabetes mellitus and decreased risk of CVD were significantly associated with reduced LDL-C levels. [ABSTRACT FROM AUTHOR]

RNA interference (RNAi) presents great potential against intractable liver diseases. However, the establishment of specific, efficient, and safe delivery systems targeting hepatocytes remains a great challenge. Herein, we described a promising hepatocytes-targeting system through integrating triantennary N- acetylgalactosamine (GalNAc)-engineered cell membrane with biodegradable mesoporous silica nanoparticles, which efficiently and safely delivered siRNA to hepatocytes and silenced the target PCSK9 gene expression for the treatment of non-alcoholic fatty liver disease. Having optimized the GalNAc-engineering strategy, insertion orders, and cell membrane source, we obtained the best-performing GalNAc-formulations allowing strong hepatocyte-specific internalization with reduced Kupffer cell capture, resulting in robust gene silencing and less hepatotoxicity when compared with cationic lipid-based GalNAc-formulations. Consequently, a durable reduction of lipid accumulation and damage was achieved by systemic administering siRNAs targeting PCSK9 in high-fat diet-fed mice, accompanied by displaying desirable safety profiles. Taken together, this GalNAc-engineering biomimetics represented versatile, efficient, and safe carriers for the development of hepatocyte-specific gene therapeutics, and prevention of metabolic diseases. Compared to MSN@LP-GN3 (MC3-LNP), MSN@CM-GN3 exhibited strong hepatocyte targeting and Kupffer cell escaping, as well as good biocompatibility for safe and efficient siRNA delivery. Furthermore, siPCSK9 delivered by MSN@CM-GN3 reduced both serum and liver LDL-C, TG, TC levels and lipid droplets in HFD-induced mice, resulting in better performance than MSN/siPCSK9@LP-GN3 in terms of lipid-lowering effect and safety profiles. These findings indicated promising advantages of our biomimetic GN3-based systems for hepatocyte-specific gene delivery in chronic liver diseases. Our work addressed the challenges associated with the lower targeting efficiency of cell membrane-mimetic drug delivery systems and the immunogenicity of traditional GalNAc delivery systems. In conclusion, this study provided an effective and versatile approach for efficient and safe gene editing using ligand-integrated biomimetic nanoplatforms. [Display omitted] [ABSTRACT FROM AUTHOR]

Bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases (CVDs), the world's primary cause of death. Ginkgo biloba , a well-known traditional Chinese medicine with notable cardiovascular actions, has been used as a cardio- and cerebrovascular therapeutic drug and nutraceutical in Asian countries for centuries. Preclinical studies have shown that ginkgolide B, a bioactive component in Ginkgo biloba , can ameliorate atherosclerosis in cultured vascular cells and disease models. Of clinical relevance, several clinical trials are ongoing or being completed to examine the efficacy and safety of ginkgolide B-related drug preparations in the prevention of cerebrovascular diseases, such as ischemia stroke. Here, we present a comprehensive review of the pharmacological activities, pharmacokinetic characteristics, and mechanisms of action of ginkgolide B in atherosclerosis prevention and therapy. We highlight new molecular targets of ginkgolide B, including nicotinamide adenine dinucleotide phosphate oxidases (NADPH oxidase), lectin-like oxidized LDL receptor-1 (LOX-1), sirtuin 1 (SIRT1), platelet-activating factor (PAF), proprotein convertase subtilisin/kexin type 9 (PCSK9) and others. Finally, we provide an overview and discussion of the therapeutic potential of ginkgolide B and highlight the future perspective of developing ginkgolide B as an effective therapeutic agent for treating atherosclerosis. Ginkgolide B possesses the antiatherosclerotic advantage of "multitarget and multipathway", which is closely linked to its regulating endothelial dysfunction, thrombosis, leukocyte action, and risk factors. [Display omitted] [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) is a major cause of deaths in industrialized countries and a constantly growing cause of morbidity and mortality worldwide Hypercholesterolemia is one of the main risk factors for CVD progression that may be prevented by lifestyle changes, including diet. This chapter will discuss the role of peptides from plants (soybean, lupin, cowpea, hempseed, and rice bran) sources with pleotropic activity for the prevention of CVD. Overall, the bioactivity that will be mainly discussed it is the hypocholesterolemic one. The very diversified structures of the hypocholesterolemic peptides so far identified explains the reason why they exert their activity through different mechanisms of action that will be extensively described in this review. Doubtlessly, their potential use in nutritional application is desirable, however, only few of them have been tested in vivo. Therefore, more efforts need to be pursued for singling out good candidates for the development of functional foods or dietary supplements. [ABSTRACT FROM AUTHOR]

Individuals with diabetes have increased cardiovascular risk. Although PCSK9 inhibitors bring about a wide reduction in lipids, there is uncertainty about the effects for diabetic patients. We conducted a systematic review and meta-analysis to assess the efficacy and safety of PCSK9 inhibitors for diabetes. We performed a meta-analysis comparing treatment with PCSK9 inhibitors versus controls up to July 2022. Primary efficacy endpoints were percentage changes in lipid profile parameters. We used random effects meta-analyses to combine data. Subgroups of diabetic patients (by diabetes type, baseline LDL-C, baseline HbA1c and follow-up time) were also compared. We included 12 RCTs comprising 14,702 patients. Mean reductions in LDL-C were 48.20% (95% CI: 35.23%, 61.17%) in patients with diabetes. Reductions observed with PCSK9 inhibitors were 45.23% (95% CI: 39.43%, 51.02%) for non-HDL-cholesterol, 30.39% (95% CI: 24.61%, 36.17%) for total cholesterol, 11.96% (95% CI: 6.73%, 17.19%) for triglycerides, 27.87% (95% CI: 22.500%, 33.17%) for lipoprotein(a), 42.43% (95% CI: 36.81%, 48.06%) for apolipoprotein B; increases in HDL-C of 5.97% (95% CI: 4.59%, 7.35%) were also observed. There was no significant difference in fasting plasma glucose (FPG) (WMD: 2.02 mg/mL; 95% CI: −1.83, 5.87) and HbA1c (WMD: 1.82%; 95% CI: −0.63, 4.27). Use of a PCSK9 inhibitor was not associated with increased risk of treatment-emergent adverse event (TEAE) (p = 0.542), serious adverse event (SAE) (p = 0.529) and discontinuations due to AEs (p = 0.897). PCSK9 inhibitor therapy should be considered for all diabetic individuals at high risk of atherosclerotic cardiovascular disease. CRD42022339785. • Individuals with diabetes need a more intensive approach to lipid-lowering. • Efficacy and safety of PCSK9 inhibitors for patients with diabetes are uncertain. • PCSK9 inhibitors reduce lipids with no adverse effects on glycaemic control. • PCSK9 inhibitors could be used more extensively in diabetic population. [ABSTRACT FROM AUTHOR]

• The effectiveness of PCSK9 inhibition therapy in a real-world context was -66%. • The relative LDL-C change was significantly higher in men (-70%) than women (-59%). • The absolute LDL-C change was not significantly different between men and women. • In women, older age did not modify PCSK9 inhibitor efficacy for decreasing LDL-C. • With high-intensity statin, both sexes reached treatment target with PCSK9 inhibitor. Previous studies have shown the efficacy of PCSK9 inhibitors (PCSK9i) in lowering LDL-C. One clinical trial with alirocumab suggested that the LDL-C reduction effect is larger in men than women. In contrast, none of the studies with evolocumab have observed a difference in the treatment effect between men and women. However, sex differences data from real life experience is lacking. In addition, the difference in LDL-C response to PCSK9i between pre- and post-menopausal women has not been investigated so far. To compare the relative change in LDL-C following the introduction of a PCSK9i in a real-life clinical setting according to sex and menopausal status. All patients were recruited at the IRCM lipid clinic. Lipid profiles before and after the introduction of PCSK9i were available in the medical file for 259 patients (160 men and 99 women (72 post-menopausal, 20 pre-menopausal and 7 unknown menopausal status). We observed a significant difference in relative LDL-C change between men (-70%) and women (-59%), p <0.0001. However, no difference was observed between pre-menopausal (-58%) and post-menopausal (-58%) women. In a linear regression model, sex remains a significant predictor of the response to PCSK9i after correction for confounding factors such as statin intensity (beta coefficient=-0.245, p <0.0001). We observed a greater relative LDL-C response to PCSK9i in men than in women in a real-life clinical context. However, it is still unknown whether this difference in LDL-C change between men and women translates into a meaningful difference on long-term cardiovascular risk. [ABSTRACT FROM AUTHOR]

• We present a case with FHBL caused by homozygous LOF mutations in PCSK9. • A novel missense mutation in PCSK9 was associated with reduced serum PCSK9 level. • She had no complications, except for mild fatty liver. Here, we present the first case of a Japanese patient with familial hypobetalipoproteinemia (HBL) that is caused by homozygous loss-of-function mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9). A 46-year-old female patient who was born in a consanguineous marriage of parents who were second cousins was referred to our hospital due to decreased low-density lipoprotein (LDL)-cholesterolemia (22 mg/dL). She did not have any secondary HBL causes. Novel homozygous mutations were identified in PCSK9 (c.1133G>A [p.Cys378Tyr]) using panel sequencing. The serum levels of heterodimer PCSK9 and furin-cleaved PCSK9 were extremely low (<32 and 15 ng/mL, respectively), leading to the diagnosis of familial HBL diagnosis caused by loss-of-function mutations in PCSK9. The patient did not exhibit any complications associated with low LDL cholesterol, except for mild fatty liver and reduced serum 25-OH vitamin D level (15.7 ng/mL). Here, we provide a detailed molecular and functional characterization of a novel loss-of-function mutation in PCSK9. [ABSTRACT FROM AUTHOR]

• Evolocumab did not impair cognitive function in pediatric FH after 24 weeks. • Abnormal cognitive decline was less frequent with evolocumab than with placebo. • Small improvements observed with evolocumab in psychomotor function and attention. Evolocumab is a fully human monoclonal antibody inhibitor of PCSK9 approved for lowering low-density lipoprotein cholesterol in adults and pediatric patients with familial hypercholesterolemia (FH). The cognitive safety of evolocumab has been established in adults but has not yet been described in pediatric patients. To determine the effects of evolocumab on cognitive function in pediatric heterozygous FH. Cognitive function was assessed during a 24-week, randomized, double-blind, placebo-controlled study (HAUSER-RCT) evaluating the efficacy, safety, and tolerability of 24 weeks of monthly subcutaneous injections of evolocumab in pediatric patients with FH. Cognitive safety endpoints included changes from baseline to week 24 in test scores in domains of psychomotor function, attention, visual learning, and executive function. Between-group differences in age-standardized mean test score changes were analyzed using analysis of covariance models and point estimates with 95% confidence interval (CI). Magnitudes of difference between treatment groups (Cohen's d) and reliable change indices were calculated for each cognitive function test. At week 24, changes from baseline in age-standardized cognitive test scores were similar between the treatment groups. Differences (95% CI) between the evolocumab and placebo groups in mean test score changes for the Groton Maze Learning, One-Card Learning, Identification, and Detection tests were 0.1 (–0.2, 0.4), –0.1 (–0.5, 0.4), 0.3 (0.0, 0.7), 0.3 (–0.1, 0.8), respectively. For all tests, abnormal and clinically important cognitive decline occurred with lesser frequency in the evolocumab group. In pediatric patients with FH, 24-week treatment with evolocumab did not negatively influence cognition. This study was funded and designed by Amgen. [Display omitted] [ABSTRACT FROM AUTHOR]

Background and Aims: While the role of PCSK9 in lipid metabolism is well established, its link with endothelial function is less clear. The aim of the present study is to evaluate the relationship between PCSK9 and endothelial dysfunction in the setting of acute myocardial infarction.Methods and Results: To this purpose, we analyzed the serum of 74 patients with ST-elevation myocardial infarction (STEMI) at the time of admission and after 5 days. Endothelial dysfunction was evaluated as rate of apoptosis (AR) of human umbilical vein endothelial cells incubated with patients' serum. There was a good correlation between PCSK9 and the apoptosis rate values, both at baseline (r = 0.649) and 5-day (r = 0.648). In the 5 days after STEMI, PCSK9 increased significantly (242-327 ng/ml, p < 0.001), while AR did not (p = 0.491). Overall, 21 (28%) patients showed a reduction of PCSK9, and they had a significantly higher decrease of AR as compared to others (-13.87 vs 5.8%, p = 0.002). At the univariable analysis, the 5-day change of PCSK9 resulted to be the only variable associated with the 5-day change of the apoptosis rate (beta 0.217, 95%CI 0.091-0.344, p = 0.001).Conclusion: The variation of endothelial function and PCKS9 in the first days after an acute myocardial infarction are related. Further validation and research are necessary to confirm our findings.Clinical Trial: NCT02438085. [ABSTRACT FROM AUTHOR]

and Purpose: The aim of this study was to assess, compare and correlate the ability of PCSK9 and IL6 as potential common serum and salivary biomarkers for stage III/IV periodontitis and the risk of developing atherosclerotic cardiovascular diseases. 76 patients were alloted into 4 groups consisting of subjects with clinically healthy periodontium and stage III/IV periodontitis with and without ACVD. Clinical parameters – PD, CAL, number of teeth, PI, mSBI, TC, Tg, HDL and LDL were recorded. Serum and saliva samples were obtained and subjected to ELISA for quantifying the biomarker levels. The level of these biomarkers was found to be the lowest (IL6 Serum: 21.92 ± 14.54, IL6 Saliva: 12.34 ± 7.72, PCSK9 Serum: 178.82 ± 35.07, PCSK9 Saliva: 80.82 ± 25.43) in group I and highest in group IV (IL6 Serum: 73.4 ± 24.86, IL6 Saliva: 37.66 ± 15.77, PCSK9 Serum: 346.54 ± 45.11, PCSK9 Saliva: 157.72 ± 43.28). The clinical parameters PI, mSBI, PPD, CAL, total number of teeth, TC, HDL and LDL showed a significant correlation with biomarkers PCSK9 and IL6. This study features the elevation of serum and salivary PCSK9 and IL6 in periodontitis and ACVD. A triad of serum and salivary PCSK9 and IL6 along with the clinical markers of periodontal disease can relatively predict the future risk of developing ACVD. [Display omitted] [ABSTRACT FROM AUTHOR]

• Total and active PCSK9, Lp(a), TG, LDL, and nonHDL particles rise during pregnancy. • Obese have higher levels, and the highest are in the last trimester. • Physiologic vs. atherogenic levels are to be determined. Serum lipids, including total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-c), increase during pregnancy. Serum Proprotein Convertase Subtilisin Kexin 9 (PCSK9) is a vital regulator in lipoprotein metabolism. Circulating PCSK9 downregulates the LDL receptor on the surface of liver cells inhibiting clearance of LDL-c. To determine the influence of weeks of pregnancy and obesity on circulating levels of essential lipid lipoproteins and PCSK9 in women with normal, uncomplicated pregnancies and deliveries. We performed a comprehensive lipid and lipoprotein profile during each trimester of pregnancy in 70 mostly Caucasian women with uncomplicated normal pregnancies and deliveries. Based on their first trimester BMI, we placed them into one of three categories: (<25 kg/m2 n=23, 25-30 kg/m2 n=25, or >30 n=22) kg/m2. Cholesterol, triglycerides, LDL cholesterol (LDL-c), non-HDL particles, and lipoprotein(a) were measured by spectrophotometry, ion mobility, and immunoturbidimetric assays. Elisa assay determined PCSK9 (active and total). Homeostatic Model Assessment (HOMA-IR) assessed insulin resistance in the second and third trimesters of pregnancy. Total and active PCSK9, LDL-c, and nonHDL particle concentrations were higher than reported for non-pregnant normal values, increased after the first trimester of pregnancy, and were highest from mid-gestation to the last trimester of pregnancy in the overweight and the obese. PCSK9 levels rise as normal pregnancy progresses. Levels are higher in persons who are obese, even after adjustment for insulin resistance. Defining normal PCSK9 levels during pregnancy must adjust for gestational age and BMI. [ABSTRACT FROM AUTHOR]

• South Asians have extreme ASCVD risk, necessitating updated recommendations for ACS. • Risk of adverse cardiovascular outcomes after ACS is highest within the first 30 days. • Many patients have persistent hypercholesterolemia and risk after ACS despite statins. • Lipoprotein(a) elevation is prevalent and increases risk of adverse CV outcomes. • The Lipid Association of India recommends earlier aggressive lipid lowering after ACS. Patients with acute coronary syndrome (ACS) have a high risk of subsequent adverse cardiovascular outcomes, particularly within the first 30 days. Although it is well documented that initiation of statin therapy in the setting of ACS improves short- and long-term cardiovascular outcomes, and achievement of lower levels of low density lipoprotein cholesterol (LDL-C) incrementally improves outcomes, many patients with ACS have persistent hypercholesterolemia after discharge from the hospital. This is a missed opportunity that prompted the Lipid Association of India to develop recommendations for earlier initiation of more aggressive LDL-C lowering treatment, particularly for patients of South Asian descent who are well-documented to have earlier onset of more aggressive atherosclerotic cardiovascular disease. The Lipid Association of India recommends individualized aggressive LDL-C goals after ACS, which can be rapidly achieved with high intensity statin therapy and subsequent goal-directed adjunctive treatment with ezetimibe and PCSK9 inhibitors. Improved treatment of hypercholesterolemia achieved within weeks after ACS has the potential to reduce the high rate of morbidity and mortality in these high risk patients. [Display omitted] [ABSTRACT FROM AUTHOR]

Acaudina molpadioides has been long used as traditional medicinal resources and reported to demonstrate various important bioactivities such as anticoagulation, antithrombosis, anti-hyperglycemia and anticancer. However, its lipid lowering activity is yet to be fully explored. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme that enhances the lysosomal degradation of hepatic low density lipoprotein receptor (LDLR) resulting in excessive accumulation of the plasma levels of LDL-cholesterols (LDL-C) which subsequently accelerate atherosclerosis. In the present study, A. molpadioides fractions were subjected to promoter-reporter luciferase assay to determine its role as PCSK9 inhibitors. It was found both fractions (EFA and EFB) reduced the transcriptional activity of PCSK9 promoter. Among the seven 5′end deletion constructs of PCSK9 promoter, fragments D1 (−1,711/−94), D3 (−709/−94) and D4 (−440/−94), were suppressed in the presence of both fractions whereas D2 (−1,214/−94), and, D6 (−351/−94) as well as D7 (−335/−94) were inhibited only by EFA and EFB, respectively. Further transcription factor binding sites prediction using MatInspector software discovered various potential cis -regulatory elements namely, PPAR, KLFs, RBPJ-kappa and SREBP that may potentially be involved in ameliorating the transcriptional activity of PCSK9. Immunofluorescence staining was used to evaluate the effects of both fractions on LDL-C and LDLR. Results showed that levels of LDL-C uptake in EFA-treated cells were 69.1% followed by EFB at 32.6%, as compared to untreated control after 24 h treatment. The LDLR protein distribution was induced by 62.41% and 32.2%, which corresponded to an increase in LDL-C uptake in both EFA and EFB treatment, respectively. Hence, the inhibition of PCSK9 by bioactive compounds in EFA and EFB could be another promising therapeutic agent in reducing the cholesterol levels and atherosclerosis by targeting PCSK9. [ABSTRACT FROM AUTHOR]

• Evolocumab was well tolerated in patients aged ≥12 and <80 years with HoFH in India. • Evolocumab was generally associated with reduction in LDL-C. • Lipid-lowering efficacy of evolocumab varied by age and baseline LDL-C. • Pharmacogenetic testing of HoFH patients may identify responders to evolocumab. Evolocumab is a fully human monoclonal antibody inhibitor of proprotein convertase subtilisin/kexin type 9 approved in India for treatment of homozygous familial hypercholesterolemia (HoFH) in patients aged ≥12 years. RAMAN (NCT03403374) was a single-country, open-label, phase 4 study evaluating the safety and tolerability of evolocumab in patients with HoFH in India. Patients ≥12 to ≤80 years of age on stable lipid-lowering therapy with fasting low-density lipoprotein cholesterol (LDL-C) >3.4 mmol/L (>130 mg/dL) received evolocumab 420 mg subcutaneously monthly (every 2 weeks if on apheresis). The primary endpoint was patient incidence of treatment-emergent adverse events. Secondary endpoints included percent changes at week 12 in LDL-C and other lipids. Of 30 enrolled patients, 13 were <18 years of age. Mean±SD baseline levels of LDL-C, apolipoprotein B, and lipoprotein(a) were 12.3 ± 3.5 mmol/L (473.5 ± 135.2 mg/dL), 2.8 ± 0.7 g/L (275.3 ± 69.1 mg/dL), and 201.3 ± 177.6 nmol/L, respectively. Ten patients (33%) reported treatment-emergent adverse events, with 2 (7%) serious adverse events and none leading to discontinuation; no deaths occurred during evolocumab treatment. At week 12, mean (SE) percent changes from baseline in LDL-C, apolipoprotein B, and lipoprotein(a) were −6.4% (4.2), −6.0% (3.7), and −0.2% (4.9), respectively. Reductions in LDL-C among individual patients were variable and greatest in patients ≥18 years of age and with baseline LDL-C <13 mmol/L (<500 mg/dL). Evolocumab was safe and well tolerated in patients with HoFH in India with smaller reductions in LDL-C and other lipids than those observed in previous studies with HoFH and different populations. [Display omitted] [ABSTRACT FROM AUTHOR]

• The LDL receptor and serum LDL-C levels play a critical role in various pathogens. • Decreasing LDLR expression may improve outcomes with VSV, T. Cruzi, T. gondii. • Increasing LDLR expression may improve outcomes with HCV, PL's, and DENV. • Lower serum LDL-C may improve outcomes with T. Cruzi , and T. gondii. • Greater serum LDL-C may improve outcomes with HCV, and DENV. Although the role of the LDL receptor concerning lipids is well known, its role in various viral and parasitic infections, and in regulating the inflammatory response is poorly understood. Several infectious agents use the LDL receptor as a port of entry, and others depend on it for their cycle of infection. In this review, we focus on the discovery, structure, and normal function of the LDL receptor, as well as its role in a selection of infections. The LDL receptor plays an important role in certain infections and is a potential target for treatment deserving further research. [ABSTRACT FROM AUTHOR]

• Lipid specialists may see patients with low or extremely low LDL-C. • Standard-of-care does not include genetic testing for such patients. • We used whole exome sequencing in 9 such patients. • APOB truncating mutations were the most common cause. In clinical setting, current standard-of-care does not include genetic testing for patients with low (<50 mg/dL) and extremely low (<20 mg/dL) levels of serum low-density lipoprotein-cholesterol (LDL-C). We aimed identify the underlying molecular cause – both monogenic and polygenic - of low and extremely low LDL-C levels in a cohort of patients presenting to specialty lipid clinics. Whole exome sequencing was done in patients with low or extremely low LDL-C not due to any secondary causes. Nine patients (4 women), ranging in age from 25 to 63 years old, with low or extremely low LDL-C levels were evaluated. Median LDL-C was 16 mg/dL (range undetectable - 43), total cholesterol 82 mg/dL (42 – 101), triglycerides 35 mg/dL (19–239), and high-density lipoprotein-cholesterol 45 mg/dL (24–81). Of nine patients, two carried known pathogenic variants in APOB (one stop-gain, one deletion; LDL-C range undetectable -10 mg/dL); three patients had novel APOB heterozygous mutations (two frameshift deletions and one splice site; LDL-C range undectable-13 mg/dL); two had heterozygous APOB frameshift deletions previously reported as variants of unknown significance (LDL-C 18 mg/dL in both patients); one (LDL-C 43 mg/dL) had two heterozygous mutations in PCSK9, both previously reported to be benign; and one patient (LDL-C 16 mg/dL) had the APO E2/E2 genotype along with several variants of unknown significance in genes associated with triglycerides. No patients had an LDL-C polygenic risk score below the 5th percentile (range 26th percentile to 93rd percentile). We found APOB mutations to be the most common molecular defect in patients presenting to lipid clinics with low or extremely low LDL-C. Whether clinical genetic testing and LDL-C polygenic risk scores have any utility - other than diagnostic purposes - for such patients remains unclear. In addition, further efforts may be needed to better reclassify pathogenicity of variants of unknown significance. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We aimed at demonstrating the effect of thyroid function status on proprotein convertase subtilisin kexin type 9 (PCSK9) and determining the effect of thyroid hormones on lipid metabolism by comparing the PCSK9 levels of patients with subclinical hypothyroidism, overt hypothyroidism, and hyperthyroidism. PATIENTS AND METHODS: 124 patients with thyroid disorders, aged between 18 and 65 years, were included in this study. The participants were divided into 3 groups. Group 1 comprised 52 patients with subclinical hypothyroidism, Group 2 comprised 40 patients with overt hypothyroidism, and Group 3 comprised 32 patients with hyperthyroidism. In all of these groups, the thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, total cholesterol, fasting serum glucose, antithyroid peroxidase antibody, antithyroglobulin antibody, and PCSK9 levels were measured. RESULTS: No significant difference was found between the 3 groups in terms of age, gender, and body mass indices. Median PCSK9 measurements were 14.55 ng/mL in Group 1, 14.895 ng/mL in Group 2, and 9.775 ng/mL in Group 3. There was a significant difference in the PCSK9 levels between Group 1-Group 3 and Group 2-Group 3 (p <0.0001 and p <0.0001, respectively). A positive correlation between PCSK9 and the TSH levels (r = 0.211, p= 0.019), and a negative correlation (r = -0,239, p = 0.009 and r = -, 0.218, p = 0.015) between the fT3 and fT4 levels were found. CONCLUSIONS: The serum PCSK9 levels were shown to be associated with thyroid dysfunction. However, no relationship was observed between the serum PCSK9 level and thyroid autoantibody positivity, and obesity in this study. [ABSTRACT FROM AUTHOR]

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OBJECTIVE: Various biomarkers have been studied in the early post-kidney transplantation (post-KTx) period in order to identify potential therapeutic targets for improving long-term graft survival. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a biomarker that has recently gained interest in cardiovascular disease but its role still remains to be defined post-KTx. PATIENTS AND METHODS: We prospectively evaluated the levels of PCSK9, interleukin (IL)-6, WBC and C-reactive protein in seventy-three hemodialysis patients undergoing KTx, at 3 timepoints; pre-transplantation (day 0) and at 1 and 6-months post-KTx. All data were also analyzed according to donor-type (living or deceased) and compared with hemodialysis patients on transplant waiting list. RESULTS: At Day 0 there was no difference in WBC, CRP, IL-6 and PCSK9 levels between patients scheduled for transplantation and those who remained on hemodialysis. In transplanted patients WBC, CRP and IL-6 levels were significantly reduced early post-KTx [logIL-6 Day 0: 0.68 (0.33, 0.85) vs. 1-month: 0.57 (0.37, 0.75) vs. 6-months: 0.50 (0.32, 0.69) pg/ml, p=0.01], while PCSK9 levels were significantly increased (Day 0: 199.8±63.0 vs. 1-month: 276.2±79.4 vs. 6-months: 245.9±62.5 ng/ml, p<0.001). In contrast, no change of WBC, CRP, IL-6 and PCSK9 levels was observed in hemodialysis patients on follow-up (p=NS for all). Between living-donor and deceased-donor recipients, analysis showed reduced CRP and increased PCSK9 levels in both groups (p<0.05 for all), while IL-6 levels were reduced in living-donor and increased in deceased-donor recipients 1-month postKTx. PCSK9 levels were not correlated with renal function, delayed graft function, rejection episodes or inflammatory biomarkers. CONCLUSIONS: PCSK9 levels were increased post-KTx independently from renal function and inflammatory biomarkers, in both living and deceased-donor recipients. [ABSTRACT FROM AUTHOR]

Dysregulated cholesterol metabolism is the major factor responsible for cholesterol gallstones (CGS). Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in cholesterol homeostasis and its inhibitors secure approval for treating various cholesterol metabolic disorders such as hypercholesterolemia and cardiovascular diseases, but its role in CGS remains unclear. Our study aims to clarify mechanisms by which PCSK9 promotes CGS formation and explore the application of the PCSK9 inhibitor, alirocumab, in preventing and treating CGS. The expressions of PCSK9 were notably increased in CGS patients' serum, bile, and liver tissues compared to those without gallstones. Moreover, among CGS patients, hepatic PCSK9 was positively correlated with hepatic cholesterol and negatively correlated with hepatic bile acids (BAs), suggesting PCSK9 was involved in disrupted hepatic cholesterol metabolism related to CGS. Mechanistically, in vitro experiments demonstrated that inhibition of PCSK9 enhanced nuclear expression of PPARα by diminishing its lysosomal degradation and subsequently activated CYP7A1 transcription. Finally, inhibition of PCSK9 prevented CGS formation and dissolved the existing stones in CGS mice by elevating the conversion of cholesterol into BAs through PPARα-mediated CYP7A1 activation. Additionally, serum PCSK9 level may function as a prognostic signature to evaluate the therapeutic efficacy of PCSK9 inhibitors. Inhibition of PCSK9 exerts preventive and therapeutic effects on CGS by activating PPARα-mediated CYP7A1 expression and facilitating the conversion of cholesterol into BAs, which highlights the potential of PCSK9 inhibition as a promising candidate for preventing and treating CGS in clinical applications. PCSK9 plays a pivotal role in cholesterol metabolism and its inhibitors are approved for clinical use in cardiovascular diseases. Our study observes inhibition of PCSK9 prevents and dissolves CGS by activating PPARα-mediated CYP7A1 expression and facilitating the conversion of cholesterol into BAs. Mechanistically, PCSK9 inhibition enhanced the nuclear expression of PPARα by diminishing its lysosomal degradation and subsequently activated CYP7A1 transcription. Our study sheds light on the new function and mechanism of PCSK9 in CGS, providing a novel preventive and therapeutic target with potential clinical applications. [Display omitted] • PCSK9 involves in disrupted hepatic cholesterol metabolic related to CGS. • PCSK9 inhibition enhanced nuclear PPARα by reducing its lysosomal degradation and thus activated CYP7A1 transcription. • PCSK9 inhibition facilitates the conversion of cholesterol into BAs and decreases biliary cholesterol saturation index. • PCSK9 inhibitor, alirocumab, prevents and dissolves CGS by PPARα-mediated CYP7A1 activation. [ABSTRACT FROM AUTHOR]

• Stable CAD patients show higher circulating PCSK9 levels when treated with statins. • CAD patients on statins with high PCSK9 levels show increased classical monocytes. • Conversely, those patients are characterized by reduced non-classical monocytes. • Our results suggest a link between PCSK9 levels and innate immunity in stable CAD. Proprotein convertase subtilisin/kexin type-9 (PCSK9) is an enzyme promoting the degradation of low-density lipoprotein receptors (LDL-R) in hepatocytes. Inhibition of PCSK9 has emerged as a novel target for lipid-lowering therapy. Monocytes are crucially involved in the pathogenesis of atherosclerosis and can be divided into three subsets. The aim of this study was to examine whether circulating levels of PCSK9 are associated with monocyte subsets. We included 69 patients with stable coronary artery disease. PCSK9 levels were measured and monocyte subsets were assessed by flow cytometry and divided into classical monocytes (CD14++CD16-; CM), intermediate monocytes (CD14++CD16+; IM) and non-classical monocytes (CD14+CD16++; NCM). Mean age was 64 years and 80% of patients were male. Patients on statin treatment (n = 55) showed higher PCSK9-levels (245.4 (206.0–305.5) ng/mL) as opposed to those without statin treatment (186.1 (162.3–275.4) ng/mL; p = 0.05). In patients on statin treatment, CM correlated with circulating PCSK9 levels (R = 0.29; p = 0.04), while NCM showed an inverse correlation with PCSK9 levels (R = -0.33; p = 0.02). Patients with PCSK9 levels above the median showed a significantly higher proportion of CM as compared to patients with PCSK9 below the median (83.5 IQR 79.2–86.7 vs. 80.4, IQR 76.5–85.2%; p = 0.05). Conversely, PCSK9 levels >median were associated with a significantly lower proportion of NCM as compared to those with PCSK9

Background and Aims: It remains unclear whether serum PCSK9 levels can predict the severity of the disease and the risk of future events in patients with coronary artery disease (CAD). We aimed to evaluate the association between PCSK9 levels, metabolic parameters, severity of CAD on coronary angiography (SYNTAX score), and the risk of in-hospital events and at one-year follow-up.Methods and Results: From September 2015 to December 2016, serum PCSK9 levels were measured on admission in patients not previously receiving statin therapy, and admitted for an acute myocardial infarction (MI), in an intensive care unit from a university hospital. In a total of 648 patients (mean age: 66 years, 67% male), median PCSK9 was 263 ng/ml, higher for females compared with males (270 vs 256 ng/ml, p = 0.009). Serum PCSK9 was associated with LDL cholesterol (r = 0.083, p = 0.036), total cholesterol (r = 0.136, p = 0.001) and triglycerides (r = 0.137, p = 0.001). A positive association was also observed in the subgroup of patients with CRP >10 mg/L (p < 0.001), but not with NT-proBNP, troponin and creatine kinase. PCSK9 levels were similar whatever the SYNTAX score or the number of significant coronary lesions. PCSK9 levels were not associated with in-hospital events (death, recurrent MI and stroke) and events (cardiovascular death, cardiovascular events, recurrent MI) at one-year follow-up.Conclusions: In this large cohort of patients hospitalized for acute MI and not previously receiving statin therapy, PCSK9 levels was not associated with the severity or the recurrence of cardiovascular events. The clinical utility of measuring PCSK9 levels for this category of patients therefore appears limited. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolemia (FH) is an autosomal dominant disorder mainly caused by mutations in the low-density lipoprotein (LDL) receptor or associated genes, resulting in elevated serum cholesterol levels and an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). We aimed to evaluate the prognostic impact of cascade screening for FH. We retrospectively investigated the health records of 1050 patients with clinically diagnosed FH, including probands and their relatives who were cascade-screened, who were referred to our institute. We used Cox models that were adjusted for established ASCVD risk factors to assess the association between cascade screening and major adverse cardiac events (MACE). The median period of follow-up evaluating MACE was 12.3 years (interquartile ranges [IQR] = 9.1–17.5 years), and MACE included death associated with ASCVD, or acute coronary syndrome. During the observation period, 113 participants experienced MACE. The mean age of patients identified through cascade screening was 18-years younger than that of the probands (38.7 yr vs. 57.0 yr, P < 0.0001), with a lower proportion of ASCVD risk factors. Interestingly, patients identified through cascade screening under milder lipid-lowering therapies were at reduced risk for MACE (hazard ratio [HR] = 0.67; 95%CI = 0.44 to 0.90; P = 0.0044) when compared with the probands, even after adjusting for those known risk factors, including age, and prior ASCVD. The identification of patients with FH via cascade screening appeared to result in better prognosis. • Cascade-screened FH patients were younger than the probands. • Cascade-screened FH patients were under milder LDL-lowering therapies. • Cascade-screened FH patients exhibited better prognosis than the probands. [ABSTRACT FROM AUTHOR]

Background and Aim: Diallyl disulfide (DADS), a volatile sulfide extracted from garlic, has been suggested as a chemical of anti-atherosclerotic drugs, while its molecular mechanism for this benefit has not fully been understood. The aim of the present study was to investigate the effects of DADS on lipid metabolism and its potential mechanisms in HepG2 cells induced by lipopolysaccharides (LPS).Methods and Results: HepG2 cells were treated with LPS with or without different concentrations of DADS (0, 20, 40, 80, 160 μg/ml) for 24 h. The cell activity was detected by CCK8, and Dil-LDL uptake assay was used to examine the LDL uptake. Real-time PCR and Western blot were used to detect the expression of LDLR, PCSK9 SREBP2 and HMGCR. In addition, we examined the effect of the combination of DADS with atorvastatin on PCSK9 expression. The results showed that LPS significantly increased PCSK9 and SREBP2 expressions in a dose-dependent manner in HepG2 cells. DADS attenuated PCSK9, SREBP2 and HMGCR expressions and up-regulated the expression of LDLR. Moreover, DADS reversed the expressions of PCSK9, SREBP2, HMGCR and LDLR induced by LPS and DADS could promote the LDL uptake in HepG2 cells. Furthermore, DADS decreased the expression of PCSK9 by activating the PI3K/Akt-SREBP2 signal pathway. Notably, DADS could reduce PCSK9 expression induced by atorvastatin in HepG2 cells.Conclusion: DADS could significantly attenuated PCSK9 expression in a dose-dependent manner induced by LPS and increased the LDLR expression in HepG2 cells, which was associated with the activation of PI3K/Akt-SREBP2 signaling pathway. [ABSTRACT FROM AUTHOR]

Background and Aims: To investigate the effect of obesity and bariatric-induced weight loss on circulating levels of proprotein convertase subtilisin/kexin 9 (PCSK9) in severely obese patients.Methods and Results: In this non-randomized interventional study, we enrolled 36 severely obese patients (BMI 43.7 ± 5.6 kg/m2), of which 20 underwent bariatric surgery, and 12 nonobese healthy controls. An oral glucose tolerance test (75-g OGTT) was performed in 31 of these obese patients at baseline (T0) and in 14 patients at 6 months after bariatric surgery (T6) to assess plasma glucose, insulin and PCSK9 levels. Plasma PCSK9 levels were also measured in 18 of these obese patients at T0 during a 2-h hyperinsulinemic-euglycemic clamp (HEC). At T0, PCSK9 levels were higher in obese patients than in controls (274.6 ± 76.7 ng/mL vs. 201.4 ± 53.3 ng/mL) and dropped after bariatric surgery (T6; 205.5 ± 51.7 ng/mL) along with BMI (from 44.1 ± 5.9 kg/m2 to 33.1 ± 5.6 kg/m2). At T6, there was also a decrease in plasma glucose (T0 vs. T6: 6.0 ± 1.8 vs. 5.0 ± 0.5 mmol/L) and insulin (15.7 ± 8.3 vs. 5.4 ± 2.1 mU/L) levels. At T0, plasma PCSK9 levels decreased during OGTT in obese patients, reaching a nadir of 262.0 ± 61.4 ng/mL at 120 min with a hyperinsulinemic peak of 75.1 ± 40.0 mU/L, at 60 min. Similarly, at T0 insulin infusion during 2-h HEC acutely reduced plasma PCSK9 levels in obese patients. The aforementioned OGTT-induced changes in plasma PCSK9 levels were not observed neither in nonobese healthy controls nor in obese patients after bariatric-surgery weight loss.Conclusions: These results suggest a pivotal role of adipose tissue and insulin resistance on PCSK9 homeostasis in severely obese patients. [ABSTRACT FROM AUTHOR]

This study examined the status of plasma levels of protein convertase subtilisin/kexin 9 (PCSK9) in association with glucose-and lipid-lowering medications in subjects with type 2 diabetes (T2D). This study comprised 177 diabetics and 115 non-diabetic subjects recruited from the United Arab Emirates National Diabetes Study (UAEDIAB). Clinical and biomedical data were collected by standard techniques. Plasma levels of PCSK9 were determined using ELISA. PCSK9 levels were higher in diabetics than non-diabetics (P < 0.001). Diabetics with disease duration >5 years, HbA1c > 7.0%, or male subjects, had significantly higher levels of PCSK9 than their counterparts (P < 0.05). Regression analysis revealed that HbA1c and age are predictors for PCSK9 in T2D subjects. Diabetic subjects with abnormal lipids profile on lipid-lowering medications had a higher level of PCSK9 compared to those with normal lipids profile (85.6 ± 40.5 vs. 63.7 ± 39.5 ng/ml, respectively; P < 0.01). Diabetics on combined intake of insulin and oral glucose-lowering drugs had higher levels of PCSK9 than those not taking any (86.1 ± 41.6 vs 69.7 ± 36.1 ng/ml, respectively; P < 0.05). The highest levels of PCSK9 however, were in diabetics on combined lipid- and glucose-lowering therapy when compared to those, not on any (96.2 ± 34.0 vs 66.0 ± 35.1 ng/ml, respectively; P < 0.01). Age and HbA1c are the most predictors for the elevated levels of PCSK9 in Emirati T2D subjects. Combined therapy of glucose-and lipid-lowering medications further elevates plasma levels of PCSK9 in diabetic subjects. • PCSK9 levels are higher in type 2 diabetics than non-diabetics. • Age and HbA1c are the most predictors for elevated levels of PCSK9 in type 2 diabetes. • Levels of PCSK9 are influenced by glucose- and lipid-lowering medications. • Combined intake of insulin and statins exacerbate levels of PCSK9 in type 2 diabetes. [ABSTRACT FROM AUTHOR]

• Roux-en-Y gastric bypass (RYGB), but not sleeve gastrectomy, reduces plasma PCSK9 levels. • Plasma PCSK9 changes after RYGB are not associated with changes in LDL-C. • Changes in plasma PCSK9 are correlated with changes in glucose parameters after bariatric surgery. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a master regulator of low-density lipoprotein cholesterol (LDL-C) metabolism, acting as an endogenous inhibitor of the LDL receptor. While it has been shown that bariatric surgery differentially affects plasma LDL-C levels, little is known of its effects on plasma PCSK9 concentrations. Therefore, the present study aimed to: (i) investigate the effect of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on plasma PCSK9 concentrations; and (ii) correlate baseline or postoperative plasma PCSK9 concentration variations with anthropometric and metabolic parameters. Fasting plasma PCSK9 levels were measured by ELISA in morbidly obese patients before and 6 months after bariatric surgery. Patients were recruited from three prospective cohorts (in Nantes and Colombes in France, and Antwerp in Belgium). A total of 156 patients (34 SG, 122 RYGB) were included. Plasma PCSK9 , LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) levels were significantly reduced after RYGB (−19.6%, −16.6% and −19.5%, respectively; P < 0.0001), but not after SG. In all patients, postoperative PCSK9 change was positively correlated with fasting plasma glucose (FPG; r = 0.22, P = 0.007), HOMA-IR (r = 0.24, P = 0.005), total cholesterol (r = 0.17, P = 0.037) and non-HDL-C (r = 0.17, P = 0.038) variations, but not LDL-C. In contrast to what was observed for glucose parameters (FPG, HOMA-IR), correlation between PCSK9 and non-HDL-C changes after RYGB was independent of total weight loss. RYGB, but not SG, promotes a significant reduction in plasma PCSK9 levels, and such changes in circulating PCSK9 levels after RYGB appear to be more associated with glucose improvement than with lipid homoeostasis parameters. [ABSTRACT FROM AUTHOR]

The ODYSSEY CHOICE I study (NCT01926782) evaluated alirocumab 300 mg every 4 weeks (Q4W) in patients with hypercholesterolemia receiving maximally tolerated statin or no statin. The objective of the study was to assess the relationship between alirocumab, proprotein convertase subtilisin/kexin type 9 (PCSK9), and low-density lipoprotein cholesterol (LDL-C) concentrations with the CHOICE I alirocumab dosing regimen. This analysis included 803 patients (547 statin-treated, 256 without statin) who were randomized to alirocumab 300 mg Q4W, alirocumab 75 mg every 2 weeks (Q2W), or placebo. 300 mg Q4W and 75 mg Q2W doses were adjusted to 150 mg Q2W at Week 12 if Week 8 LDL-C was >70 or >100 mg/dL, depending on cardiovascular risk, or if LDL-C reduction was <30% from baseline. Most patients remained on 300 mg Q4W without dose adjustment as they achieved study-defined LDL-C goals at Week 8 (statin-treated: 80.7%; no statin: 85.3%). LDL-C was reduced by 60.5%–71.9% over Weeks 20–24 in patients on 300 mg Q4W and 57.2%–63.0% in patients with dose adjustment from 300 mg Q4W to 150 mg Q2W. Statin-treated patients had higher cardiovascular risk as well as higher free PCSK9 and lower alirocumab concentrations (vs no statin), suggesting increased target-mediated clearance. Regardless of statin status, the most common adverse events in alirocumab-treated patients were injection-site reaction and headache. Data provide further insight on alirocumab's mode of action in terms of relationship between alirocumab, PCSK9, and LDL-C, and disease severity, and support the use of alirocumab 300 mg Q4W as an efficacious dosing regimen for clinically meaningful LDL-C reductions. • Alirocumab, PCSK9, and LDL-C relationships were assessed with alirocumab 300 mg Q4W. • >80% of patients (including those on statins) achieved low-density lipoprotein cholesterol (LDL-C) goals with 300 mg Q4W. • Greater target-mediated clearance of alirocumab suggested in statin-treated patients. • Change to 150 mg Q2W more likely in statin-treated or higher baseline LDL-C patients. • Results provide further insight on alirocumab's mode of action. [ABSTRACT FROM AUTHOR]

Rates of atherosclerotic cardiovascular disease (ASCVD) are strikingly high in India compared to Western countries and are increasing. Moreover, ASCVD events occur at a younger age with only modest hypercholesterolemia, most commonly with low levels of high-density lipoprotein cholesterol. The course of ASCVD also appears to be more fulminant with higher mortality. In light of these issues, the Lipid Association of India (LAI) endeavored to develop revised guidelines with more aggressive low-density lipoprotein cholesterol (LDL-C) goals in secondary prevention and for patients with familial hypercholesterolemia compared to guidelines in the United States and other countries. Owing to the paucity of clinical outcomes data in India, it was necessary to place major emphasis on expert opinion as a complement to randomized placebo-controlled data generated mostly in non-Indian cohorts. To facilitate this process, the LAI conducted a series of 19 meetings among 162 lipid specialists in 13 cities throughout India over a period of 11 months before formulating this expert consensus statement. The LAI recommends an LDL-C goal <50 mg/dL in all patients in secondary prevention or very high-risk primary prevention but proposes an optional goal ≤30 mg/dL in category A extreme-risk patients (eg, coronary artery disease + familial hypercholesterolemia) and a recommended goal ≤30 mg/dL in category B extreme-risk patients [coronary artery disease + (1) diabetes and polyvascular disease/≥3 major ASCVD risk factors/end organ damage, or (2) recurrent acute coronary syndrome within 12 months despite LDL-C <50 mg/dL, or (3) homozygous familial hypercholesterolemia]. More aggressive LDL-C goals are needed for prevention of ASCVD in India, as described in this expert consensus statement. Use of statins and ezetimibe needs to increase in India in combination with improved control of other ASCVD risk factors. Proprotein convertase subtilisin kexin type 9 inhibitors can improve LDL-C goal achievement in patients with refractory hypercholesterolemia. • Atherosclerotic cardiovascular disease events are skyrocketing in India and occur with only modest hypercholesterolemia. • More aggressive low-density lipoprotein cholesterol goals are needed in India, especially in secondary prevention. • Statin and ezetimibe use needs to increase in India. • Proprotein convertase subtilisin kexin type 9 inhibitors can facilitate low-density lipoprotein cholesterol goal achievement, but cost is a barrier. [ABSTRACT FROM AUTHOR]

Background and Aims: In the association between hypercholesterolemia (HC) and thrombotic risk platelet hyper-reactivity plays an important role. The inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) to reduce plasma LDL-cholesterol merges as effective therapeutic strategy to prevent cardiovascular (CV) events. Aim of this study was to verify whether a treatment up to 12 months with the monoclonal antibodies (mAbs) anti-PCSK9 influences platelet function in primary HC.Methods and Results: In patients affected by primary HC (n = 24), all on background of statin and 17 on acetyl salicylic acid (ASA), platelet function parameters were evaluated at baseline up to 12 months of treatment with the mAb anti-PCSK9 alirocumab or evolocumab. From baseline, the treatment with anti-PCSK9 mAbs: i) in ASA HC patients, significantly decreased platelet aggregation detected in platelet-rich plasma by light transmission aggregometry and in whole blood Platelet Function Analyzer-100 assay; ii) in all HC patients, significantly decreased platelet membrane expression of CD62P and plasma levels of the in vivo platelet activation markers soluble CD40 Ligand, Platelet Factor-4, and soluble P-Selectin. Furthermore, CD62P expression, and sP-Selectin, PF-4, sCD40L levels significantly correlated with serum PCSK9.Conclusion: Besides markedly lowering LDL-c levels, our results suggest that HC patients benefit from anti-PCSK9 mAb treatment also for reducing platelet reactivity and increasing platelet sensitivity to the inhibitory effects of aspirin. These effects on platelets could play a role in the reduction of CV event incidence in patients treated with PCSK9 inhibitors. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolemia (FH), an autosomal codominant disorder characterized by very high low-density lipoprotein cholesterol, is strongly associated with premature coronary artery disease. Molecular landscape of FH in Asian Indians is not well studied, although this ethnic group comprises a large proportion of the world population. Knowledge of mutations in these groups is useful for identifying persons affected with FH, saving their lives, and cascade screening in their relatives. Potential cases of FH (n = 100) were identified by criteria adapted for the Indian population from Dutch Lipid Clinic Network criteria. Pathogenic variants were analyzed in LDLR , APOB 100 (exons 26 and 29), PCSK9, and APOE genes using Sanger sequencing and multiplex ligation-dependent probe amplification technique. Cases in whom there were no pathogenic variants were tested by next-generation sequencing using a targeted panel of genes. Thirty-eight pathogenic variants were identified in 47 of 100 unrelated probands. Of these variants, 33 were identified in LDLR , 3 in APOB, and 2 in PCSK9 genes. Ten pathogenic variants were novel. Mutations were detected in 91.4% of those subjects classified as definite, 40% as probable, and in 18.8% as possible FH cases based on modified Dutch Lipid Clinic Network criteria. A likely founder mutation in intron 10 (c.1587-1G>A) of LDLR gene was observed in 6 North Indian families. The conventional pathogenic variants in APOB and PCSK9 genes and those previously reported in LDLR gene among Asian Indians were not detected in this cohort. This study demonstrates genetic heterogeneity of FH in India. The variants observed were different from those described in Western populations. Next-generation sequencing technology helped identify new mutations in APOB gene, suggesting that in less-studied populations, it is better to sequence the whole gene rather than test for specific mutations. • There is paucity of data on genetic studies of FH in Asian Indians. • 100 unrelated cases with clinical suspicion of FH classified using modified DLCN. • Sanger sequencing of LDLR , PCSK9 , 2 fragments of ApoB, and targeted lipid panel by NGS. • 38 different disease-causing mutations (10 novel) identified in 47 unrelated cases. • Mutations identified in the study not reported before in Indians. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9) significantly lower the levels of low-density lipoprotein and very-low-density lipoproteins (VLDL), but their effect on postprandial lipoprotein metabolism in dyslipidemic subjects is unclear. This study aimed to investigate the effects of evolocumab on postprandial lipid responses, ectopic fat depots, whole-body cholesterol synthesis, hepatic lipogenesis, and fat oxidation in patients with type II diabetes. The trial was a single-phase, nonrandomized study of 12-week treatment with evolocumab 140 mg subcutaneously every 2 weeks in 15 patients with type II diabetes on background statin therapy. Cardiometabolic responses to a high-fat mixed meal were assessed before and at the end of the intervention period. Evolocumab treatment reduced significantly postprandial rises in plasma total triglyceride (by 21%; P <.0001) and VLDL 1 triglyceride (by 15%; P =.018), but the increase in chylomicron triglyceride after the meal was not significantly perturbed (P =.053). There were reduced postprandial responses in plasma total apolipoprotein C-III (by 14%; P <.0001) and apolipoprotein B-48 concentration (by 17%; P =.0046) and in "remnant-like particles" cholesterol (by 29%; P <.0001) on the PCSK9 inhibitor. Treatment reduced the steady-state (ie, fasting and postprandial) concentrations of VLDL 2 cholesterol by 50% (P <.0001) and VLDL 2 triglyceride by 29% (P <.0001), in addition to the 78% reduction of low-density lipoprotein cholesterol (P <.001). The changes in apolipoprotein C-III associated significantly with reduction in postprandial responses of remnant-like particles cholesterol and triglyceride-rich lipoprotein cholesterol. Evolocumab therapy did not influence liver fat accumulation, hepatic de novo lipogenesis, or fasting β-hydroxybutyrate but did increase total body cholesterol synthesis (P <.01). Evolocumab treatment improved postprandial responses of triglyceride-rich lipoproteins and measures of cholesterol-enriched remnant particles in type II diabetic subjects. These results indicate that postprandial phenomena need to be taken into account in assessing the full range of actions of PCSK9 inhibitors in dyslipidemic individuals. • Evolocumab treatment improves postprandial responses of triglyceride-rich lipoproteins in type II diabetics. • Evolocumab treatment decreases remnant lipoproteins as well as small very-low-density lipoprotein and low-density lipoprotein. • This reduces atherosclerotic cardiovascular disease risk as the atherogenic potential of remnants equal that of low-density lipoprotein. • It is important to test postprandial responses when evaluating novel drug therapies. [ABSTRACT FROM AUTHOR]

Atherosclerosis (AS) is one of the most critical reasons behind the high morbidity and mortality of cardiovascular diseases. Limited therapeutic options are available to effectively preventing AS. Recently, clustered, regularly interspaced, short palindromic repeat/CRISPR-associated nuclease 9 (CRISPR/Cas9)-based genome-editing technology has shown great potential to permanently silence Pcsk9 gene to decrease cholesterol level and prevent AS. However, due to the poor ability of gene editing and the arising gene off-target, delivering the CRISPR/Cas9 system effectively to the liver for in vivo gene editing of AS is still a challenge. Herein, we reported a non-viral CRISPR/Cas9 delivery nanosystem (PuPGEA/pCas9- Pcsk9) composed of low-toxic and liver-targeting polycation (pullulan-based ethanolamine-modified poly(glycidyl methacrylate), PuPGEA), which can efficiently deliver a plasmid pCas9- Pcsk9 for the knockout of Pcsk9 gene. PuPGEA/pCas9- Pcsk9 nanosystem can effectively knock out Pcsk9 in embryonic liver cells of mice (BNL CL.2) in vitro. Particularly, compared with the control group (linear polycationic without polysaccharide), PuPGEA/pCas9- Pcsk9 nanosystems can effectively target liver and successfully edit Pcsk9 , which contributed to the effective decrease of cholesterol level. Such a targeted therapeutic modality with CRISPR/Cas9 system exhibits impressive performances in preventing the process of AS, providing a programmed strategy for the design of CRISPR/Cas9 treatment system for various genetic liver diseases and vascular diseases. [Display omitted] • The designed CRISPR/Cas9 plasmid can be efficiently delivered into liver by PuPGEA, exhibiting significant cholesterol-lowering and preventing the atherosclerosis deterioration and high liver gene editing efficiency. • It's the first report of a cationic CRISPR/Cas9 delivery system being used for liver gene editing and ASCVD-related treatment. • Such liver-targeting delivery system would provide the reference for treating various genetic liver diseases and related ASCVD. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolemia is characterized by high levels of low-density lipoprotein cholesterol (LDL-C), and causes of familial hypercholesterolemia include apolipoprotein B (APOB) loss-of-function mutations (LOFm) and proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GOFm). The aim of this study was to compare the pharmacokinetics and pharmacodynamics of alirocumab between patients with APOB LOFm vs PCSK9 GOFm. Patients (6 APOB LOFm and 17 PCSK9 GOFm carriers) with LDL-C ≥70 mg/dL on maximally tolerated lipid-lowering therapies received alirocumab 150 mg at Weeks 0, 2, 4, and 6, placebo at Week 8, alirocumab at Week 10, placebo at Weeks 12 and 14, then completed a follow-up period at Week 22. At Week 8, mean ± standard error (SE) alirocumab concentration was lower in APOB LOFm carriers compared with PCSK9 GOFm carriers (12.12 ± 1.81 vs 16.74 ± 2.53 mg/L). APOB LOFm carriers had higher mean ± SE total PCSK9 (6.56 ± 0.73 mg/L) and lower mean ± SE free PCSK9 (0.025 ± 0.016 mg/L) at Week 8 compared with PCSK9 GOFm carriers (4.21 ± 0.35 and 0.11 ± 0.035 mg/L for total and free PCSK9, respectively). Despite this observed greater PCSK9 suppression, mean ± SE percent LDL-C reduction was lower in APOB LOFm (55.3 ± 1.0%) compared with PCSK9 GOFm carriers (73.1 ± 0.9%). Treatment-emergent adverse events occurred in 16 patients (94.1%) in the PCSK9 GOFm group and 5 patients (83.3%) in the APOB LOFm group. Overall, PCSK9 inhibition with alirocumab results in clinically meaningful reductions in LDL-C in both APOB LOFm and PCSK9 GOFm carriers, although reductions were greater in the PCSK9 GOFm carriers. The results indicate a possible underlying contributor to hypercholesterolemia other than PCSK9 in patients with APOB LOFm. NCT01604824; clinicaltrials.gov. • For the apolipoprotein B (APOB) loss-of-function mutations (LOFm) group, mean low-density lipoprotein cholesterol reduction from baseline was 55.3% at Week 8. • For the proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GOFm) group, mean low-density lipoprotein cholesterol reduction from baseline was 73.1% at Week 8. • At Week 8, alirocumab levels were lower in APOB LOFm vs PCSK9 GOFm carriers. • PCSK9 suppression by alirocumab was greater in APOB LOFm vs PCSK9 GOFm carriers. • Treatment-emergent adverse events occurred in 94.1% and 83.3% of PCSK9 GOFm and APOB LOFm groups, respectively. [ABSTRACT FROM AUTHOR]

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. A novel series of tetrahydroprotoberberine derivatives (THPBs) were designed, synthesized, and evaluated as PCSK9 modulators for the treatment of hyperlipidemia. Compound 22 demonstrated significant reductions of TC and LDL-C in hyperlipidemic hamsters, which is a promising lead compound for the development of PCSK9 modulator for the treatment of hyperlipidemia. Image 1 [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the role of coronary artery calcium (CAC) as a predictor of atherosclerotic cardiovascular disease (ASCVD) (fatal or not myocardial infarction, stroke, unstable angina requiring revascularization, and elective myocardial revascularization) events in asymptomatic primary prevention molecularly proven heterozygous familial hypercholesterolemia (FH) subjects receiving standard lipid-lowering therapy. FH is associated with premature ASCVD. However, the clinical course of ASCVD in subjects with FH is heterogeneous. CAC score, a marker of subclinical atherosclerosis burden, may optimize ASCVD risk stratification in FH. Subjects with FH underwent CAC measurement and were followed prospectively. The association of CAC with ASCVD was evaluated using multivariate analysis. A total of 206 subjects (mean age 45 ± 14 years, 36.4% men, baseline and on-treatment low-density lipoprotein cholesterol 269 ± 70 mg/dl and 150 ± 56 mg/dl, respectively) were followed for a median of 3.7 years (interquartile range: 2.7 to 6.8 years). CAC was present in 105 (51%), and 15 ASCVD events (7.2%) were documented. Almost one-half of events were hard outcomes, and the others were elective myocardial revascularizations. The annualized rates of events per 1,000 patients for CAC scores of 0 (n = 101 [49%]), 1 to 100 (n = 62 [30%]) and >100 (n = 43 [21%]) were, respectively, 0, 26.4 (95% confidence interval: 12.9 to 51.8), and 44.1 (95% confidence interval, 26.0 to 104.1). In multivariate Cox regression analysis, log(CAC score + 1) was independently associated with incident ASCVD events (hazard ratio: 3.33; 95% CI: 1.635 to 6.790; p = 0.001). CAC was independently associated with ASCVD events in patients with FH receiving standard lipid-lowering therapy. This may help further stratify near-term risk in patients who might be candidates for further treatment with newer therapies. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolemia (FH) is a frequent genetic disorder characterized by elevated low-density lipoprotein (LDL)-cholesterol (LDL-C) levels and early onset of atherosclerotic cardiovascular disease. FH is caused by mutations in genes that regulate LDL catabolism, mainly the LDL receptor (LDLR), apolipoprotein B (APOB) and gain of function of proprotein convertase subtilisin kexin type 9 (PCSK9). However, the phenotype may be encountered in individuals not carrying the latter monogenic defects, in approximately 20% of these effects of polygenes predominate, and in many individuals no molecular defects are encountered at all. These so-called FH phenocopy individuals have an elevated atherosclerotic cardiovascular disease risk in comparison with normolipidemic individuals but this risk is lower than in those with monogenic disease. Individuals with FH are exposed to elevated LDL-C levels since birth and this explains the high cardiovascular, mainly coronary heart disease, burden of these subjects. However, recent studies show that this risk is heterogenous and depends not only on high LDL-C levels but also on presence of previous cardiovascular disease, a monogenic cause, male sex, smoking, hypertension, diabetes, low HDL-cholesterol, obesity and elevated lipoprotein(a). This heterogeneity in risk can be captured by risk equations like one from the SAFEHEART cohort and by detection of subclinical coronary atherosclerosis. High dose high potency statins are the main stain for LDL-C lowering in FH, however, in most situations these medications are not powered enough to reduce cholesterol to adequate levels. Ezetimibe and PCSK9 inhibitors should also be used in order to better treat LDL-C in FH patients. [ABSTRACT FROM AUTHOR]

Age, smoking, hypercholesterolemia, and hypertension are major risk factors for atherosclerotic cardiovascular disease. We examined whether the effects of alirocumab on low-density lipoprotein cholesterol (LDL-C) differed according to age, hypertension, or smoking status. Data were pooled from 10 Phase 3 ODYSSEY randomized trials (24–104 weeks' duration) in 4983 people with heterozygous familial hypercholesterolemia (FH) or non–familial hypercholesterolemia (3188 on alirocumab, 1795 on control [620 on ezetimibe and 1175 on placebo]). Most participants received concomitant maximum tolerated statin therapy. In 8 trials, the alirocumab dose was increased from 75 mg every 2 weeks (Q2W) to 150 mg Q2W at Week 12 if predefined risk-based LDL-C goals were not achieved at Week 8 (≥70 mg/dL in very high cardiovascular risk; ≥100 mg/dL in moderate or high cardiovascular risk). Two trials compared alirocumab 150 mg Q2W vs placebo. The efficacy and safety of alirocumab were assessed post hoc in subgroups stratified by age (<65, ≥65 to <75, ≥75 years) and baseline hypertension or smoking status. Alirocumab reduced LDL-C by 23.7% (75/150 mg vs ezetimibe + statin) to 65.4% (150 mg vs placebo + statin) from baseline to Week 24 vs control. Subgroup analyses confirmed no significant interactions in response to alirocumab between age group, hypertension, or smoking status. Overall rates of treatment-emergent adverse events were similar between alirocumab and control groups. In this pooled analysis from 10 trials, alirocumab led to substantial LDL-C reductions vs control in every age group and regardless of hypertension or smoking status. Alirocumab was well tolerated in all subgroups. • Alirocumab substantially reduced low-density lipoprotein cholesterol in adults aged <65, ≥65 to <75, ≥75 years. • Alirocumab substantially reduced low-density lipoprotein cholesterol, regardless of hypertension or smoking. • Alirocumab was well tolerated in all subgroups. [ABSTRACT FROM AUTHOR]

Background and Aim: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is rapidly gaining attention as a potential risk of developing atherosclerosis due to its crucial role in the regulation of low-density lipoprotein cholesterol (LDL-C) metabolism. The present study investigated the relationship between serum PCSK9 levels and early atherosclerosis as assessed by carotid intimal-medial thickness (CIMT) and brachial-ankle pulse wave velocity (ba-PWV) in newly diagnosed type 2 diabetes mellitus (T2DM).Methods and Results: A total of 100 newly diagnosed T2DM were enrolled and further divided into the thickened CIMT group (n = 41) and the non-thickened CIMT group (n = 59) according to the results of color Doppler ultrasonography. Serum PCSK9 levels, CIMT, ba-PWV, and metabolic parameters were measured. Patients in the thickened CIMT group had higher serum PCSK9 levels than patients in the non-thickened CIMT group (all P < 0.05). CIMT and ba-PWV were both positively correlated to serum PCSK9 levels, while serum PCSK9 levels were positively correlated to white blood cell count, neutrophil, lymphocyte, and high-sensitivity C-reactive protein (P < 0.05). Multiple linear regression indicated that serum PCSK9 level was an independent predictor of CIMT (β = 0.637, P < 0.001) and ba-PWV (β = 0.600, P < 0.001). Binary logistic regression analysis showed that serum PCSK9 levels were independent risk factors of thickened CIMT [OR = 1.120, 95%CI (1.041-1.204), P = 0.002].Conclusion: Serum PCSK9 levels are significantly correlated with CIMT and ba-PWV, independent of CAD risk factors. Therefore, serum PCSK9 level may have the potential to serve as a prescriptive biomarker for early arteriosclerosis in newly diagnosed T2DM. [ABSTRACT FROM AUTHOR]

Purpose: To investigate associations for polymorphisms in β-carotene 9',10'-oxygenase (BCO2, rs10431036 and rs11214109), proprotein convertase subtilisin kexin type 9 (PCSK9, rs11583680), and tribbles pseudokinase 1 (TRIB1, rs17321515 and rs2954029), as well as lifestyle factors, with ischemic stroke (IS). Materials and Methods: This nested case-control study included 161 patients with IS and 483 matched control individuals. We collected medical reports, lifestyle details, and blood samples from individuals and used the PCR-ligase detection reaction method to genotype single nucleotide polymorphisms (SNPs). Results: The GA+AA genotype of rs10431036 (p<0.001) and rs17321515 (p=0.003), the CT+TT genotype of rs11214109 (p=0.005), and the TA+AA genotype of rs2954029 (p=0.006) in dominant models increased the risk of IS. In additive models, the GG genotype of rs17321515 (p=0.005) and the TT genotype of rs2954029 (p=0.008) increased the risk of IS. Adequate intake of fruits/vegetables reduced the risk of IS (p=0.005). Although there was no interaction between genes and fruits/vegetables, people with inadequate intake of fruits/vegetables who carried a risk genotype had a higher risk of IS than those only having inadequate fruits/vegetables intake or those only carrying a risk genotype. Also, the haplotypes AC, AT, and GT (comprising rs10431036 and rs11214109) and GT (comprising rs2954029 and rs17321515) were found to be associated with an increased risk of IS (p<0.05). Conclusion: Polymorphisms in BCO2 and TRIB1 and fruits/vegetables intake were associated with IS. These results provide the theoretical basis for gene screening to prevent chronic cerebrovascular diseases. [ABSTRACT FROM AUTHOR]

Patients with prior cardiovascular events are at very high risk of recurrent events and may benefit from low-density lipoprotein cholesterol (LDL-C) lowering beyond that achieved with maximally tolerated statins. To assess potential differences between the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor, alirocumab, in patients with vs without prior myocardial infarction (MI)/ischemic stroke. Data (n = 4880) were pooled from nine ODYSSEY phase 3 trials of alirocumab 75/150 mg or 150 mg every 2 weeks, mostly on background statins ± other lipid-lowering therapies. Analyses were performed according to statin status, alirocumab dose, and control (placebo or ezetimibe). Baseline LDL-C, non–high-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and apolipoprotein B levels were lower and lipoprotein(a) higher in patients with than without prior MI/ischemic stroke. LDL-C levels were reduced from baseline to week 24 in patients with (51.1%–62.9%) and without (43.6%–58.3%) prior MI/ischemic stroke, with no significant interaction between prior MI/ischemic stroke status and LDL-C–lowering efficacy of alirocumab vs controls. Alirocumab significantly reduced other lipid/lipoproteins (including lipoprotein[a]) similarly in patients with/without MI/ischemic stroke. Week 24 LDL-C goal attainment rates for subgroups with/without prior MI/ischemic stroke on background statins were 74.1%–84.8% and 63.7%–74.7%, respectively. The safety profile of alirocumab was generally similar regardless of prior MI/ischemic stroke status. Alirocumab significantly reduced LDL-C and other atherogenic lipids/lipoproteins in patients with prior MI/ischemic stroke, and the majority of this very high cardiovascular risk population achieved LDL-C goals; efficacy and safety results were similar in patients without prior MI/ischemic stroke. • Analysis of alirocumab ODYSSEY trials by MI/ischemic stroke status (with/without). • Alirocumab reduced LDL-C in patients with or without MI/ischemic stroke. • Alirocumab reduced lipoprotein(a) regardless of MI/ischemic stroke status. • Most patients with/without prior MI/ischemic stroke attained LDL-C goals. • Alirocumab's safety profile was generally similar regardless of prior MI/ischemic stroke. [ABSTRACT FROM AUTHOR]

Abstract Objective Low-density lipoprotein cholesterol (LDL-C) is the hallmark of atherosclerotic cardiovascular diseases. The hepatic LDL receptor (LDLR) plays an important role in clearance of circulating LDL-C. PCSK9 facilitates degradation of LDLR in the lysosome and antagonizing PCSK9 has been successfully used in the clinic to reduce blood LDL-C level. Here we identify a new player that modulates LDLR interaction with PCSK9, thus controlling LDLR degradation and cholesterol homeostasis. Methods The blood LDL-C and cholesterol levels were analyzed in mice with hepatic deletion of Paqr3 gene. The half-life of LDLR was analyzed in HepG2 cells. The interaction of PAQR3 with LDLR and PCSK9 was analyzed by co-immunoprecipitation and immunofluorescent staining. Results The blood LDL-C and total cholesterol levels in the mice with hepatic deletion of Paqr3 gene were significantly lower than the control mice after feeding with high-fat diet (p < 0.001 and p < 0.05 respectively). The steady-state level of LDLR protein is elevated by Paqr3 knockdown/deletion and reduced by PAQR3 overexpression. The half-life of LDLR protein is increased by Paqr3 knockdown and accelerated by PAQR3 overexpression. PAQR3 interacts with the β-sheet domain of LDLR and the P-domain of PCSK9 respectively. In addition, PAQR3 can be localized in early endosomes and colocalized with LDLR, PCSK9 and LDL. Mechanistically, PAQR3 enhances the interaction between LDLR and PCSK9. Conclusion Our study reveals that PAQR3 plays a pivotal role in controlling hepatic LDLR degradation and blood LDL-C level via modulating LDLR-PCSK9 interaction. Highlights • The blood LDL and cholesterol levels are reduced by hepatic deletion of Paqr3 gene in the mice. • PAQR3 affects the steady-state level and half-life of LDLR protein. • PAQR3 interacts and colocalizes with both LDLR and PCSK9. • PAQR3 enhances the interaction between LDLR and PCSK9 to control the degradation of LDLR. [ABSTRACT FROM AUTHOR]

Access to proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors that lower low-density lipoprotein cholesterol in patients at high risk of atherosclerotic cardiovascular disease events has proven challenging. Methods to overcome access barriers are needed to fully realize the benefits of these novel agents. This study evaluated medication access rates in patients prescribed a PCSK9 inhibitor at a health care system with integrated specialty pharmacy services. We performed a single-center, ambispective cohort study of patients prescribed a PCSK9 inhibitor between September 2015 and December 2016 at Vanderbilt University Medical Center outpatient clinics. The primary end point was the percentage of PCSK9 inhibitor prescriptions resulting in access of the total prescriptions triaged to Vanderbilt Specialty Pharmacy. Secondary end points assessed among patients approved for therapy included time between benefits investigation and insurance approval, financial assistance use, and treatment initiation rates. Two hundred ninety-nine patients met inclusion criteria (average age = 63 years). Forty-six percent were female, 57% held commercial insurance, and 70% had an atherosclerotic cardiovascular disease indication. Overall, 96% of prescriptions resulted in access to a PCSK9 inhibitor. Most patients were approved with an initial prior authorization (58%) or after one appeal (29%). The median time to approval was 8 days. Among patients approved for therapy, 53% received financial assistance and 94% initiated therapy. An integrated specialty pharmacy service model in outpatient clinics produced high rates of PCSK9 inhibitor therapy access and initiation. This high level of access supports this model as a best practice for prescribing PCSK9 inhibitor therapy. • High rates of PCSK9 inhibitor access and initiation are possible. • An integrated specialty pharmacy successfully facilitates treatment access. • ASCVD and government insurance were negatively associated with time to access. [ABSTRACT FROM AUTHOR]

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been found to play a major role in atherosclerotic cardiovascular disease (ASCVD) by promoting hyperlipidemia. Its inhibition has therefore emerged as a viable drug target for improving the outcome of ASCVD. However, current monoclonal antibody PCSK9 inhibitors are considered cost ineffective and there is the need to discover new effective and cheaper small molecule alternatives.Purpose: The methanolic and ethanolic crude extracts of Nauclea latifolia have been shown to possess anti-hyperlipidemic activity, but the chemical component(s) responsible for this activity and the mechanism of action have remained unknown. The objective of this study was therefore to identify N. latifolia constituents with anti-hyperlipidemic activity and to investigate the inhibition of PCSK9 as a probable mechanism of action.Method: In the present study, compounds were isolated from the ethanolic extract of the stem of N. latifolia. The alkaloids were evaluated for their DiI-LDL uptake promoting activity in HepG2 cell. The most active compound was further assessed for its effect on low density lipoprotein receptor (LDLR) and PCSK9 protein expressions by western blot.Results: 3R-3,14-dihydroangustoline (5), showed a relatively good activity in promoting LDL uptake (1.26-fold). It further increased LDLR protein expression and decreased the protein expression of PCSK9 in a dose dependent manner (1-50  µM).Conclusion: Alkaloids from N. latifolia may serve as a source of new PCSK9 inhibitors. [ABSTRACT FROM AUTHOR]

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Abstract Obesity, a pandemic of the modern world, is intimately associated with dyslipidemia, which is mainly driven by the effects of insulin resistance and pro-inflammatory adipokines. However, recent evidence suggests that obesity-induced dyslipidemia is not a unique pathophysiological entity, but rather has distinct characteristics depending on many individual factors. In line with that, in a subgroup of metabolically healthy obese (MHO) individuals, dyslipidemia is less prominent or even absent. In this review, we will address the main characteristics of dyslipidemia and mechanisms that induce its development in obesity. The fields, which should be further investigated to expand our knowledge on obesity-related dyslipidemia and potentially yield new strategies for prevention and management of cardiometabolic risk, will be highlighted. Also, we will discuss recent findings on novel lipid biomarkers in obesity, in particular proprotein convertase subtilisin/kexin type 9 (PCSK9), as the key molecule that regulates metabolism of low-density lipoproteins (LDL), and sphingosine-1-phosphate (S1P), as one of the most important mediators of high-density lipoprotein (HDL) particles function. Special attention will be given to microRNAs and their potential use as biomarkers of obesity-associated dyslipidemia. Highlights • Obesity is mainly driven by insulin resistance and pro-inflammatory adipokines. • Vitamin D deficiency affects adipose tissue function and lipid status in obesity. • Metabolically healthy obesity is characterised by a favorable lipid profile. • Further data on PCSK9 and S1P in obesity might upgrade therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background Patients with heterozygous familial hypercholesterolemia (HeFH) who completed the double-blind ODYSSEY LONG TERM parent trial and subsequently enrolled in the open-label extension (OLE) study, ODYSSEY OLE (NCT01954394), provide a unique opportunity to investigate effects of 2 doses of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, within the same patient cohort. Objective The aim of the study was to characterize long-term efficacy and safety of 2 alirocumab dosages and utility of a dose titration strategy in patients with HeFH. Methods After an 8-week washout period, patients with HeFH who completed the LONG TERM study (receiving alirocumab 150 mg every 2 weeks [Q2W]) were eligible to enroll in OLE (n = 214) for up to 40 months' treatment duration. In OLE, patients started on alirocumab 75 mg Q2W. From Week 12, dose adjustment from 75 to 150 mg Q2W or vice versa was possible based on physician's clinical judgment. Results During the LONG TERM trial, alirocumab 150 mg Q2W reduced mean low-density lipoprotein cholesterol (LDL-C) from baseline (162.3 mg/dL) to Week 8 by 63.1%; during OLE, alirocumab 75 mg Q2W reduced mean LDL-C from baseline (166.6 mg/dL) by 47.3% within the same patient cohort. At Week 96, mean LDL-C reduction from OLE baseline was 55.4% vs 46.8% for patients with or without alirocumab dose increase, respectively. Treatment-emergent adverse events leading to permanent treatment discontinuation were observed in 4 patients (1.9%). Conclusions In patients with HeFH, both alirocumab dosages provided consistent LDL-C reductions over a treatment duration of up to 4 years (including 1.5 years of the LONG TERM trial), allowing an individualized approach to LDL-C lowering, depending on baseline LDL-C levels. Graphical abstract Highlights • Alirocumab 150 mg Q2W reduced low-density lipoprotein cholesterol (LDL-C) by 63.1% at Week 8 of LONG TERM trial (HeFH cohort). • Alirocumab 75 mg Q2W reduced LDL-C by 47.3% at Week 8 of OLE (same cohort, n = 214). • Choice of alirocumab dose allowed for an individualized approach to LDL-C lowering. • Alirocumab provided steady LDL-C reductions over ≤3 years of treatment. • Treatment-emergent adverse events leading to treatment discontinuation occurred in 4 patients (1.9%) [ABSTRACT FROM AUTHOR]