Search Results (23)

Atherosclerotic cardiovascular disease (ASCVD) has long been screened using the traditional lipid profile, mainly focusing on LDL cholesterol. However, despite growing evidence supporting lipoprotein(a) [Lp(a)] as an independent risk factor involved in atherosclerosis, its clinical use remains limited. This review examines the reasons behind the limited use of Lp(a) screening in clinical practice, assessing its role in cardiovascular risk, comparing it to traditional lipid markers and evaluating current assessment methods. It also explores existing and emerging treatments, including gene-silencing therapies, for managing elevated Lp(a) levels. One in four clinicians does not routinely check Lp(a) levels, which proves a lack of awareness amongst them. The reasons for that are implied to be that the cost is too high and that available treatments are scarce. The traditional lipid profile, including LDL, high-density lipoprotein (HDL) and triglycerides, continues to be the gold standard for CV risk assessment. One limitation of using Lp(a) in clinical practice is the significant variability in apo(a) sizes, which results from the presence of multiple isoforms determined by the number of kringle domains. This structural diversity poses challenges in standardizing measurement methods, affecting the accuracy and comparability of results. While statins have a minimal impact on Lp(a), PCSK9-i lowers its levels by 20–25%, although this class is not prescribed primarily for this reason. Lastly, gene-silencing therapies, which achieve the greatest reduction in Lp(a) levels, are still in phase III trials, and there is still a need to examine whether this reduction translates into CV benefits. These limitations should not discourage further research, because ASCVD’s complexity requires a more tailored approach. Current lipid-lowering therapy still fails in a minority of cases, as evidenced by new-onset cardiovascular events in patients with well-controlled LDL levels. There is a need for future interventional studies to assess whether a reduction in Lp(a) by PCSK9-i really translates into CV benefits, independent of LDL. Full article

The accumulation of high levels of cholesterol associated with low-density lipoprotein (LDL) in the bloodstream is the key risk factor for stroke and cardiovascular diseases. Therefore, reducing the concentration of LDL-cholesterol in the blood and maintaining it at an optimum level are vital especially for hypercholesterolemic individuals and cardiovascular patients. Thus, the study of cholesterol management and regulation in the physiological system has drawn significant attention from researchers across the globe. This led to the discovery of several cholesterol-lowering drugs which have been approved for administration either via oral or non-oral routes. Owing to the high comfort level, reduced or no pain, and fewer side effects with oral administration, more focus has been directed towards the development of oral-based cholesterol-lowering drugs. The other modes of administration such as intravenous or intramuscular injections are complex and sometimes painful and less tolerable. Therefore, there was a significant interest to develop oral drugs targeting PCSK9. In fact, some progress has been accomplished in recent years. This review provides an overview of the existing cholesterol-lowering drugs, and the progress made so far with oral-based PCSK9 drugs for lowering LDL-cholesterol. The review is presented in several sections highlighting the molecular targets, the individual drugs, and the modes of administration, with a focus on the oral route. Full article

Background/Objectives: This study investigated the potential of green algae-derived carotenoids as natural inhibitors of the proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of cholesterol metabolism. PCSK9 promotes the degradation of low-density lipoprotein receptors (LDLR), thereby increasing blood cholesterol levels and elevating the risk of cardiovascular diseases. Methods/Results: We screened the pharmacophore fit score of 27 carotenoids with PCSK9 and identified 14 that were analyzed for binding affinity and molecular interactions. Astaxanthin, siphonaxanthin, and prasinoxanthin were identified as the top candidates, demonstrating strong binding affinity (−10.5, −10.3, and −9.4 Kcal/mol, respectively) and stable interactions with several known key residues within the active site of PCSK9, including Pro-331, Arg-357, Cys-358, Val-359, Asp-360, Ile-416, Leu-436, Thr-437, Pro-438, Leu-440, Arg-458, Val-460, Trp-461, Arg-476, Cys-477, Ala-478, Ala-649, Val-650, and Asp-651. Density functional theory analysis confirmed the stability of astaxanthin and its favorable electronic properties, suggesting its potential as an effective inhibitor. Molecular dynamics simulations of the PCSK9–astaxanthin complex revealed sustained structural stability and key interactions critical for maintaining the functional integrity of the protein. Conclusions: These findings provide evidence that specific carotenoids, particularly astaxanthin, may offer a cost-effective alternative to existing PCSK9 inhibitors, providing a potential approach for managing cholesterol levels and reducing cardiovascular risk. Pre-clinical and clinical validations are required to confirm the therapeutic potential of these compounds. Full article

The primary cause of atherosclerotic cardiovascular disease (ASCVD) is elevated levels of low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in this process by binding to the LDL receptor (LDL-R) domain, leading to reduced influx of LDL-C and decreased LDL-R cell surface presentation on hepatocytes, resulting higher circulating levels of LDL-C. As a consequence, PCSK9 has been identified as a crucial target for drug development against dyslipidemia and hypercholesterolemia, aiming to lower plasma LDL-C levels. This research endeavors to identify promising inhibitory candidates that target the allosteric site of PCSK9 through an in silico approach. To start with, the FDA-approved Drug Library from Selleckchem was selected and virtually screened by docking studies using Glide extra-precision (XP) docking mode and Smina software (Version 1.1.2). Subsequently, rescoring of 100 drug compounds showing good average docking scores were performed using Gnina software (Version 1.0) to generate CNN Score and CNN binding affinity. Among the drug compounds, amikacin, bestatin, and natamycin were found to exhibit higher docking scores and CNN affinities against the PCSK9 enzyme. Molecular dynamics simulations further confirmed that these drug molecules established the stable protein–ligand complexes when compared to the apo structure of PCSK9 and the complex with the co-crystallized ligand structure. Moreover, the MM-GBSA calculations revealed binding free energy values ranging from −84.22 to −76.39 kcal/mol, which were found comparable to those obtained for the co-crystallized ligand structure. In conclusion, these identified drug molecules have the potential to serve as inhibitors PCSK9 enzyme and these finding could pave the way for the development of new PCSK9 inhibitory drugs in future in vitro research. Full article

Type 2 diabetes mellitus (T2DM) is a common metabolic disease characterised by insulin resistance and elevated blood glucose levels, affecting millions of people worldwide. T2DM individuals with dyslipidaemia have an increased risk of cardiovascular disease (CVD). A complex interplay of risk factors such as hyperglycaemia, dyslipidaemia, hypertension, obesity, inflammation, and oxidative stress favour the development of atherosclerosis, a central mechanism in the pathogenesis of cardiovascular disease. Dyslipidaemia, a hallmark of T2DM, is characterised by elevated triglycerides, decreased high-density lipoprotein (HDL) cholesterol and the presence of small, dense low-density lipoprotein (LDL) particles, all of which promote atherosclerosis. In this article, we have attempted to present various treatment strategies that include pharmacological interventions such as statins, ezetimibe, PCSK9 inhibitors, fibrates, and omega-3 fatty acids. We have also tried to highlight the pivotal role of lifestyle modifications, including physical activity and dietary changes, in improving lipid profiles and overall cardiovascular health in T2DM individuals. We have also tried to present the latest clinical guidelines for the management of dyslipidaemia in T2DM individuals. In conclusion, the treatment of dyslipidaemia in T2DM individuals is of great importance as it lowers lipid particle levels, slows the progression of atherosclerosis, and ultimately reduces susceptibility to cardiovascular disease. Full article

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

This review aims to examine the complex interaction between dyslipidemia, platelet function, and related drug treatments. In particular, the manuscript provides an overview of the effects of major hypolipidemic drugs on platelet function. Indeed, growing evidence supports the view that statins, ezetimibe, PCSK9 inhibitors, inclisiran, and icosapent ethyl also act as antithrombotics. It is known that platelets play a key role not only in the acute phase of coronary syndromes but also in the early phase of atherosclerotic plaque formation. The goal of cholesterol-lowering therapy is to reduce cardiovascular events. The direct effects of cholesterol-lowering drugs are widely described in the literature. Lowering LDL-c (low-density lipoprotein cholesterol) by 1 mmol/L results in a 22–23% reduction in cardiovascular risk. Numerous studies have examined the direct antithrombotic effects of these drugs on platelets, endothelium, monocytes, and smooth muscle cells, and thus, potentially independent of blood LDL-cholesterol reduction. We reviewed in vitro and in vivo studies evaluating the complex interaction between hypercholesterolemia, hypertriglyceridemia, platelet function, and related drug treatments. First, we discussed the role of statins in modulating platelet activation. Discontinuation of statin therapy was associated with increased cardiovascular events with increased ox-LDL, P-selectin, and platelet aggregation. The effect of PCSK9-I (inhibitors of proprotein convertase subtilisin/kexin type 9, PCSK9 involved in the degradation of LDL receptors in the liver) was associated with a statistically significant reduction in platelet reactivity, calculated in P2Y12 reaction units (PRU), in the first 14 days and no difference at 30 days compared to placebo. Finally, in patients with hypertriglyceridemia, the REDUCE-IT study showed that icosapent ethyl (an ethyl ester of eicosapentaenoic acid that reduces triglyceride synthesis and improves triglyceride clearance) resulted in a 25% reduction in ischemic events and cardiovascular death. However, to date, there is not yet clear clinical evidence that the direct antithrombotic effects of the drugs may have a beneficial impact on outcomes independently from the reduction in LDL-C or triglycerides. Full article

In this study we analyzed the concentration of lipoprotein(a) (Lp(a)), PCSK9-Lp(a) complexes and the circulating monocyte subsets in coronary atherosclerosis. For this study, 257 patients with coronary atherosclerosis and 68 patients without stenotic atherosclerosis in the coronary, carotid and lower extremity arteries (control group) were enrolled. The monocyte subpopulations (classical CD14++CD16-, intermediate CD14++CD16+ and non-classical CD14+CD16++) were analyzed by direct immunofluorescence and flow cytometry. The Lp(a) and PCSK9-Lp(a) complexes in the serum were detected by ELISA. The concentration of Lp(a) was higher in the coronary atherosclerosis group compared with the controls (23.0 (9.1; 73.3) mg/dL versus 10.7 (4.7; 25.0) mg/dL, p < 0.05). No correlations between the level of Lp(a) and the concentration of the PCSK9-Lp(a) complexes, nor between the level of Lp(a) or PCSK9 and the total number of monocytes, were observed in either group. A slight positive correlation between the concentration of PCSK9-Lp(a) complexes and the absolute level of monocytes was obtained (r = 0.20, p = 0.002) in the patients with atherosclerosis due to the intermediate monocyte subsets (r = 0.33, p = 0.04). According to regression analysis, both the PCSK9-Lp(a) complexes concentration and BMI were related to the absolute number of blood monocytes in patients with atherosclerosis. Further studies are required to determine the pathogenetic contribution of PCSK9-Lp(a) complexes to the development of atherosclerosis. Full article

MOMAST^® is a patented natural phenolic complex, rich in tyrosol (9.0 g/kg, Tyr), hydroxityrosol (43,5 g/kg, OH-Tyr), and verbascoside (5.0 g/Kg), which is obtained from the OVW by-product of the Coratina cultivar with potent direct antioxidant activity (measured by DPPH and FRAP assays, respectively). Indeed, MOMAST^® represents an innovative sustainable bioactive ingredient which has been obtained with ethical and empowering behavior by applying the principles of a circular economy. In the framework of research aimed at fostering its health-promoting activity, in this study it was clearly demonstrated that MOMAST^® treatment reduced the oxidative stress and levels of total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol, and increased the HDL levels, without changes in the triglyceride (TG) levels in Western diet (WD)-fed mice. The modulation of the plasmatic lipid profile is similar to red yeast rice (RYR) containing Monacolin K (3%). In addition, at the molecular level in liver homogenates, similarly to RYR, MOMAST^® exerts cholesterol-lowering activity through the activation of LDL receptor, whereas, unlike RYR, MOMAST^® reduces proprotein convertase subtilisin/kexin type 9 (PCSK9) protein levels via hepatic nuclear factor 1 (HNF1)-α activation. Hence, this study provides the proof of concept regarding the hypocholesterolemic activity of MOMAST, which could be successfully exploited as an active ingredient for the development of innovative and sustainable dietary supplements and functional foods. Full article

The control of cardiovascular risk factors, the promotion of a healthy lifestyle, and antithrombotic therapy are the cornerstones of secondary prevention after acute coronary syndrome (ACS). However, many patients have recurrent ischemic events despite the optimal control of traditional modifiable risk factors and the use of tailored pharmacological therapy, including new-generation antiplatelet and lipid-lowering agents. This evidence emphasizes the importance of identifying novel risk factors and targets to optimize secondary preventive strategies. Lipoprotein(a) (Lp(a)) has emerged as an independent predictor of adverse events after ACS. New molecules such as anti-PCSK9 monoclonal antibodies, small interfering RNAs, and antisense oligonucleotides can reduce plasma Lp(a) levels and are associated with a long-term outcome benefit after the index event. The inflammatory stimulus and the inflammasome, pivotal elements in the development and progression of atherosclerosis, have been widely investigated in patients with coronary artery disease. More recently, randomized clinical trials including post-ACS patients treated with colchicine and monoclonal antibodies targeting cytokines yielded promising results in the reduction in major cardiovascular events after an ACS. Gut dysbiosis has also raised great interest for its potential pathophysiological role in cardiovascular disease. This evidence, albeit preliminary and needing confirmation by larger population-based studies, suggests the possibility of targeting the gut microbiome in particularly high-risk populations. The risk of recurrent ischemic events after ACS is related to the complex interaction between intrinsic predisposing factors and environmental triggers. The identification of novel risk factors and targets is fundamental to customizing patient clinical management with a precision medicine perspective. Full article

Metabolic rewiring and defective immune responses are considered to be the main driving forces sustaining cell growth and oncogenesis in many cancers. The atypical enzyme, proprotein convertase subtilisin/kexin type 9 (PCSK9), is produced by the liver in large amounts and plays a major role in lipid metabolism via the control of the low density lipoprotein receptor (LDLR) and other cell surface receptors. In this context, many clinical studies have clearly demonstrated the high efficacy of PCSK9 inhibitors in treating hyperlipidemia and cardiovascular diseases. Recent data implicated PCSK9 in the degradation of major histocompatibility complex I (MHC-I) receptors and the immune system as well as in other physiological activities. This review highlights the complex crosstalk between PCSK9, lipid metabolism and immunosuppression and underlines the latest advances in understanding the involvement of this convertase in other critical functions. We present a comprehensive assessment of the different strategies targeting PCSK9 and show how these approaches could be extended to future therapeutic options to treat cancers with a main focus on the liver. Full article

Familial hypercholesterolemia (FH) is an underdiagnosed disease that contributes to a significant number of cardiovascular incidents through high serum Low-Density Lipoprotein Cholesterol (LDL-C) values. Its treatment primarily requires healthy lifestyle and therapy based on statins, ezetimibe and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9); however, there are also new treatment options that can be used in patients who do not respond to therapy, among which we highlight evinacumab. Elevated LDL-C values, together with clinical manifestations associated with cholesterol deposition (e.g., tendon xanthomas, xanthelasma and arcus cornealis) and family history are the main elements in the diagnosis of FH. Pathognomonic signs of FH include extensor tendon xanthomas; however, their absence does not exclude the diagnosis. Elevated LDL-C levels lead to premature Atherosclerotic Cardiovascular Disease (ASCVD), which is why early diagnosis and treatment of FH is essential. Evinacumab, a novelty in pharmacological practice, having a complex mechanism of action, causes desirable changes in lipid parameters in patients with homozygous form of familial hypercholesterolemia (HoFH). This review collects and summarizes the most important aspects of the new drug, especially being a discovery in the treatment of HoFH, giving these patients hope for a longer and more comfortable life. Full article

Acute ischemic stroke (AIS) represents an important cause of disability and death. Since only a minor percentage of patients with AIS are eligible for acute therapy, the management of risk factors is mandatory. An important risk factor of AIS is hyperlipemia. The current guidelines recommend a strict correction of it. Statins are recommended as the first-line treatment, while proprotein convertase subtilin/kexin type 9 (PCSK-9) inhibitors are administered as a second or even third option when the goal for a low-density lipoprotein cholesterol (LDL-C) level is not achieved. PCSK-9 inhibitors effectively decrease the LDL-C levels through the inhibition of PCSK-9-LDL-receptor complex formation. The in-depth understanding of the PCSK-9 protein mechanism in the metabolism of LDL-C led to the development of effective targeted approaches. Furthermore, a better understanding of the LDL-C metabolic pathway led to the development of newer approaches, which increased the therapeutic options. This article aims to offer an overview of the PCSK-9 inhibitors and their mechanism in reducing the LDL-C levels. Moreover, we will present the main indications of the current guidelines for patients with hyperlipemia and for those who have suffered an acute ischemic stroke, as well as the importance of LDL-C reduction in decreasing the rate of a recurrence. Full article

Familial hypercholesterolemia (FH) is the most common monogenic metabolic disorder characterized by considerably elevated low-density lipoprotein cholesterol (LDL-C) levels leading to enhanced atherogenesis, early cardiovascular disease (CVD), and premature death. However, the wide phenotypic heterogeneity in FH makes the cardiovascular risk prediction challenging in clinical practice to determine optimal therapeutic strategy. Beyond the lifetime LDL-C vascular accumulation, other genetic and non-genetic risk factors might exacerbate CVD development. Besides the most frequent variants of three genes (LDL-R, APOB, and PCSK9) in some proband variants of other genes implicated in lipid metabolism and atherogenesis are responsible for FH phenotype. Furthermore, non-genetic factors, including traditional cardiovascular risk factors, metabolic and endocrine disorders might also worsen risk profile. Although some were extensively studied previously, others, such as common endocrine disorders including thyroid disorders or polycystic ovary syndrome are not widely evaluated in FH. In this review, we summarize the most important genetic and non-genetic factors that might affect the risk prediction and therapeutic strategy in FH through the eyes of clinicians focusing on disorders that might not be in the center of FH research. The review highlights the complexity of FH care and the need of an interdisciplinary attitude to find the best therapeutic approach in FH patients. Full article

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a key regulator of low-density lipoprotein (LDL) metabolism involved in the degradation of the low-density lipoprotein receptor (LDLR) through complex mechanisms. The PCSK9 plasma levels change according to lipid lowering therapy (LLT). Few data exist regarding the role of PCSK9 in vascular damage. We aimed to evaluate the impact of PCSK9 plasma levels on pulse wave velocity (PWV) and the effect of PCSK9 inhibitors (PCSK9-i) on circulating PCSK9 and PWV in a cohort of heterozygous familial hypercholesterolemia (HeFH) subjects. In a previous step, HeFH patients were enrolled and LLT was prescribed according to guidelines. Biochemical analyses and PWV assessment were performed at baseline (T0), after 6 months of high-efficacy statin plus ezetimibe (T1) and after 6 months of PCSK9-i (T2). The PCSK9 levels were evaluated in 26 selected HeFH subjects at the three time points and 26 healthy subjects served as controls for the reference value for PCSK9 plasma levels. The PWV values decreased at each time point in HeFH subjects after LLT starting (8.61 ± 2.4 m/s, −8.7%; p < 0.001 vs. baseline at T1, and 7.9 ± 2.1 m/s, −9.3%; p < 0.001 vs. both T1 and baseline) and it was correlated to PCSK9 (r = 0.411, p = 0.03). The PCSK9 levels increased on statin/EZE therapy (+42.8% at T1) while it decreased after PCSK9-i was started (−34.4% at T2). We noted a significant relationship between PCSK9 levels and PWV changes at T1 and T2. In conclusion, PCSK9 levels were associated with baseline PWV values in HeFH subjects; moreover, we found that PCSK9 level variations seemed to be correlated with PWV changes on LLT. A longer observation time and wider sample size are needed to assess the potential role of PCSK9 plasma levels on the vascular function and remodelling, and to clarify the effects of PCSK9-i in these pathways. Full article