Targeting PCSK9 as a key player in lipid metabolism: exploiting the therapeutic and biosensing potential of aptamers.

The degradation of low-density lipoprotein receptor (LDLR) is induced by proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in elevated plasma concentrations of LDL cholesterol. Therefore, inhibiting the interactions between PCSK9 and LDLR is a desirable therapeutic goal for managing hypercholesterolemia. Aptamers, which are RNA or single-stranded DNA sequences, can recognize their targets based on their secondary structure. Aptamers exhibit high selectivity and affinity for binding to target molecules. The systematic evolution of ligands by exponential enrichment (SELEX), a combination of biological approaches, is used to screen most aptamers in vitro. Due to their unique advantages, aptamers have garnered significant interest since their discovery and have found extensive applications in various fields. Aptamers have been increasingly utilized in the development of biosensors for sensitive detection of pathogens, analytes, toxins, drug residues, and malignant cells. Furthermore, similar to monoclonal antibodies, aptamers can serve as therapeutic tools. Unlike certain protein therapeutics, aptamers do not elicit antibody responses, and their modified sugars at the 2'-positions generally prevent toll-like receptor-mediated innate immune responses. The focus of this review is on aptamer-based targeting of PCSK9 and the application of aptamers both as biosensors and therapeutic agents.

The clinical value of ß-blockers in patients with stable angina.

Stable angina, one manifestation of chronic coronary syndrome (CCS), is characterised by intermittent episodes of insufficient blood supply to the myocardium, provoking symptoms of myocardial ischaemia, particularly chest pain. These attacks usually occur during exercise or stress. Anti-ischaemic drugs are the mainstay of pharmacologic management of CCS with symptoms of angina. ß-blockers reduce heart rate and myocardial contractility, thus reducing myocardial oxygen consumption. These drugs have been shown to ameliorate the frequency of anginal attacks and to improve exercise capacity in these patients. Current management guidelines include ß-blockers as a first-line management option for most patients with CCS and symptoms of myocardial ischaemia, alongside dihydropyridine calcium channel blockers (CCB). The presence of comorbid angina and heart failure is a strong indication for starting with a ß-blocker. ß-blockers are also useful in the management of angina symptoms accompanied by a high heart rate, hypertension (with or without a renin-angiotensin-aldosterone-system [RAS] blocker or CCB), or microvascular angina (with a RAS blocker and a statin). A ß-blocker is not suitable for a patient with low heart rate (<50 bpm), although use of a ß-blocker may be supported by a pacemaker if the ß-blocker is strongly indicated) and should be used at a low dose only in patients with low blood pressure.

Identification of Critical Genes Differentiating Stable and Unstable Atherosclerotic Plaques: A Bioinformatic and Computational Analysis.

BACKGROUND: Identification of biomarkers to distinguish between stable and unstable plaque formation would be very useful to predict plaque vulnerability. METHODS: We downloaded microarray profiles of gene set enrichment (GSE) accession numbers including GSE71226 and GSE20680 (group A: containing healthy vs stable plaque samples) and GSE62646 and GSE34822 (group B: containing stable vs unstable plaque samples) from Gene expression omnibus (GEO) database. Differentially expressed genes were compared in both data sets of each group. RESULTS: Ten and 12 key genes were screened in groups A and B, respectively. Gene Ontology (GO) enrichment was applied by the plugin "BiNGO" (Biological networks gene ontology tool) of the Cytoscape. The key genes were mostly enriched in the biological process of positive regulation of the cellular process. The protein-protein interaction and co-expression network were analyzed by the STRING (search tool for the retrieval of interacting genes/proteins) and GeneMANIA (gene multiple association network integration algorithm) plugin of Cytoscape, respectively, which showed that Epidermal growth factor (EGF), Heparin-binding EGF like growth factor (HBEGF), and Matrix metalloproteinase 9 (MMP9) were at the core of the network. Further validation of key genes using two datasets showed that Phosphodiesterase 5A (PDE5A) and Protein S (PROS1) were decreased in unstable plaques, while Suppressor of cytokine signaling (SOCS3), HBEGF, and Leukocyte immunoglobulin-like receptor B4 (LILRB4) were increased. CONCLUSION: The present study used several datasets to identify key genes associated with stable and unstable atherosclerotic plaque.

GlycA Levels Independently Predict Coronary Artery Calcium Incidence and Progression in the ELSA-Brasil Cohort (Brazilian Longitudinal Study of Adult Health).

Atherosclerosis is an inflammatory disease. Coronary artery calcium (CAC) is a marker of atherosclerotic disease events and mortality risk. Increased GlycA, an emerging marker of inflammation, is associated with a higher risk for coronary artery disease (CAD). However, there is conflicting evidence on whether GlycA predicts subclinical CAD progression. We hypothesized that GlycA can predict subclinical CAC incidence/progression in healthy participants. We included 2,690 ELSA-Brasil cohort participants without cardiovascular/chronic inflammatory disease not receiving statin therapy who had GlycA levels measured and 2 interval CAC assessments between 2010 and 2018. Multivariable logistic and linear regression models were computed to evaluate GlycA as a predictor of CAC incidence and progression. CAC incidence required a baseline CAC of 0. CAC progression required a baseline CAC >0. The mean age of participants was 48.6 ± 7.7 years, 56.7% were women, and 54.6% and 16.1% (429 of 2,690) were White and Black, respectively. The mean CAC interscan period was 5.1 ± 0.9 years, the mean GlycA level was 414.7 ± 65 µmol/L, and the incidence of CAC was 13.1% (280 of 2,129). The GlycA level odds ratio for CAC incidence was 1.002 (95% confidence interval 1.0005 to 1.005, p = 0.016), adjusted for demographics, lifestyle, a family history of early CAD (≤60 years), lipids, and co-morbidities. The GlycA (≤p25 vs ≥p75) odds ratio for CAC progression (Berry definition) was 1.77 (95% confidence interval 1.07 to 2.96, p = 0.03) in a similar multivariable-adjusted model. Higher GlycA levels were associated with CAC incidence and progression in a healthy Brazilian cohort.

Statins use for primary prevention of cardiovascular disease: A population-based digitally enabled real-world evidence cross-sectional study in primary care in Brazil.

BACKGROUND: Statins consist of the main strategy to reduce dyslipidemia-related cardiovascular risk. Nevertheless, there is scarce evidence on the real-world statins use in primary care settings in low-middle-income countries. OBJECTIVE: We conducted a cross-sectional retrospective study using anonymized data routinely collected by community health workers in Brazil aimed to evaluate statin use and associated factors in a primary prevention population with cardiovascular risk enhancers. METHODS: Study population consisted of adults with hypertension, diabetes and/or dyslipidemia. The primary and secondary outcomes were the proportion of individuals self-reporting statins use on any dose, and high-dose statins/high-intensity lipid lowering therapy (LLT) respectively. RESULTS: Of the 2,133,900 adult individuals on the database, 415,766 (19.5%) were included in the study cohort. From this cohort, 89.1% had hypertension, 28.9% diabetes and 5.5% dyslipidemia. The mean age was 61.5 (SD 14.5) years, 63.4% were female and 61.0% were of mixed-race. Only 2.6% and 0.1% of individuals self-reported the use of statins and high-dose statins/high-intensity LLT, respectively. Older age (OR 1.96; 95% CI 1.88,2.05;p < 0.001), living in the South region of Brazil (OR 4.39; 95%CI 3.97,4.85,p < 0.001), heart failure (OR 2.60; 95%CI 2.33,2.89,p < 0.001), chronic kidney disease (OR 1.49; 95%CI 1.35,1.64,p < 0.001) and anti-hypertensive medications use (OR 4.38; 95%CI 4.07,4.71,p < 0.001) were independently associated with statin use. CONCLUSION: In a real-world evidence study analyzing data routinely collected in a digitized primary care setting, we observed a very low use of statins in a primary prevention population with cardiovascular risk enhancers in Brazil. Socio-demographic factors and co-morbidities were associated to higher statins use rates.

Evolocumab Treatment in Pediatric Patients With Homozygous Familial Hypercholesterolemia: Pooled Data From Three Open-Label Studies.

BACKGROUND: Pediatric patients with homozygous familial hypercholesterolemia (HoFH) have an increased risk of atherosclerotic cardiovascular disease and difficulty meeting low-density lipoprotein cholesterol (LDL-C) goals. In this post hoc analysis, we evaluated pooled safety and efficacy data from 3 studies in pediatric patients with HoFH treated with the PCSK9 (proprotein convertase subtilisin/kexin type 9) monoclonal antibody inhibitor evolocumab. METHODS: Patients with HoFH aged 10 to 17 years received treatment with open-label evolocumab 420 mg subcutaneously monthly or biweekly in the TAUSSIG, RAMAN, or HAUSER-OLE clinical studies. All patients received background statins with or without ezetimibe. Study duration ranged from 12 to 260 weeks. The primary end point was treatment-emergent adverse events per 100 patient-years. Efficacy end points were changes from baseline to week 12 in lipids and PCSK9. RESULTS: Of the 39 patients in the pooled analysis, 69.2% were males, median age was 13.0 years, and 79.5% (31/39) had genotyped HoFH with LDLR pathogenic variants. Overall, median exposure to evolocumab was 18.2 (Q1, Q3: 3.0, 18.5) months. Treatment-emergent adverse events with an exposure-adjusted patient incidence rate of ≥5% were upper respiratory tract infection (6.6%), influenza (5.2%), and acne (5.0%) per 100 patient-years. Exposure-adjusted patient incidence of serious treatment-emergent adverse events was 13.3% per 100 patient-years. Excluding 4 patients receiving lipoprotein apheresis, week 12 median percentage change from baseline in LDL-C was -2.9% (Q1, Q3: -21.7, 1.5); however, 42.9% (15/35) of patients achieved ≥15% reduction in LDL-C from baseline. Residual LDLR (LDL receptor) activity was not associated with a reduction in LDL-C. CONCLUSIONS: In this pooled data analysis from 3 studies in pediatric patients with HoFH, evolocumab was well tolerated, with no new safety signals reported. These safety findings are consistent with findings from previous studies of evolocumab. Patients showed marked variability in LDL-C reduction. Results from this pooled analysis support guidelines suggesting a trial of PCSK9 inhibitor therapy regardless of estimated residual LDLR function. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01624142, NCT03403374, and NCT02624869.

Alirocumab in Pediatric Patients With Heterozygous Familial Hypercholesterolemia: A Randomized Clinical Trial.

Importance: Many pediatric patients with heterozygous familial hypercholesterolemia (HeFH) cannot reach recommended low-density lipoprotein cholesterol (LDL-C) concentrations on statins alone and require adjunct lipid-lowering therapy (LLT); the use of alirocumab in pediatric patients requires evaluation. Objective: To assess the efficacy of alirocumab in pediatric patients with inadequately controlled HeFH. Design, Setting, and Participants: This was a phase 3, randomized clinical trial conducted between May 2018 and August 2022 at 43 centers in 24 countries. Pediatric patients aged 8 to 17 years with HeFH, LDL-C 130 mg/dL or greater, and receiving statins or other LLTs were included. Following consecutive enrollment into dosing cohorts, 25 of 99 patients screened for dosing every 2 weeks (Q2W) failed screening; 25 of 104 patients screened for dosing every 4 weeks (Q4W) failed screening. A total of 70 of 74 Q2W patients (95%) and 75 of 79 Q4W patients (95%) completed the double-blind period. Interventions: Patients were randomized 2:1 to subcutaneous alirocumab or placebo and Q2W or Q4W. Dosage was based on weight (40 mg for Q2W or 150 mg for Q4W if <50 kg; 75 mg for Q2W or 300 mg for Q4W if ≥50 kg) and adjusted at week 12 if LDL-C was 110 mg/dL or greater at week 8. After the 24-week double-blind period, patients could receive alirocumab in an 80-week open-label period. Main Outcomes and Measures: The primary end point was percent change in LDL-C from baseline to week 24 in each cohort. Results: Among 153 patients randomized to receive alirocumab or placebo (mean [range] age, 12.9 [8-17] years; 87 [56.9%] female), alirocumab showed statistically significant reductions in LDL-C vs placebo in both cohorts at week 24. Least squares mean difference in percentage change from baseline was -43.3% (97.5% CI, -56.0 to -30.7; P < .001) Q2W and -33.8% (97.5% CI, -46.4 to -21.2; P < .001) Q4W. Hierarchical analysis of secondary efficacy end points demonstrated significant improvements in other lipid parameters at weeks 12 and 24 with alirocumab. Two patients receiving alirocumab Q4W experienced adverse events leading to discontinuation. No significant difference in adverse event incidence was observed between treatment groups. Open-label period findings were consistent with the double-blind period. Conclusions and Relevance: The findings in this study indicate that alirocumab Q2W or Q4W significantly may be useful for reducing LDL-C and other lipid parameters and be well tolerated in pediatric patients with HeFH inadequately controlled with statins. Trial Registration: ClinicalTrials.gov Identifier: NCT03510884.

Glp-1 Mimetics and Autophagy in Diabetic Milieu: State-of-the-Art.

The diabetic milieu is associated with cascades of pathophysiological pathways that culminate in diabetic complications and tissue injuries. Autophagy is an essential process mandatory for cell survival and tissue homeostasis by degrading damaged organelles and removing injured cells. However, it may turn into a pathological process in an aberrant mode in the diabetic and/or malignant milieu. Moreover, autophagy could serve as a promising therapeutic target for many complications related to tissue injury. Glp-1 mimetics are a class of newer antidiabetic agents that reduce blood glucose through several pathways. However, some evidence suggests that they can provide extra glycemic benefits by modulating autophagy, although there is no complete understanding of this mechanism and its underlying molecular pathways. Hence, in the current review, we aimed to provide new insights on the possible impact of Glp-1 mimetics on autophagy and consequent benefits as well as mediating pathways.

The association between consumption of red and processed meats with metabolic syndrome and its components in obese and overweight women: a cross-sectional study.

OBJECTIVES: Previous studies have shown a relation between the consumption of different types of meats and chronic disorders. This study aims to investigate the association between red and processed meat intake with metabolic syndrome (MetS) and its components in healthy obese and overweight women. METHODS: This cross-sectional study was conducted on Iranian women. The dietary assessment and body composition were measured by a validated food frequency questionnaire (FFQ) and bioelectrical impedance analysis, respectively. Blood samples were collected by standard protocols. RESULTS: A total of 231 women (mean age 36.47 ± 8.44 years) were included in the current study. After controlling for potential confounders, there was a marginally significant associations between higher intake of processed meat with the MetS (OR:1.01, 95% CI: 0.94,2.94, P:0.06) and high serum triglycerides (TG) (OR:1.27, 95% CI: 0.94,2.98, P:0.07). There was a significant associations between high intake of red meats with lower odds of higher waist circumference (WC) (OR:0.31, 95% CI: 0.10,0.97, P:0.04). Also, there was a significant associations were found between high intake of processed meats with greater odds of having lower high-density lipoprotein cholesterol (HDL-c) (OR:0.64, 95% CI: 0.30,0.95, P:0.03). CONCLUSIONS: The current study suggests that higher intakes of processed meat may be associated with the MetS in Iranian women with excess body weight, while this was not the case for red meat. More studies however are necessary in different communities to draw definitive conclusions.

Atorvastatin Effect on COVID-19 Outcomes: A Propensity Score Matched Study on Hospitalized Patients.

BACKGROUND: This study investigated the association of atorvastatin use on survival, need for intensive care unit (ICU) admission, and length of hospital stay (LOS) among COVID-19 inpatients. MATERIALS AND METHODS: A retrospective study was conducted between March 20th, 2020, and March 18th, 2021, on patients with confirmed COVID-19 admitted to three hospitals in Tehran, Iran. The unadjusted and adjusted effects of atorvastatin on COVID-19 prognosis were investigated. Propensity score matching (PSM) was used to achieve a 1:1 balanced dataset with a caliper distance less than 0.1 and the nearest neighbor method without replacement. RESULTS: Of 4322 COVID-19 patients, 2136 (49.42%) were treated with atorvastatin. After PSM, 1245 atorvastatin inpatients and 1245 controls were included with a median age of 62.0 (interquartile range [IQR]: 51.0, 76.0) and 63.0 (IQR: 51.0, 75.0) years, respectively. The standardized mean differences were less than 0.1 for all confounders, suggesting a good covariate balance. The use of atorvastatin was associated with decreased COVID-19 mortality (HR: 0.80; 95% CI: 0.68-0.95), whereas no relationship was found between atorvastatin and the need for ICU admission (HR: 1.21; 95% CI: 0.99-1.47). LOS was significantly higher in the atorvastatin cohort than controls (Atorvastatin vs. others: 7 [5, 11] vs. 6 [4, 10] days; p = 0.003). The survival rate was higher in combination therapy of atorvastatin plus enoxaparin than in those who received atorvastatin alone (p-value=0.001). CONCLUSION: Atorvastatin may reduce the risk of COVID-19 in-hospital mortality and could be a beneficial option for an add-on therapy. Randomized trials are warranted to confirm the results of the current observational studies.

International Atherosclerosis Society Roadmap for Familial Hypercholesterolaemia.

Familial hypercholesterolaemia (FH), a common monogenic disorder, is a preventable cause of premature coronary artery disease and death. Up to 35 million people worldwide have FH, but most remain undetected and undertreated. Several clinical guidelines have addressed the gaps in care of FH, but little focus has been given to implementation science and practice. The International Atherosclerosis Society (IAS) has developed an evidence-informed guidance for the detection and management of patients with FH, supplemented with implementation strategies to optimize contextual models of care. The guidance is partitioned into detection, management and implementation sections. Detection deals with screening, diagnosis, genetic testing and counselling. Management includes risk stratification, treatment of adults and children with heterozygous and homozygous FH, management of FH during pregnancy, and use of lipoprotein apheresis. Specific and general implementation strategies, guided by processes specified by the Expert Recommendations for Implementing Change taxonomy, are provided. Core generic implementation strategies are given for improving care. Nation-specific cholesterol awareness campaigns should be utilized to promote better detection of FH. Integrated models of care should be underpinned by health policy and adapted to meet local, regional and national needs. Clinical centres of excellence are important for taking referrals from the community. General practitioners should work seamlessly with multidisciplinary teams. All health-care providers must receive training in essential skills for caring for patients and families with FH. Management should be supported by shared decision-making and service improvement driven by patient-reported outcomes. Improvements in services require sharing of existing resources that can support care. Advocacy should be utilized to ensure sustainable funding. Digital health technologies and clinical quality registries have special value. Finally, academic-service partnerships need to be developed to identify gaps in care and set priorities for research. This new IAS guidance on FH complements the recent World Heart Federation Cholesterol Roadmap.

Acute myocardial infarction preferentially alters low-abundant, long-chain unsaturated phospholipid and sphingolipid species in plasma high-density lipoprotein subpopulations.

Aim: High-density lipoprotein (HDL) particles in ST-segment elevation myocardial infarction (STEMI) are deficient in their anti-atherogenic function. Molecular determinants of such deficiency remain obscure. Methods: Five major HDL subpopulations were isolated using density-gradient ultracentrifugation from STEMI patients (n = 12) and healthy age- and sex-matched controls (n = 12), and 160 species of phosphatidylcholine, lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol, phosphatidylserine, phosphatidic acid, sphingomyelin and ceramide were quantified by LC-MS/MS. Results: Multiple minor species of proinflammatory phosphatidic acid and lysophosphatidylcholine were enriched by 1.7-27.2-fold throughout the majority of HDL subpopulations in STEMI. In contrast, minor phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, sphingomyelin and ceramide species were typically depleted up to 3-fold in STEMI vs. control HDLs, while abundances of their major species did not differ between the groups. Intermediate-to-long-chain phosphatidylcholine, phosphatidylinositol and phosphatidylglycerol species were more affected by STEMI than their short-chain counterparts, resulting in positive correlations between their fold decrease and the carbon chain length. Additionally, fold decreases in the abundances of multiple lipid species were positively correlated with the double bond number in their carbon chains. Finally, abundances of several phospholipid and ceramide species were positively correlated with cholesterol efflux capacity and antioxidative activity of HDL subpopulations, both reduced in STEMI vs controls. KEGG pathway analysis tied these species to altered glycerophospholipid and linoleic acid metabolism. Conclusions: Minor unsaturated intermediate-to-long-chain phospholipid and sphingolipid species in HDL subpopulations are most affected by STEMI, reflecting alterations in glycerophospholipid and linoleic acid metabolism with the accumulation of proinflammatory lysolipids and maintenance of homeostasis of major phospholipid species.

First Report of Inclisiran Utilization for Hypercholesterolemia Treatment in Real-world Clinical Settings in a Middle East Population.

PURPOSE: Inclisiran is the first small interfering RNA-based treatment approved for reducing pro-atherogenic lipoproteins in patients with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of low-density lipoprotein cholesterol (LDL-C). We report the first evaluation of the effects of inclisiran in a Middle East population. METHODS: We conducted a retrospective review of patients initiating inclisiran treatment at an outpatient diabetology, endocrinology, and cardiology center between May 2021 and December 2022. All patients followed up for 90 days or more, or with at least 1 lipid determination post initiation were included. Participants were categorized into primary prevention (n = 57) and secondary prevention (n = 89) groups according to previous atherosclerotic cardiovascular disease. FINDINGS: Inclisiran was initiated in 146 patients; mean (SD) age was 54.8 (12.12) years, 82 patients (56.2%) were male, 28 patients (19.2%) had received a diagnosis of familial hypercholesterolemia, 89 patients (61%) had received a diagnosis of diabetes mellitus, and 35 patients (23.9%) had a statin intolerance. Median (interquartile range) follow-up was 137 (90 to 193) days. At 90 days, median (interquartile range) reductions in serum LDL-C and triglycerides were -37.9% (-9.5% to -51.2%) and -12.0% (-9.8% to -40.5%), respectively, in primary prevention and -54.1% (-17.1% to -71.4%) and -15.3% (-14% to -38.8%), respectively, in secondary prevention (all, P < 0.001). LDL-C goals were attained in 110 patients (75.3%). Nonattainment of LDL-C goal was attributed to system effect in 26 patients (72.2%), biological effect in 5 patients (13.9%), and discontinuation of treatment in 5 patients (13.9%). Therapy was well tolerated. IMPLICATIONS: This study is the first from the Middle East and North Africa region that reported the real-world efficacy and safety profile of inclisiran in a mixed-risk population of patients with heterozygous familial hypercholesterolemia and other non-familial hypercholesterolemia indications. Clinically meaningful and sustained reductions in pro-atherogenic lipids with good tolerability were observed after inclisiran initiation. Fewer AEs were reported in this predominantly Arabic population, consistent with previous safety reports for inclisiran. It is important to note that no patient stopped inclisiran treatment due to AEs. Strengths of our study included an optimal cohort, patient heterogeneity, and high retention. In addition, we were able to report mean robust effects of inclisiran and good medication tolerability, quite like randomized studies and open-label extension periods. Despite this, our study had some limitations, including selection bias due to the retrospective design and the absence of a comparative group.

New-Onset Diabetes Mellitus in COVID-19: A Scoping Review.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic became superimposed on the pre-existing obesity and diabetes mellitus (DM) pandemics. Since COVID-19 infection alters the metabolic equilibrium, it may induce pathophysiologic mechanisms that potentiate new-onset DM, and we evaluated this issue. METHOD: A systematic review of the literature published from the 1 January 2020 until the 20 July 2023 was performed (PROSPERO registration number CRD42022341638). We included only full-text articles of both human clinical and randomized controlled trials published in English and enrolling adults (age > 18 years old) with ongoing or preceding COVID-19 in whom hyperglycemia was detected. The search was based on the following criteria: "(new-onset diabetes mellitus OR new-onset DM) AND (COVID-19) AND adults". RESULTS: Articles on MEDLINE (n = 70) and the Web of Science database (n = 16) were included and analyzed by two researchers who selected 20 relevant articles. We found evidence of a bidirectional relationship between COVID-19 and DM. CONCLUSIONS: This link operates as a pathophysiological mechanism supported by epidemiological data and also by the clinical and biological findings obtained from the affected individuals. The COVID-19 pandemic raised the incidence of DM through different pathophysiological and psychosocial factors.