Proprotein Convertase Subtilisin Kexin Research Articles

The Gulf Achievement of Cholesterol Targets in Out-Patients Study (GULF ACTION): Design, Rationale, and Preliminary Results.

To assess the current dyslipidemia management in the Arabian Gulf region by describing the demographics, study design, and preliminary results of out-patients who achieved low-density lipoprotein cholesterol (LDL-C) goals at the time of the survey. The Arabian Gulf population is at high risk for atherosclerotic cardiovascular disease at younger ages. There is no up-to-date study regarding dyslipidemia management in this region, especially given the recent guideline-recommended LDL-C targets. Up-to-date comprehensive assessment of the current dyslipidemia management in the Arabian Gulf region, particularly in view of the recent evidence of the additive beneficial effects of ezetimibe and proprotein convertase subtilisin/kexin-9 (PCSK-9) inhibitors on LDL-C levels and cardiovascular outcomes. The Gulf Achievement of Cholesterol Targets in Out-Patients (GULF ACTION) is an ongoing national observational longitudinal registry of 3000 patients. In this study, adults ≥18 years on lipid-lowering drugs for over three months from out-patients of five Gulf countries were enrolled between January 2020 and May 2022 with planned six-month and one-year follow-ups. Of the 1015 patients enrolled, 71% were male, aged 57.9±12 years. In addition, 68% had atherosclerotic cardiovascular disease (ASCVD), 25% of these patients achieved the LDL-C target, and 26% of the cohort were treated using combined lipid-lowering drugs, including statins. The preliminary results of this cohort revealed that only one-fourth of ASCVD patients achieved LDL-C targets. Therefore, GULF ACTION shall improve our understanding of current dyslipidemia management and "guideline gaps" in the Arabian Gulf region.

Evidence of an anti-inflammatory effect of PCSK9 inhibitors within the human atherosclerotic plaque

Background and aimsPreclinical evidence suggests that proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors hold anti-inflammatory properties independently of their ability to lower LDL-cholesterol (C). However, whether PCSK9 inhibitors exert anti-inflammatory effects within the atherosclerotic plaque in humans is unknown. We explored the impact of PCSK9 inhibitors, used as monotherapy, compared with other lipid-lowering drugs (oLLD) on the expression of inflammatory markers within the plaque, assessing also the subsequent incidence of cardiovascular events. MethodsIn an observational study, we recruited 645 patients on stable therapy for at least six months and undergoing carotid endarterectomy, categorizing patients according to the use of PCSK9 inhibitors only (n = 159) or oLLD (n = 486). We evaluated the expression of NLRP3, caspase-1, IL-1β, TNFα, NF-kB, PCSK9, SIRT3, CD68, MMP-9, and collagen within the plaques in the two groups through immunohistochemistry, ELISA, or immunoblot. A composite outcome including non-fatal myocardial infarction, non-fatal stroke, and all-cause mortality was assessed during a 678 ± 120 days follow-up after the procedure. ResultsPatients treated with PCSK9 inhibitors had a lower expression of pro-inflammatory proteins and a higher abundance of SIRT3 and collagen within the plaque, a result obtained despite comparable levels of circulating hs-CRP and observed also in LDL-C-matched subgroups with LDL-C levels <100 mg/dL. Patients treated with PCSK9 inhibitors showed a decreased risk of developing the outcome compared with patients on oLLD, also after adjustment for multiple variables including LDL-C (adjusted hazard ratio 0.262; 95% CI 0.131–0.524; p < 0.001). The expression of PCSK9 correlated positively with that of pro-inflammatory proteins, which burden was associated with a higher risk of developing the outcome, independently of the therapeutic regimen. ConclusionsThe use of PCSK9 inhibitors is accompanied by a beneficial remodelling of the inflammatory burden within the human atheroma, an effect possibly or partly independent of their LDL-C lowering ability. This phenomenon might provide an additional cardiovascular benefit.

Role of Different Low-Density Lipoprotein-Lowering Medications on Secondary Prevention of Atherosclerotic Cardiovascular Disease in Patients With Diabetes Mellitus.

Purpose The objective of this study was to explore the optimal cholesterol-lowering therapy for diabetic patients categorized as having a very high risk for future atherosclerotic cardiovascular disease (ASCVD) events. The primary medications under investigation were statins, ezetimibe, and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors (PCSK9-Is). The efficacy of different medication regimens helped to draw conclusions regarding the evolution of cholesterol management recommended under the American College of Cardiology's (ACC) 2013 and 2018 guidelines. Methods A retrospective chart review was conducted on a cohort of patients from a large, community-based cardiology practice. Inclusion criteria specified patients aged 30-82 with a past medical history of two or more ASCVD events or one ASCVD event and at least two high-risk comorbidities. Acquired data included demographics, all lipid panels, medications used, and ASCVD events between December 1, 2013, and December 31, 2019. The data were stored and encrypted on a REDCap account. Sub-group analysis was conducted on only diabetic patients, who were then categorized by medication regimen. The statistical analysis was completed using Fisher's exact test. A p-value <0.05 was considered significant. Results A total of 102 diabetic patients met the inclusion criteria. Our primary analysis determined the percentage of patients who achieved their goals on each medication regimen. The goal was defined as a low-density lipoprotein cholesterol (LDL-C) level of less than 70 mg/dL or at least a 50% reduction from baseline levels. The results are as follows: none (0%), statin (33.9%), ezetimibe (21.1%), statin + ezetimibe (73.5%), PCSK9-Is ± statin (83.3%), and PCSK9-Is and ezetimibe ± statin (100%). There proved to be a significant difference favoring all combination regimens over statins alone; however, there was no significant difference between these advanced regimens. A follow-up analysis determined if these patients were able to maintain their goals in the subsequent lipid panel after achieving their goals. The results are as follows: none (0%), statin (61.5%), ezetimibe (50%), statin + ezetimibe (77.8%), PCSK9-Is ± statin (100%), and PCSK9-Is and ezetimibe ± statin (66.6%). The only significant difference found was between PCSK9-Is ± statins and statins alone. Conclusions Our study revealed that regimens using PCSK9 inhibitors and ezetimibe, in addition to maximally tolerated statin therapy, were more effective than statin therapy alone in achieving the goal. On extended analysis, only PCSK9 inhibitors showed superior ability in terms of maintaining the goals for diabetic patients at very high risk for future ASCVD events. This implies that statins alone may be inadequate to properly treat this specific patient population. In the context of clinical practice, physicians could have heightened consideration for dual therapy consisting of maximally tolerated statins and a secondary agent in accordance with the 2018 ACC guidelines.

Effect of alirocumab on cataracts in patients with acute coronary syndromes

BackgroundSome data suggest that low levels of low-density lipoprotein cholesterol (LDL-C) are associated with risk of cataracts. Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors reduce LDL-C below levels achieved with statins alone. We determined whether the incidence of cataracts was influenced by treatment with the PCSK9 inhibitor alirocumab versus placebo, and whether that incidence was affected by achieved LDL-C levels.MethodsThe ODYSSEY OUTCOMES trial (NCT01663402) compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome receiving high-intensity or maximum-tolerated statin. Incident cataracts were pre-specified events of interest. In multivariable analysis using propensity score-matching on characteristics including cataract risk factors, incident cataracts were compared in the alirocumab and placebo groups according to LDL-C levels achieved with alirocumab.ResultsOver median follow-up of 2.8 years (interquartile range 2.3 − 3.4), the incidence of cataracts was similar with alirocumab (127/9462 [1.3%]) versus placebo (134/9462 [1.4%]); hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.74 − 1.20). In patients treated with alirocumab with ≥ 2 LDL-C values < 25 mg/dL (0.65 mmol/L), the incidence of cataracts was 71/4305 (1.6%), versus 60/4305 (1.4%) in propensity score-matched patients from the placebo group (HR 1.10, CI 95% 0.78 − 1.55). In patients treated with alirocumab with ≥ 2 LDL-C values < 15 mg/dL (0.39 mmol/L), the incidence of cataracts was 13/782 (1.7%), versus 36/2346 (1.5%) in matched patients from the placebo group (HR 1.03, CI 95% 0.54 − 1.94).ConclusionTreatment with alirocumab versus placebo, added to statin, did not influence the incidence of cataracts, even when achieved LDL-C levels on alirocumab were very low. Longer follow-up studies might be necessary to exclude the long-term effects on the incidence or progression of cataracts.Trial registrationClinicalTrials.gov Identifier: NCT01663402.

Obicetrapib plus ezetimibe as an adjunct to high-intensity statin therapy: A randomized phase 2 trial

Obicetrapib, a selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein particles, and apolipoproteins, when added to high-intensity statin in patients with dyslipidemia. To evaluate the safety and lipid-altering efficacy of obicetrapib plus ezetimibe combination therapy as an adjunct to high-intensity statin therapy. This double-blind, randomized, phase 2 trial administered 10mg obicetrapib plus 10mg ezetimibe (n=40), 10mg obicetrapib (n=39), or placebo (n=40) for 12 weeks to patients with LDL-C >70mg/dL and triglycerides (TG) <400mg/dL, on stable high-intensity statin. Endpoints included concentrations of lipids, apolipoproteins, lipoprotein particles, and proprotein convertase subtilisin kexin type 9 (PCSK9), safety, and tolerability. Ninety-seven patients were included in the primary analysis (mean age 62.6 years, 63.9% male, 84.5% white, average body mass index of 30.9kg/m2). LDL-C decreased from baseline to week 12 by 63.4%, 43.5%, and 6.35% in combination, monotherapy, and placebo groups, respectively (p<0.0001vs. placebo). LDL-C levels of <100, <70, and <55mg/dL were achieved by 100%, 93.5%, and 87.1%, respectively, of patients taking the combination. Both active treatments also significantly reduced concentrations of non-HDL-C, apolipoprotein B, and total and small LDL particles. Obicetrapib was well tolerated and no safety issues were identified. The combination of obicetrapib plus ezetimibe significantly lowered atherogenic lipid and lipoprotein parameters, and was safe and well tolerated when administered on top of high-intensity statin to patients with elevated LDL-C.

Computational Design, Synthesis, and Biological Evaluation of Diimidazole Analogues Endowed with Dual PCSK9/HMG-CoAR-Inhibiting Activity.

Proprotein convertase subtilisin/kexin 9 (PCSK9) is responsible for the degradation of the hepatic low-density lipoprotein receptor (LDLR), which regulates circulating cholesterol levels. Consequently, the PCSK9 inhibition is a valuable therapeutic approach for the treatment of hypercholesterolemia and cardiovascular diseases. In our studies, we discovered Rim13, a polyimidazole derivative reducing the protein-protein interaction between PCSK9 and LDLR with an IC50 of 1.6 μM. The computational design led to the optimization of the shape of the PCSK9/ligand complementarity, enabling the discovery of potent diimidazole derivatives. In fact, carrying out biological assays to fully characterize the cholesterol-lowering activity of the new analogues and using both biochemical and cellular techniques, compound Dim16 displayed improved PCSK9 inhibitory activity (IC50 0.9 nM). Interestingly, similar to other lupin-derived peptides and their synthetic analogues, some compounds in this series showed dual hypocholesterolemic activity since some of them complementarily inhibited the 3-hydroxy-3-methylglutaryl coenzyme A reductase.

Immune Regulation of the Liver Through the PCSK9/CD36 Pathway During Heart Transplant Rejection.

PCSK9 (proprotein convertase subtilisin/kexin 9), which is mainly secreted by the liver, is not only a therapeutic target for hyperlipidemia and cardiovascular disease, but also has been implicated in the immune regulation of infections and tumors. However, the role of PCSK9 and the liver in heart transplant rejection (HTR) and the underlying mechanisms remain unclear. We assessed serum PCSK9 expression in both murine and human recipients during HTR and investigated the effect of PCSK9 ablation on HTR by using global knockout mice and a neutralizing antibody. Moreover, we performed multiorgan histological and transcriptome analyses, and multiomics and single-cell RNA-sequencing studies of the liver during HTR, as well. We further used hepatocyte-specific Pcsk9 knockout mice to investigate whether the liver regulated HTR through PCSK9. Last, we explored the regulatory effect of the PCSK9/CD36 pathway on the phenotype and function of macrophages in vitro and in vivo. Here, we report that murine and human recipients have high serum PCSK9 levels during HTR. PCSK9 ablation prolonged cardiac allograft survival and attenuated the infiltration of inflammatory cells in the graft and the expansion of alloreactive T cells in the spleen. Next, we demonstrated that PCSK9 was mainly produced and significantly upregulated in the recipient liver, which also showed a series of signaling changes, including changes in the TNF-α (tumor necrosis factor α) and IFN-γ (interferon γ) signaling pathways and the bile acid and fatty acid metabolism pathways. We found mechanistically that TNF-α and IFN-γ synergistically promoted PCSK9 expression in hepatocytes through the transcription factor SREBP2 (sterol regulatory element binding protein 2). Moreover, in vitro and in vivo studies indicated that PCSK9 inhibited CD36 expression and fatty acid uptake by macrophages and strengthened the proinflammatory phenotype, which facilitated their ability to promote proliferation and IFN-γ production by donor-reactive T cells. Last, we found that the protective effect of PCSK9 ablation against HTR is dependent on the CD36 pathway in the recipient. This study reveals a novel mechanism for immune regulation by the liver through the PCSK9/CD36 pathway during HTR, which influences the phenotype and function of macrophages and suggests that the modulation of this pathway may be a potential therapeutic target to prevent HTR.

In-Hospital Use of PCSK9 Inhibitors in the Post ACS Patient: What Does the Evidence Show?

The purpose of this review is to analyze and discuss the most recent data on in hospital prescription of Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) inhibitors in patients with acute coronary syndrome (ACS). Recent randomized clinical trials (RTCs) have demonstrated a beneficial effect of monoclonal antibodies (mAb) PCSK9i prescription in patients with ACS on rapid reduction of low-density lipoprotein cholesterol (LDL-C) and on coronary atherosclerosis assessed by intracoronary imaging. Additionally, the safety profile of mAb PCSK9i was confirmed in all RTCs. Available RCTs show the effectiveness and rapid achievement of LDL-C levels according to American College of Cardiology/American Heart Association and European Society of Cardiology guidelines for ACS patients. However, RCTs addressing cardiovascular outcomes of PCSK9i in-hospital initiation in ACS patients are currently ongoing.

A Metabolic Enhancer Protects against Diet-Induced Obesity and Liver Steatosis and Corrects a Pro-Atherogenic Serum Profile in Mice.

Metabolic Syndrome (MetS) affects hundreds of millions of individuals and constitutes a major cause of morbidity and mortality worldwide. Obesity is believed to be at the core of metabolic abnormalities associated with MetS, including dyslipidemia, insulin resistance, fatty liver disease and vascular dysfunction. Although previous studies demonstrate a diverse array of naturally occurring antioxidants that attenuate several manifestations of MetS, little is known about the (i) combined effect of these compounds on hepatic health and (ii) molecular mechanisms responsible for their effect. We explored the impact of a metabolic enhancer (ME), consisting of 7 naturally occurring antioxidants and mitochondrial enhancing agents, on diet-induced obesity, hepatic steatosis and atherogenic serum profile in mice. Here we show that a diet-based ME supplementation and exercise have similar beneficial effects on adiposity and hepatic steatosis in mice. Mechanistically, ME reduced hepatic ER stress, fibrosis, apoptosis, and inflammation, thereby improving overall liver health. Furthermore, we demonstrated that ME improved HFD-induced pro-atherogenic serum profile in mice, similar to exercise. The protective effects of ME were reduced in proprotein convertase subtilisin/kexin 9 (PCSK9) knock out mice, suggesting that ME exerts it protective effect partly in a PCSK9-dependent manner. Our findings suggest that components of the ME have a positive, protective effect on obesity, hepatic steatosis and cardiovascular risk and that they show similar effects as exercise training.

Feasibility of Short-Term Aggressive Lipid-Lowering Therapy with the PCSK9 Antibody in Acute Coronary Syndrome.

The guideline-recommended low-density lipoprotein cholesterol target level of <70 mg/dL may not be achieved with statin administration in some patients with acute coronary syndrome (ACS). Therefore, the proprotein convertase subtilisin-kexin type 9 (PCSK9) antibody can be added to high-risk patients with ACS. Nevertheless, the optimal duration of PCSK9 antibody administration remains unclear. Patients were randomized to receive either 3 months of lipid lowering therapy (LLT) with the PCSK9 antibody followed by conventional LLT (with-PCSK9-antibody group) or 12 months of conventional LLT alone (without-PCSK9-antibody group). The primary endpoint was the composite of all-cause death, myocardial infarction, stroke, unstable angina, and ischemia-driven revascularization. A total of 124 patients treated with percutaneous coronary intervention (PCI) were randomly assigned to the two groups (n = 62 in each). The primary composite outcome occurred in 9.7% and 14.5% of the patients in the with- and without-PCSK9-antibody groups, respectively (hazard ratio: 0.70; 95% confidence interval: 0.25 to 1.97; p = 0.498). The two groups showed no significant differences in hospitalization for worsening heart failure and adverse events. In ACS patients who underwent PCI, short-term PCSK9 antibody therapy with conventional LLT was feasible in this pilot clinical trial. Long-term follow-up in a larger scale clinical trial is warranted.

Abstract 440: Role Of Retinoid X Receptor In Regulating Pcsk9 Transcription In The Liver And Atherosclerosis

Nonalcoholic fatty liver diseases ( NALFD) are associated with high cardiovascular disease ( CVD ) risk. The demand for novel CVD treatments leads to the recent discovery of the Proprotein Convertase Subtilisin Kexin 9 ( PCSK9 ), which promotes the degradation of low-density lipoprotein receptor ( LDLR ) to increase atherogenic lipoprotein LDL cholesterol ( LDL-C ) levels. Targeting PCSK9 shows promising benefits in mitigating CVD and NAFLD. However, the underlying mechanism causing the NAFLD-associated PCSK9 induction is still unclear. Our findings fill the critical knowledge gap by elucidating that Retinoid X Receptor alpha ( RXRα ) is essential to regulate the transcription of PCSK9 in the liver. Our preliminary data showed that hepatic depletion of RXRα leads to hepatic steatosis. To reveal the underlying mechanism by which hepatic RXRα deficiency promotes NAFLD development, we carried out the RNA-seq analysis. The Gene Set Enrichment Analysis ( GSEA ) of RNA-seq data showed the expected downregulation of PPARα signaling genes and the unexpected upregulation of cholesterol pathway genes in the liver of RXRα hepatocyte-specific knockout ( hepKO ) mice. One of the significantly upregulated genes in the cholesterol pathway is PCSK9, which induction in the liver of RXRα hepKO mice can be abolished by AAV8-mediated overexpression of RXRα. Consistently, we observed the increased cholesterol and LDL-C in the plasma of RXRα hepKO mice, and hepatic overexpression of RXRα can significantly reduce the plasma cholesterol and LDL-C levels. Recently, we identified a previously unrecognized acetylation residue of RXRα, which controls the heterodimerization between RXRα and PPARα. The inhibitory effects of constitutively acetylated RXRα mutant further indicate that acetylation of RXRα is essential for preventing the induction of PCSK9 in the liver of RXRα hepKO mice. Interestingly, we also observed the decreased acetylation of RXRα in the liver of high-fat diet ( HFD )-fed mice and human NAFLD patients. These results suggest that RXRα acetylation is required for regulating the PPARα-mediated repression of PCSK9 transcription in the liver, and impaired RXRα acetylation in the NAFLD liver results in increased PCSK9 and atherosclerosis risk.

The clinical effects of inclisiran, a first-in-class LDL-C lowering siRNA therapy, on the LDL-C levels in Chinese patients with hypercholesterolemia

Inclisiran is a novel siRNA therapy that inhibits the synthesis of proprotein convertase subtilisin-kexin type 9 (PCSK9) by targeting the PCSK9 mRNA, consequently, decreases low-density lipoprotein cholesterol (LDL-C). To assess the safety, PK and LDL-C lowering effects of inclisiran in the Chinese patients with elevated LDL-C despite treatment with maximally tolerated LDL-C lowering therapies. Forty Chinese patients with hypercholesterolemia (LDL-C ≥100 mg/dL) who were on maximally tolerated statin were randomized to receive a single dose of either inclisiran sodium 100 or 300mg s.c. injection (each for 15 patients) or placebo (10 patients). Safety, pharmacokinetics and pharmacodynamics (i.e., PCSK9 and LDL-C levels) were evaluated for up to 90 days after the s.c. injection of study drug. Following single subcutaneous injections inclisiran sodium at 100 mg or 300 mg, inclisiran has a relative short elimination half-life (T1/2, 6.5 hours). Both plasma PCSK9 and serum LDL-C decreased rapidly and consistently, with the maximal reduction between Day 30 and Day 60; then the decreases of PCSK9 and LDL-C were generally maintained up to 56.4% and 49.6% of 100 mg, 74.9% and 58.3% of 300 mg, respectively, at day 90. All adverse events were mild or moderate in severity, and no discontinuations due to adverse events. There were no serious adverse events being reported. Inclisiran was generally safe and well tolerated. Single dose of both Inclisiran 100 and 300 mg significantly reduced PCSK9 and LDL-C levels in Chinese patients up to Day 90. The greatest reductions were observed with the 300 mg regimen of Inclisiran. ClinicalTrials.gov: NCT04774003.

Soluble PCSK9 Inhibition: Indications, Clinical Impact, New Molecular Insights and Practical Approach-Where Do We Stand?

Current research on cardiovascular prevention predominantly focuses on risk-stratification and management of patients with coronary artery disease (CAD) to optimize their prognosis. Several basic, translational and clinical research efforts aim to determine the etiological mechanisms underlying CAD pathogenesis and to identify lifestyle-dependent metabolic risk factors or genetic and epigenetic parameters responsible for CAD occurrence and/or progression. A log-linear association between the absolute exposure of LDL cholesterol (LDL-C) and the risk of atherosclerotic cardio-vascular disease (ASCVD) was well documented over the year. LDL-C was identified as the principal enemy to fight against, and soluble proprotein convertase subtilisin kexin type 9 (PCSK9) was attributed the role of a powerful regulator of blood LDL-C levels. The two currently available antibodies (alirocumab and evolocumab) against PCSK9 are fully human engineered IgG that bind to soluble PCSK9 and avoid its interaction with the LDLR. As documented by modern and dedicated "game-changer" trials, antibodies against soluble PCSK9 reduce LDL-C levels by at least 60 percent when used alone and up to 85 percent when used in combination with high-intensity statins and/or other hypolipidemic therapies, including ezetimibe. Their clinical indications are well established, but new areas of use are advocated. Several clues suggest that regulation of PCSK9 represents a cornerstone of cardiovascular prevention, partly because of some pleiotropic effects attributed to these newly developed drugs. New mechanisms of PCSK9 regulation are being explored, and further efforts need to be put in place to reach patients with these new therapies. The aim of this manuscript is to perform a narrative review of the literature on soluble PCSK9 inhibitor drugs, with a focus on their indications and clinical impact.

Association of Remnant-like Particle Cholesterol with Major Adverse Cardiovascular Events in Subjects with Different Levels of Proprotein Convertase Subtilisin/Kexin 9: A 9.5-year Follow-up Study in a Beijing Community Population

Objective: The purpose of this study was to determine the relationship between remnant-like particle cholesterol (RLP-C) and major adverse cardiovascular events (MACEs) in patients with different levels of proprotein convertase subtilisin/kexin 9 (PCSK9). Methods: From September 2007 to January 2009, 1,859 subjects in Pingguoyuan communities in Beijing were initially screened. After excluding those with bedridden status, mental illness, severe systemic diseases, and missing data, 1,680 subjects were recruited for follow up. All recruited subjects were followed up from February 2013 to September 2013 (181 subjects were lost to follow-up) and from June 2017 to September 2018 (174 subjects were lost to follow up). Finally, 1,325 subjects were included in the study. General demographic characteristics, lifestyle and behaviors, disease history and use of medication was collected. Levels of total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fast blood glucose, RLP-C, low-density lipoprotein triglycerides and PCSK9 were measured. The levels of RLP-C (low: RLP-C ≤ 157 mg/L; high: RLP-C &gt; 157 mg/L) and PCSK9 (low: PCSK9 ≤ 135.87 μg/L; high: PCSK9 &gt; 135.87 μg/L) were represented using quartiles. Subjects were categorized into 4 groups according to their RLP-C and PCSK9 levels: Q4, high levels of RLP-C with high levels of PCSK9; Q3, high levels of RLP-C with low levels of PCSK9; Q2, low levels of RLP-C with high levels of PCSK9; and Q1, low levels of RLP-C with low levels of PCSK9. The association of RLP-C with MACEs in subjects with different PCSK9 levels was evaluated. Results: After a median follow-up of 9.5 years, 1,325 subjects were included in the study and a total of 191 MACEs had occurred. The incidence of MACEs was higher in the RLP-C &gt; 157 mg/L group than the RLP-C ≤ 157 mg/L group (18.40% vs. 10.42%). Cox proportional hazards regression model analysis showed that increased RLP-C levels were associated with an increased risk of MACEs (hazard ratio: 1.405; 95% confidence interval: 1.005–1.964; P &lt; 0.005). The incidence of MACEs was higher in the high RLP-C/PCSK9 group vs. the low RLP-C/PCSK9 group (20.68% vs. 8.76%). Cox proportional hazards regression model analysis showed that RLP-C was associated with an increased risk of MACEs in subjects with high PCSK9 levels independent of traditional risk factors (hazard ratio: 1.791; 95% confidence interval: 1.168–2.825; P = 0.001), but not in those with low PCSK9 levels. Conclusions: RLP-C was identified as a risk factor for MACEs, particularly in subjects with high PCSK9 levels. Lowering PCSK9 levels may reduce residual risk in subjects with elevated plasma RLP-C levels.

The Effect of 4-Methylcatechol on Platelets in Familial Hypercholesterolemic Patients Treated with Lipid Apheresis and/or Proprotein Convertase Subtilisin Kexin 9 Monoclonal Antibodies.

Elevated low-density lipoprotein (LDL) cholesterol levels lead to atherosclerosis and platelet hyperaggregability, both of which are known culprits of arterial thrombosis. Normalization of LDL cholesterol in familial hypercholesterolemia (FH) is not an easy task and frequently requires specific treatment, such as regularly performed lipid apheresis and/or novel drugs such as proprotein convertase subtilisin kexin 9 monoclonal antibodies (PCSK9Ab). Moreover, a high resistance rate to the first-line antiplatelet drug acetylsalicylic acid (ASA) stimulated research of novel antiplatelet drugs. 4-methylcatechol (4-MC), a known metabolite of several dietary flavonoids, may be a suitable candidate. The aim of this study was to analyse the antiplatelet effect of 4-MC in FH patients and to compare its impact on two FH treatment modalities via whole-blood impedance aggregometry. When compared to age-matched, generally healthy controls, the antiplatelet effect of 4-MC against collagen-induced aggregation was higher in FH patients. Apheresis itself improved the effect of 4-MC on platelet aggregation and blood from patients treated with this procedure and pretreated with 4-MC had lower platelet aggregability when compared to those solely treated with PCKS9Ab. Although this study had some inherent limitations, e.g., a low number of patients and possible impact of administered drugs, it confirmed the suitability of 4-MC as a promising antiplatelet agent and also demonstrated the effect of 4-MC in patients with a genetic metabolic disease for the first time.

Modern possibilities of intensive treatment of dyslipidemia and gaps in its control: literature review

The article discusses modern approaches to screening for dyslipidemia and its control, target levels of low-density lipoproteins (LDL), initiation of lipid-lowering therapy depending on the total risk on the Systematic Coronary Risk Evaluation (SCORE) scale, considering the effects of age, gender, smoking, blood pressure, lipid levels, which are of crucial importance for selecting preventive and therapeutic strategies in patients with several risk factors. Different types of therapy for dyslipidemia are discussed as of monotherapy with statins and, in combination with ezetimibe, inhibitors of the enzyme proprotein convertase subtilisin-kexin type 9 (PCSK9). New lipid-lowering drugs are highlighted: bempedoic acid and inclisiran, a synthetic small interfering RNA (siRNA) conjugated with a hydrocarbon of three-antennary N-acetylgalactosamine, which activates the natural RNA interference mechanism to cleave the mRNA of the PCSK9 enzyme and prevent its translation into a protein molecule. This increases the number of receptors for LDL and reducing their amount in the blood. We present our results of assessing the use of lipid-lowering therapy and achievement of the target LDL value in very high-risk patients. Innovative biotechnological drugs based on human monoclonal antibodies or antisense oligonucleodins create additional opportunities for improving the treatment of statin-resistant forms of dyslipidemia in patients with a very high cardiovascular risk. The article aims to increase the level of knowledge about modern approaches to lipid-lowering therapy of general practitioners, cardiologists of the primary care settings and will be of interest to other specialists.

Resveratrol protects against postmenopausal atherosclerosis progression through reducing PCSK9 expression via the regulation of the ERα-mediated signaling pathway

Elevated circulating proprotein convertase subtilisin/kexin 9 (PCSK9) levels are an important contributor to postmenopausal atherosclerosis (AS). We have previously reported that resveratrol (RSV), as a phytoestrogen, reduces hepatocyte steatosis and PCSK9 expression in L02 cells. This study aimed to investigate how RSV reduces PCSK9 expression to inhibit postmenopausal AS progression. Here, we found that treatment of Ovx/ApoE −/− mice with RSV significantly reduced dyslipidemia, plasma PCSK9 concentration and aortic plaque area. In addition, RSV significantly inhibited liver fat accumulation and improved the hepatocyte ultrastructure. Further studies showed that RSV upregulated estrogen receptor α (ERα) expression, while reduced the liver X receptor α (LXRα) expression and sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity. In vitro, RSV inhibited insulin-induced elevated intracellular/extracellular PCSK9 levels, enhanced receptor-mediated uptake of low-density lipoproteins in HepG2 cells. Furthermore, RSV attenuated the activity of the SRE-dependent PCSK9 promoter. However, these effects can be partially reversed by the antiestrogen ICI 182,780. Attenuation of these changes with ERα inhibition suggest that RSV may prevent the progression of postmenopausal AS by reducing PCSK9 expression in hepatocytes through ERα-mediated signaling.

French expert group proposal for lipid-lowering therapy in the first 3 months after acute myocardial infarction.

In patients admitted for acute myocardial infarction (MI), it has been demonstrated that reducing LDL cholesterol (LDL-c) is associated with a reduction in major adverse cardiovascular events. We describe a consensual proposal made by a French group of experts for lipid-lowering therapy at the acute phase of acute myocardial infarction. A group of French experts comprising cardiologists, lipidologists and general practitioners prepared a proposal for a lipid-lowering strategy with a view to optimizing LDL-c levels in patients hospitalized for myocardial infarction. We describe a strategy for the use of statins, ezetimibe and and/or proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, with a view to reaching target LDL-c levels as early as possible. This approach, which is currently feasible in France, could considerably improve lipid management in patients after ACS, thanks to its simplicity, rapidity and the magnitude of the decrease in LDL-c that it achieves.

Predictors of post-infarction left ventricular aneurysm

Post-infarction left ventricular aneurysm (LVA) is a complication of myocardial infarction (MI), which is of great clinical importance due to high mortality. Data on its incidence are contradictory. The aim of the review was to highlight the existing and novel predictors of post-infarction LVA, the identification of which will help in identifying high-risk patients in order to optimize their treatment and rehabilitation. Known predictors of post-infarction LVA include pain-to-balloon time, age, female sex, recurrent MI, coronary angiography parameters, echocardiography, and electrocardiography. Increased levels of leukocytes, C-reactive protein, growth differentiation factor, stimulating growth factor, interleukin-1β, interleukin-6, tumor necrosis factor-α, matrix metalloproteinases, proprotein convertase subtilisin-kexin type 9, N-terminal pro-brain natriuretic peptide &gt;400 pg/ml indicate the risk of pathological left ventricular remodeling and LVA. In this connection, there is a need to assess the incidence of post-infarction LVA and a comprehensive assessment of its predictors in patients with MI.

PCSK9 Inhibitors Reduce PCSK9 and Early Atherogenic Biomarkers in Stimulated Human Coronary Artery Endothelial Cells

Despite reports on the efficacy of proprotein convertase subtilisin-Kexin type 9 (PCSK9) inhibitors as a potent lipid-lowering agent in various large-scale clinical trials, the anti-atherogenic properties of PCSK9 inhibitors in reducing PCSK9 and atherogenesis biomarkers via the NF-ĸB and eNOS pathway has yet to be established. This study aimed to investigate the effects of PCSK9 inhibitors on PCSK9, targeted early atherogenesis biomarkers, and monocyte binding in stimulated human coronary artery endothelial cells (HCAEC). HCAEC were stimulated with lipopolysaccharides (LPS) and incubated with evolocumab and alirocumab. The protein and gene expression of PCSK9, interleukin-6 (IL-6), E-selectin, intercellular adhesion molecule 1 (ICAM-1), nuclear factor kappa B (NF-ĸB) p65, and endothelial nitric oxide synthase (eNOS) were measured using ELISA and QuantiGene plex, respectively. The binding of U937 monocytes to endothelial cell capacity was measured by the Rose Bengal method. The anti-atherogenic effects of evolocumab and alirocumab were contributed to by the downregulation of PCSK9, early atherogenesis biomarkers, and the significant inhibition of monocyte adhesion to the endothelial cells via the NF-ĸB and eNOS pathways. These suggest the beyond cholesterol-lowering beneficial effects of PCSK9 inhibitors in impeding atherogenesis during the initial phase of atherosclerotic plaque development, hence their potential role in preventing atherosclerosis-related complications.