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Background: Statins are the most widely used drugs for decreasing elevated serum LDL-cholesterol (LDL-C) and thus for the prevention of atherosclerotic cardiovascular disease (ASCVD), but they have also some pleiotropic effects, including anti-inflammatory properties. Atherosclerosis is a low-grade inflammatory disease, and elevated ferritin is considered to be one of the markers of inflammation. Since the results of studies on the effects of statins on serum ferritin levels are conflicting, this meta-analysis was performed., Methods: A literature search was performed using major electronic databases (MEDLINE/PubMed, Scopus, Embase, and ISI Web of Science) from inception up to 5 March 2022 to find studies evaluating the effect of different statins on serum ferritin levels. The effect size was determined using weighted mean differences (WMDs) and the corresponding 95% confidence intervals (CIs)., Results: The meta-analysis of nine studies (1611 patients) analyzing the effects of statins on serum ferritin levels that were included showed a significant decrease in circulating ferritin levels caused by statins. The results did not suggest any significant association between the changes in concentrations of serum ferritin and the duration of treatment with statins., Conclusions: Statin therapy decreases the circulating concentrations of ferritin, which might be beneficial for the prevention and/or progression of ASCVD. This effect might be explained by the anti-inflammatory effects and maybe some other pleiotropic effects of statins and not by their lipid-lowering effects.

Background: Obesity, especially severe obesity, is associated with a higher risk of atherosclerotic cardiovascular disease (ASCVD) morbidity and mortality. Bariatric surgery is a durable and effective weight loss therapy for patients with severe obesity and weight-related comorbidities. Elevated plasma levels of lipoprotein (a) (Lp(a)) are causally associated with ASCVD. The aim of this meta-analysis was to analyze whether bariatric surgery is associated with Lp(a) concentrations., Methods: A literature search in PubMed, Scopus, Embase, and Web of Science was performed from inception to May 1st, 2021. A random-effects model and the generic inverse variance weighting method were used to compensate for the heterogeneity of studies in terms of study design, treatment duration, and the characteristics of the studied populations. A random-effects metaregression model was used to explore the association with an estimated effect size. Evaluation of funnel plot, Begg's rank correlation, and Egger's weighted regression tests were used to assess the presence of publication bias in the meta-analysis., Results: Meta-analysis of 13 studies including 1551 patients showed a significant decrease of circulating Lp(a) after bariatric surgery (SMD: -0.438, 95% CI: -0.702, -0.174, p < 0.001, I 2 : 94.05%). The results of the metaregression did not indicate any significant association between the changes in Lp(a) and duration of follow-up after surgery, reduction in body mass index, or baseline Lp(a) concentration. The reduction in circulating Lp(a) was robust in the leave-one-out sensitivity analysis., Conclusion: Bariatric surgery significantly decreases circulating Lp(a) concentrations. This decrease may have a positive effect on ASCVD in obese patients., Competing Interests: RDS reports receiving the following: consulting fees and lecture fees from Abbott, Amgen, Astra Zeneca, Aché, EMS, Getz Pharma, Libbs, Merck, Merck Sharp & Dohme, PTC Therapeutics, Novo Nordisk, Novartis, and Sanofi-Regeneron Pharmaceuticals and grant support from Amgen, Kowa, Esperion, Kowa, Novartis, and Sanofi-Regeneron Pharmaceuticals outside this work. RDS has received honoraria related to consulting, speaker activities, and/or research from Abbott, Amgen, Astra Zeneca, Aché, Esperion, EMS, Hypera, Getz Pharma, Kowa, Libbs, PTC Pharmaceuticals, Pfizer, Medley, Merck, MSD, Novo-Nordisk, Novartis, and Sanofi., (Copyright © 2022 Tannaz Jamialahmadi et al.)

Background: Elevated serum low-density lipoproteins (LDL), the substrate for the formation of atherogenic oxidized LDLs (oxLDL), are a causal factor for atherosclerotic cardiovascular disease (ASCVD). Statins are well known to decrease LDL particle concentration and reduce ASCVD morbidity and mortality., Objective: To perform a meta-analysis of the effects of statins (i.e., type, dose, and duration of treatment) on serum levels of oxLDL and on immunoglobulin M (IgM) and immunoglobulin G (IgG) antibody levels against oxLDL., Methods: PubMed, Scopus, Embase, and Web of Science were searched up to February 5th, 2021, for randomized controlled trials (RCT) evaluating the effect of statins on oxLDL and anti-oxLDL antibody levels. Meta-analysis was performed using Comprehensive Meta-Analysis (CMA) V2 software. To evaluate the influence of each study on the overall effect size, a sensitivity analysis was performed using the leave-one-out method. Evaluation of the funnel plot, Begg's rank correlation, and Egger's weighted regression tests was used to assess the presence of publication bias in the meta-analysis., Results: A total of 28 RCTs including 4019 subjects were finally included in the meta-analysis. The results indicated a significant decrease in circulating concentrations of oxLDL after treatment with statins (SMD: -2.150, 95% CI: -2.640, -1.697, p < 0.001). Subgroup analysis found no significant effect of the intensity of statin treatment or statin lipophilicity on the reduction of circulating concentrations of oxLDL. An additional meta-analysis of 3 trials showed that statins did not change the serum levels of IgM and IgG antibodies to oxLDL., Conclusion: Statin therapy decreases serum oxLDL concentrations but does not affect circulating levels of anti-oxLDL antibodies., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Tannaz Jamialahmadi et al.)

Dyslipidaemia is a well-known risk factor for the development of cardiovascular disease, a leading cause of morbidity and mortality in developed countries. As a consequence, the medical community has been dealing with this problem for decades, and traditional statin therapy remains the cornerstone therapeutic approach. However, clinical trials have observed remarkable results for a few agents effective in the treatment of elevated serum lipid levels. Ezetimibe showed good but limited results when used in combination with statins. Bempedoic acid has been thoroughly studied in multiple clinical trials, with a reduction in LDL cholesterol by approximately 15%. The first approved monoclonal antibodies for the treatment of dyslipidaemia, PCSK9 inhibitors, are currently used as second-line treatment for patients with unregulated lipid levels on statin or statin combination therapy. A new siRNA molecule, inclisiran, demonstrates great potential, particularly concerning compliance, as it is administered twice yearly and pelacarsen, an antisense oligonucleotide that targets lipoprotein(a) and lowers its levels. Volanesorsen is the first drug that was designed to target chylomicrons and lower triglyceride levels, and olezarsen, the next in-line chylomicron lowering agent, is currently being researched. The newest possibilities for the treatment of dyslipidaemia are ANGPTL3 inhibitors with evinacumab, already approved by the FDA, and EMA for the treatment of familial hypercholesterolemia. This article provides a short summary of new agents currently used or being developed for lipid lowering treatment.

Background: Many of the survivors of critical illnesses in the intensive care unit (ICU) suffer from physical disability for months after the treatment in the ICU. Identifying patients who are susceptible to disability is essential. The purpose of the study was to modify a model for early in-ICU prediction of the patient's risk for physical disability two months after the treatment in the ICU., Methods: A prospective multicenter derivation-validation study was conducted from 1 July 2015, to 31 August 2016. We modified a model consisting of three risk factors in the derivation group and tested the modified model in the validation group. They were asked for their physical abilities before being admitted, two months after discharge from the ICU by a binary ADL staircases questionnaire. The univariate and multivariate logistic regression was used to modify physical disability components in the derivation data set. Receiver operating characteristic curves were used to determine the sensitivity and specificity of the threshold values in the validation group., Results: Five-hundred nineteen survivors were enrolled in the derivation group, and 271 in the validation. In multivariable analysis, the odds ratio (OR) of physical disability significantly increased with educational level ≤ elementary school (OR: 36.96, 95%CI: 18.14-75.29), inability to sit without support (OR: 15.16, 95%CI: 7.98-28.80), and having a fracture (OR: 12.74, 95%CI: 4.47-36.30). The multivariable validation model indicated that education level, inability to sit without support, and having a fracture simultaneously had sensitivity 71.3%, specificity 88.2%, LR+ 6.0, LR- 0.33, PPV 90.9, and NPV 64.9 to predict physical disability. Applying the coefficients derived from the multivariable logistic regression fitted on the derivation dataset in the validation dataset and computing diagnostic index sensitivity 100%, specificity 60.5%, LR+ 2.5, LR- 0.003, PPV 80.8, and NPV 100. The modified model had an excellent prediction ability for physical disability (AUC ± SE = 0.881 ± 0.016)., Conclusions: Low education level, inability to sit without support, and having a fracture in a modified model were associated with the development of physical disability after discharge from ICU. Therefore, these clinical variables should be considered when organizing follow-up care for ICU survivors.

Context: Familial Chylomicronemia Syndrome (FCS) is an inherited disease where lack of lipoprotein lipase results in severe hypertriglyceridemia that frequently leads to recurrent acute pancreatitis. Pregnancy in patients with familial chylomicronemia syndrome (FCS) post a risk for mother and baby with potential complications (pancreatitis, miscarriage and death). Therapeutic approach includes strict dietary measures and plasma exchange. Despite the development of new drugs for FCS, their safety in pregnancy has not yet been confirmed., Case Description: We present a case of a young, pregnant female with FCS who had miscarriage in the past during one episode of acute pancreatitis. Due to the inability to achieve lower TG levels with current therapy, from 27-th week of pregnancy we have started prophylactic therapeutic plasma exchange (two times per week). Patient was followed up until the delivery of a healthy baby boy and did not experience an episode of acute pancreatitis., Conclusions: With adequate supervision and monitoring therapeutic plasma exchange represents a safe approach in pregnant women with FCS in order to reduce TGs and prevent pancreatitis. Therefore, we prevented potential complications for both mother and child., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Statin intolerance is a clinical syndrome whereby adverse effects (AEs) associated with statin therapy [most commonly statin-associated muscle symptoms (SAMS)] result in the discontinuation of therapy and consequently increase the risk of adverse cardiovascular outcomes. However, complete statin intolerance occurs in only a small minority of treated patients (estimated prevalence of only 3-5%). Many perceived AEs are misattributed (e.g. physical musculoskeletal injury and inflammatory myopathies), and subjective symptoms occur as a result of the fact that patients expect them to do so when taking medicines (the nocebo/drucebo effect)-what might be truth even for over 50% of all patients with muscle weakness/pain. Clear guidance is necessary to enable the optimal management of plasma in real-world clinical practice in patients who experience subjective AEs. In this Position Paper of the International Lipid Expert Panel (ILEP), we present a step-by-step patient-centred approach to the identification and management of SAMS with a particular focus on strategies to prevent and manage the nocebo/drucebo effect and to improve long-term compliance with lipid-lowering therapy., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Atherosclerosis has a long preclinical phase, and the risk of cardiovascular (CV) events may be high in asymptomatic subjects. Conventional risk factors provide information for the statistical probability of developing CV events, but they lack precision in asymptomatic subjects. This review aims to summarize the role of some widely publicized indicators of early atherosclerosis in predicting CV events. The earliest measurable indicator of the atherosclerotic process is endothelial dysfunction, measured by flow-mediated dilation (FMD) of the brachial artery. However, reduced FMD is a stronger predictor of future CV events in patients with existing CV disease than in apparently healthy persons. Alternatively, measurement of carotid artery intima-media thickness does not improve the predictive value of risk factor scores, while detection of asymptomatic atherosclerotic plaques in carotid or common femoral arteries by ultrasound indicates high CV risk. Coronary calcium is a robust and validated help in the estimation of vascular changes and risk, which may improve risk stratification beyond traditional risk factors with relatively low radiation exposure. Arterial stiffness of the aorta, measured as the carotid-femoral pulse wave velocity is an independent marker of CV risk at the population level, but it is not recommended as a routine procedure because of measurement difficulties. Low ankle-brachial index (ABI) indicates flow-limiting atherosclerosis in the lower limbs and indicates high CV risk, while normal ABI does not rule out advanced asymptomatic atherosclerosis. Novel circulating biomarkers are associated with the atherosclerotic process. However, because of limited specificity, their ability to improve risk classification at present remains low., (Copyright © 2022. Published by Elsevier B.V.)

Aims: Most patients with established atherosclerotic cardiovascular disease (CVD) are at very high risk for developing recurrent events. Since this risk varies a lot between patients there is a need to identify those in whom an even more intensive secondary prevention strategy should be envisaged. Using data from the EUROASPIRE IV and V cohorts of coronary heart disease (CHD) patients from 27 European countries, we aimed at developing and internally and externally validating a risk model predicting recurrent CVD events in patients aged < 75 years., Methods and Results: Prospective data were available for 12 484 patients after a median follow-up time of 1.7 years. The primary endpoint, a composite of fatal CVD or new hospitalizations for non-fatal myocardial infarction (MI), stroke, heart failure, coronary artery bypass graft, or percutaneous coronary intervention (PCI), occurred in 1424 patients. The model was developed based on data from 8000 randomly selected patients in whom the association between potential risk factors and the incidence of the primary endpoint was investigated. This model was then validated in the remaining 4484 patients. The final multivariate model revealed a higher risk for the primary endpoint with increasing age, a previous hospitalization for stroke, heart failure or PCI, a previous diagnosis of peripheral artery disease, self-reported diabetes and its glycaemic control, higher non-high-density lipoprotein cholesterol, reduced renal function, symptoms of depression and anxiety and living in a higher risk country. The model demonstrated excellent internal validity and proved very adequate in the validation cohort. Regarding external validity, the model demonstrated good discriminative ability in 20 148 MI patients participating in the SWEDEHEART register. Finally, we developed a risk calculator to estimate risks at 1 and 2 years for patients with stable CHD., Conclusion: In patients with CHD, fatal and non-fatal rates of recurrent CVD events are high. However, there are still opportunities to optimize their management in order to prevent further disease or death. The EUROASPIRE Risk Calculator may be of help to reach this goal., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Statins are competitive inhibitors of hydroxymethylglutaryl-CoA (HMG-CoA) reductase and have been used to treat elevated low-density lipoprotein cholesterol (LDL-C) for almost four decades. Antioxidant and anti-inflammatory properties which are independent of the lipid-lowering effects of statins, i.e., their pleiotropic effects, might be beneficial in the prevention or treatment of many diseases. This review discusses the antioxidant effects of statins achieved by modulating the nuclear factor erythroid 2 related factor 2/ heme oxygenase-1 (Nrf2/HO-1) pathway in different organs and diseases. Nrf2 and other proteins involved in the Nrf2/HO-1 signaling pathway have a crucial role in cellular responses to oxidative stress, which is a risk factor for ASCVD. Statins can significantly increase the DNA-binding activity of Nrf2 and induce the expression of its target genes, such as HO-1 and glutathione peroxidase) GPx, (thus protecting the cells against oxidative stress. Antioxidant and anti-inflammatory properties of statins, which are independent of their lipid-lowering effects, could be partly explained by the modulation of the Nrf2/HO-1 pathway.

Background: Coronavirus disease 2019 (COVID-19) might affect everyone, but people with comorbidities such as hypertension and cardiovascular disease (CVD) may often have more severe complications and worse outcomes. Although vaccinations are being performed worldwide, it will take a long time until the entire population of the world is vaccinated. On the other hand, we are witnessing the emergence of new variants of this virus. Therefore, effective therapeutic approaches still need to be considered. Statins are well-known lipid-lowering drugs, but they have also anti-inflammatory and immunomodulatory effects. This study aimed to investigate the effects of statins on the survival of COVID-19 hospitalized patients., Methods: This retrospective study was performed on 583 patients admitted to a highly referenced hospital in Tabas, Iran, between February 2020 and December 2020. One hundred sixty-two patients were treated with statins and 421 patients were not. Demographic information, clinical signs, and the results of laboratory, and comorbidities were extracted from patients' medical records and mortality and survival rates were assessed in these two groups., Results: The results of the Cox crude regression model showed that statins reduced mortality in COVID-19 patients (HR = 0.56, 95% CI: 0.32, 0.97; p = 0.040), although this reduction was not significant in the adjusted model (HRs=0.51, 95%CI: 0.22, 1.17; p = 0.114). Using a composite outcome comprising intubation, ICU admission, and mortality, both crude (HR = 0.43; 95% CI: 0.26, 0.73; p = 0.002) and adjusted (HR = 0.57; 95% CI: 0.33, 0.99; p = 0.048) models suggested a significant protective effect of statin therapy., Conclusion: Due to anti-inflammatory properties of statins, these drugs can be effective as an adjunct therapy in the treatment of COVID-19 patients., Competing Interests: MB speakers bureau: Abbott/Mylan, Abbott Vascular, Actavis, Akcea, Amgen, Biofarm, KRKA, MSD, Polpharma, Sanofi-Aventis, Servier and Valeant; consultant to Abbott Vascular, Akcea, Amgen, Daichii Sankyo, Esperion, Freia Pharmaceuticals, Lilly, MSD, Polfarmex, Resverlogix, Sanofi-Aventis; Grants from Sanofi and Valeant. ŽR has received honoraria from Sanofi-Aventis and Novartis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kouhpeikar, Khosaravizade Tabasi, Khazir, Naghipour, Mohammadi Moghadam, Forouzanfar, Abbasifard, Kirichenko, Reiner, Banach and Sahebkar.)

As dyslipidemias remain one of the main risk factors for developing cardiovascular disease, the question of maintaining optimal lipid levels with pharmacotherapy remains a subject of interest worldwide. In contrast to conventional pharmacotherapy, human monoclonal antibodies directed against proprotein convertase subtilisin/kexin type 9 (PSCK9) and small interfering RNA- (siRNA-) based drug targeting PCSK9 represent a new strategy for managing lipid disorders and reducing cardiovascular risk. Inclisiran is a long-acting, synthetic siRNA that targets hepatic production of PCSK9 and consequently causes a reduction in LDL-C concentrations by approximately 50% compared to placebo. The structural modification of inclisiran has led to better stability and prolonged biological activity of the drug. The main advantage over conventional pharmacotherapy and anti-PCSK9 monoclonal antibodies is its favorable administration regimen (0-90-180 days), which should lead to much better compliance. Clinical trials conducted so far have confirmed the tolerability and efficacy of inclisiran in long-term PCSK9 and LDL-C level reductions. Moreover, a short-term follow-up on the safety of inclisiran showed a relatively good safety profile of the drug. However, it is still of great importance for ongoing and forthcoming clinical trials to be continued on a larger group of patients in order to assess long-term tolerability, efficacy, and safety of inclisiran., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Iveta Merćep et al.)

Objective: In-stent restenosis (ISR) is an unfavorable complication that occurs in patients after coronary stenting. Despite the progress with advent of modern DES and new antiplatelet agents, restenosis still hampers PCI short- and long-term results. The aim of this study was to investigate whether circulating miRNA-223, which is associated with HDL particles and involved in cholesterol efflux pathway, have diagnostic capability for determining ISR., Methods: This case-control study comprised 21 ISR and 26 NISR patients. The level of miRNA-223 expression was evaluated by TaqMan Real-Time PCR, quantified by the comparative method (fold change) and normalized to U6 expression., Results: Patients in ISR and NISR groups were not different in terms of demographic, clinical, and biochemical parameters, except that the percentage of patients who had DES was significantly greater in the NISR group (88.9%) in comparison with the ISR group (50%). The serum expression of miRNA-223 in ISR patients was 3.277 ± 0.9 times greater than that in NISR group ( p = 0.016). In addition, the results of binary logistic regression demonstrated that the high level of serum miRNA-223 was strongly and positively associated with the ISR risk (OR: 17.818, 95% CI: 1.115-284.623, p = 0.042) after adjustment for age, sex, HDL-C, LDL-C, FBS, and statin consumption., Conclusion: Elevated serum level of miRNA-223 might be helpful in predicting the occurrence of ISR. Further confirmation in future large-scale studies is warranted.

Background: Several studies have reported that statins have anti-inflammatory effects. Nevertheless, results of clinical trials concerning the effect of statins on the levels of C-reactive protein (CRP) and high-sensitivity CRP (hs-CRP) have been inconsistent. Therefore, we performed a systematic review and meta-analysis of randomized clinical trials (RCTs) evaluating the effect of statins on CRP and hs-CRP levels in patients with cardiovascular diseases (CVDs)., Methods: Literature search of the major databases was performed to find eligible RCTs assessing the effect of statins on serum levels of CRP and hs-CRP from the inception until the last week of April 2021. The effect sizes were determined for weighted mean difference (WMD) and 95% confidence intervals (CI)., Results: 26 studies were identified (3010 patients and 2968 controls) for hs-CRP and 20 studies (3026 patients and 2968 controls) for CRP. Statins reduced the serum levels of hs-CRP (WMD = -0.97 mg/L; 95% CI: -1.26 to -0.68 mg/L; P < 0.001) and CRP (WMD = -3.05 mg/L; 95% CI: -4.86 to -1.25 mg/L; P < 0.001) in patients with CVDs. Statins decreased the serum levels of hs-CRP in patients receiving both high-intensity and moderate/low-intensity treatments with these drugs. In addition, the duration of treatment longer than 10 weeks decreased hs-CRP levels. Only high-intensity statin treatment could marginally decrease serum levels of CRP in CVDs patients., Conclusions: This meta-analysis showed the efficacy of statins to reduce the concentrations of CRP and hs-CRP in patients with different types of CVDs., Competing Interests: ZR has received honoraria from Sanofi-Aventis; MK has received honoraria (for lectures and consultancy) from Abbott and Menarini and research funding from Amryt Pharma, Amgen, and Sanofi and has participated in clinical trials with Amgen, Medicines Company, Regeneron, and Sanofi within the last 2 years. All other authors have nothing to disclose., (Copyright © 2022 Tahmineh Kandelouei et al.)

Background and Aims: Niemann-Pick disease (NPD) types A (NPA) and B (NPB) are caused by deficiency of the acid sphingomyelinase enzyme, which is encoded by the SMPD1 gene, resulting in progressive pathogenic accumulation of lipids in tissues. Trehalose has been suggested as an autophagy inducer with therapeutic neuroprotective effects. We performed a single-arm, open-label pilot study to assess the potential efficacy of trehalose treatment in patients with NPA and NPB patients., Methods: Five patients with NPD type A and B were enrolled in an open-label, single-arm clinical trial. Trehalose was administrated intravenously (IV) (15 g/week) for three months. The efficacy of trehalose in the management of clinical symptoms was evaluated in patients by assessing the quality of life, serum biomarkers, and high-resolution computed tomography (HRCT) of the lungs at the baseline and end of the interventional trial (day 0 and week 12)., Results: The mean of TNO-AZL Preschool children Quality of Life (TAPQOL) scores increased in all patients after intervention at W12 compared to the baseline W0, although the difference was not statistically significant. The serum levels of lyso-SM-509 and lyso-SM were decreased in three and four patients out of five, respectively, compared with baseline. Elevated ALT and AST levels were decreased in all patients after 12 weeks of treatment; however, changes were not statistically significant. Pro-oxidant antioxidant balance (PAB) was also decreased and glutathione peroxidase (GPX) activity was increased in serum of patients at the end of the study. Imaging studies of spleen and lung HRCT showed improvement of symptoms in two patients., Conclusions: Positive trends in health-related quality of life (HRQoL), serum biomarkers, and organomegaly were observed after 3 months of treatment with trehalose in patients with NPA and NPB. Although not statistically significant, due to the small number of patients enrolled, these results are encouraging and should be further explored.

The novel coronavirus (SARS-CoV-2) causing COVID-19 disease pandemic has infected millions of people and caused more than thousands of deaths in many countries across the world. The number of infected cases is increasing day by day. Unfortunately, we do not have a vaccine and specific treatment for it. Along with the protective measures, respiratory and/or circulatory supports and some antiviral and retroviral drugs have been used against SARS-CoV-2, but there are no more extensive studies proving their efficacy. In this study, the latest publications in the field have been reviewed, focusing on the modulatory effects on the immunity of some natural antiviral dietary supplements, vitamins and minerals. Findings suggest that several dietary supplements, including black seeds, garlic, ginger, cranberry, orange, omega-3 and -6 polyunsaturated fatty acids, vitamins (e.g., A, B vitamins, C, D, E), and minerals (e.g., Cu, Fe, Mg, Mn, Na, Se, Zn) have anti-viral effects. Many of them act against various species of respiratory viruses, including severe acute respiratory syndrome-related coronaviruses. Therefore, dietary supplements, including vitamins and minerals, probiotics as well as individual nutritional behaviour can be used as adjuvant therapy together with antiviral medicines in the management of COVID-19 disease.

Cardiovascular diseases are some of the major causes of morbidity and mortality in developed and developing countries. Cardiac fibrosis is one of the most often pathological changes of heart tissues. It occurs as a result of extracellular matrix proteins accumulation at myocardia. Cardiac fibrosis results in impaired cardiac systolic and diastolic functions and is associated with other effects. Therapies with medicines have not been sufficiently successful in treating chronic diseases such as CVD. Therefore, the interest for therapeutic potential of natural compounds and medicinal plants has increased. Plants such as grapes, berries and peanuts contain a polyphenolic compound called "resveratrol" which has been reported to have various therapeutic properties for a variety of diseases. Studies on laboratory models show that resveratrol has beneficial effects on cardiovascular diseases, including myocardial infarction, high blood pressure cardiomyopathy, thrombosis, cardiac fibrosis, and atherosclerosis. In vitro animal models using resveratrol indicated protective effects on the heart by neutralizing reactive oxygen species, preventing inflammation, increasing neoangiogenesis, dilating blood vessels, suppressing apoptosis and delaying atherosclerosis. In this review, we are presenting experimental and clinical results of studies concerning resveratrol effects on cardiac fibrosis as a CVD outcome in humans., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cardiac fibrosis is one of the most common pathological conditions caused by different heart diseases, including myocardial infarction and diabetic cardiomyopathy. Cardiovascular disease is one of the major causes of mortality worldwide. Cardiac fibrosis is caused by different processes, including inflammatory reactions and oxidative stress. The process of fibrosis begins by changing the balance between production and destruction of extracellular matrix components and stimulating the proliferation and differentiation of cardiac fibroblasts. Many studies have focused on finding drugs with less adverse effects for the treatment of cardiovascular disease. Some studies show that nutraceuticals are effective in preventing and treating diseases, including cardiovascular disease, and that they can reduce the risk. However, big clinical studies to prove the therapeutic properties of all these substances and their adverse effects are lacking so far. Therefore, in this review, we tried to summarize the knowledge on pathways and mechanisms of several nutraceuticals which have shown their usefulness in the prevention of cardiac fibrosis., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Familial hypercholesterolemia (FH) as a high-frequency genetic disorder is diagnosed based on family and/or patient's history of coronary heart disease (CHD) or some other atherosclerotic diseases, LDL-C levels, and/or clinical signs such as tendinous xanthoma, arcus cornealis before age 45 years as well as a functional mutation in the LDLR, apoB or PCSK9 gene. Its clinical features are detectable since early childhood. Early diagnosis and timely treatment increase life expectancy in most patients with FH. Current FH therapies decrease the level of lowdensity lipoprotein up to ≥50% from baseline with diet, pharmacotherapeutic treatment, lipid apheresis, and liver transplantation. The cornerstone of medical therapy is the use of more potent statins in higher doses, to which often ezetimibe has to be added, but some FH patients do not achieve the target LDL-C with this therapy Therefore, besides these and the most recent but already established therapeutic approaches including PCSK9 inhibitors, inclisiran, and bempedoic acid, new therapies are on the horizon such as gene therapy, CRISPR/Cas9 strategy, etc. This paper focuses on cellular and molecular potential strategies for the treatment of FH., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Obesity is related to dyslipidemia and increased circulating oxidated LDL (ox-LDL) concentrations that may predispose to atherosclerosis. Bariatric surgery may lower the risk of cardiovascular mortality. Elevated plasma ox-LDL has been associated with atherogenesis and atherosclerotic cardiovascular disease (ASCVD) events. The aim of this meta-analysis was to investigate the impact of bariatric surgery on proatherogenic circulating ox-LDL levels in patients with severe obesity., Methods: Four databases were systematically searched from inception to May 1, 2021. Also, to clarify the heterogeneity of studies with regard to treatment duration, research design, and the demographic features, a random-effects model and the generic inverse variance weighting approach were utilized. To determine the association with the estimated effect size, a random-effect meta-regression approach was performed. Finally, a meta-regression analysis was conducted to explore the influence of, respectively, baseline and changes in body mass index (BMI), baseline ox-LDL, and postsurgery follow-up period with the estimated effect size of surgery on ox-LDL levels., Results: Meta-analysis of 11 studies including 470 subjects showed a significant decline in circulating ox-LDL following bariatric surgery (SMD: -0.971, 95% CI: -1.317, -0.626, p < 0.001, I 2 : 89.43%). The results of meta-regression did not show any significant association between the changes in ox-LDL after bariatric surgery and baseline BMI, duration of follow-up or baseline ox-LDL values. However, there was a significant association between ox-LDL alteration and percentage of BMI change., Conclusion: Bariatric surgery in patients who had severe obesity causes a decrease of circulating ox-LDL that was apparently dependent in BMI changes., Competing Interests: The authors declare that there is no conflict of interest., (Copyright © 2021 Tannaz Jamialahmadi et al.)

Heterozygous familial hypercholesterolaemia (FH) is among the most common genetic metabolic lipid disorders characterised by elevated low-density lipoprotein cholesterol (LDL-C) levels from birth and a significantly higher risk of developing premature atherosclerotic cardiovascular disease. The majority of the current pediatric guidelines for clinical management of children and adolescents with FH does not consider the impact of genetic variations as well as characteristics of vascular phenotype as assessed by recently developed non-invasive imaging techniques. We propose a combined integrated approach of cardiovascular (CV) risk assessment and clinical management of children with FH incorporating current risk assessment profile (LDL-C levels, traditional CV risk factors and familial history) with genetic and non-invasive vascular phenotyping. Based on the existing data on vascular phenotype status, this panel recommends that all children with FH and cIMT ≥0.5 mm should receive lipid lowering therapy irrespective of the presence of CV risk factors, family history and/or LDL-C levels Those children with FH and cIMT ≥0.4 mm should be carefully monitored to initiate lipid lowering management in the most suitable time. Likewise, all genetically confirmed children with FH and LDL-C levels ≥4.1 mmol/L (160 mg/dL), should be treated with lifestyle changes and LLT irrespective of the cIMT, presence of additional RF or family history of CHD.

Purpose: Weight loss during post-bariatric surgery period has been linked to both reduced ASCVD mortality and overall mortality. Atherosclerosis causes arteries to lose their elasticity and become more stiff resulting in increased pulse wave velocity (PWV). It has been revealed that PWV favorably predicts subsequent ASCVDs. The goal of this systematic review and meta-analysis was to see how bariatric surgery affected PWV, an index of arterial stiffness., Materials and Methods: A systematic literature search in four databases was performed. Also, Cochrane guidelines were reviewed to determine bias possibility in the related studies. Comprehensive Meta-Analysis (CMA) V2 software is used to conduct the meta-analysis. Studies were evaluated regarding heterogeneity in design, populations under investigation, and treatment duration using random-effects model and the generic inverse variance weighting approach. A random-effect meta-regression approach was used to investigate the association with the estimated effect size. Evaluation of funnel plot, Egger's weighted regression, and Begg's rank correlation tests were utilized to estimate the presence of publication bias in the meta-analysis., Results: The results of meta-analysis on 13 trials including 1426 individuals demonstrated a remarkable decline of PWV after bariatric surgery (WMD: -0.652, 95% CI: -1.004, -0.301, p<0.001). The random-effects meta-regression revealed no evidence of significant correlation between the changes in PWV and initial BMI, BMI changes, or duration of follow-up., Conclusion: The decrease of PWV might be utilized as an independent surrogate marker of improvement of ASCVD risk after bariatric surgery., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Elevated plasma low-density lipoprotein cholesterol (LDL-C) is the main risk factor for atherosclerotic cardiovascular disease (ASCVD). Statins are the drugs of choice for decreasing LDL-C and are used for the prevention and management of ASCVD. Guidelines recommend that subjects with high and very high ASCVD risk should be treated with high-intensity statins or a combination of high-intensity statins and ezetimibe. The lipophilicity or hydrophilicity (solubility) of statins is considered to be important for at least some of their LDL-C lowering independent pleiotropic effects. Oxidative modification of LDL (ox-LDL) is considered to be the most important atherogenic modification of LDL and is supposed to play a crucial role in atherogenesis and ASCVD outcomes., Objective: The aim of this systematic review and meta-analysis was to find out what are the effects of statin intensity, lipophilicity, and combination of statins plus ezetimibe on ox-LDL., Methods: PubMed, Scopus, Embase, and Web of Science were searched from inception to February 5, 2021, for randomized controlled trials (RCTs). Two independent and blinded authors evaluated eligibility by screening the titles and abstracts of the studies. Risk of bias in the studies included in this meta-analysis was evaluated according to the Cochrane instructions. Meta-analysis was performed using Comprehensive Meta-Analysis (CMA) V2 software. Evaluation of funnel plot, Begg's rank correlation, and Egger's weighted regression tests were used to assess the presence of publication bias., Results: Among the 1427 published studies identified by a systematic databases search, 20 RCTs were finally included in the systematic review and meta-analysis. A total of 1874 patients are included in this meta-analysis. This meta-analysis suggests that high-intensity statin treatment is associated with a significant decrease in circulating concentrations of ox-LDL when compared with low-to-moderate treatment (SMD: -0.675, 95% CI: -0.994, -0.357, p < 0.001; I 2 : 55.93%). There was no difference concerning ox-LDL concentration between treatments with hydrophilic and lipophilic statins (SMD: -0.129, 95% CI: -0.330, -0.071, p = 0.206; I 2 : 45.3%), but there was a significant reduction in circulating concentrations of ox-LDL associated with statin plus ezetimibe combination therapy when compared with statin monotherapy (SMD: -0.220, 95% CI: -0.369, -0.071, p = 0.004; I 2 : 0%)., Conclusion: High-dose statin or combination of statins with ezetmibe reduces plasma ox-LDL in comparison low-to-moderate intensity statin therapy alone. Statin lipophilicity is not associated with reduction in ox-LDL plasma concentrations., Competing Interests: RDS has received honoraria related to speaker activities, consulting, or research from Abbott, Aché, Astra Zeneca, Amgen, EMS, Esperion, Getz Pharma, Kowa, Merck SA, MSD, Novo Nordisk, Novartis, Pfizer, PTC Therapeutics, and Sanofi. Other authors have no competing interests to disclose., (Copyright © 2021 Tannaz Jamialahmadi et al.)

Statins are the low-density lipoproteins (LDL)-cholesterol-lowering drugs of first choice and are used to prevent the increased risk of cardiovascular and cerebrovascular diseases. Although some of their effects are well known, little is known about their ability to regulate other lipid-related proteins which control apoptotic mechanisms. The aim of this study was to explore whether statins can bind to cell death-inducing DNA fragmentation factor-like effector A (CIDEA), which might be a possible pleiotropic mechanism of action of these drugs on the modulation of apoptosis and lipid metabolism. The structures of statins were subjected to molecular docking and dynamics with the human CIDEA protein to investigate the interaction pattern and identify which residues are important. The docking results indicated that atorvastatin and rosuvastatin showed the best interaction energy (-8.51 and -8.04 kcal/mol, respectively) followed by fluvastatin (-7.39), pitavastatin (-6.5), lovastatin (-6.23), pravastatin (-6.04) and simvastatin (-5.29). Atorvastatin and rosuvastatin were further subjected to molecular dynamics at 50 ns with CIDEA and the results suggested that rosuvastatin-CIDEA complex had lower root-mean square deviation and root-mean square fluctuation when compared with atorvastatin-CIDEA. Since two arginine residues -ARG19 and ARG22-were identified to be common for the interaction with CIDEA, a single-point mutation was induced in these residues to determine whether they are important for binding interaction. Mutation of these two residues seemed to affect mostly the interaction of atorvastatin with CIDEA, suggesting that they are important for the binding and therefore indicate another possible metabolic mechanism of the pleiotropic effects of this statin., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Lymphoma is a name for malignant diseases of the lymphatic system including Hodgkin's lymphoma and non-Hodgkin's lymphoma. Although several approaches are used for the treatment of these diseases, some of them are not successful and have serious adverse effects. Therefore, other effective treatment methods might be interesting. Studies have indicated that plant ingredients play a key role in treating several diseases. Some plants have already shown a potential therapeutic effect on many malignant diseases. Quercetin is a flavonoid found in different plants and could be useful in the treatment of different malignant diseases. Quercetin has its antimalignant effects through targeting main survival pathways activated in tumor cells. In vitro / in vivo experimental studies have demonstrated that quercetin possesses a cytotoxic effect on lymphoid cancer cells. Regardless of the optimum results that have been obtained from both in vitro / in vivo studies, few clinical studies have analyzed the antitumor effects of quercetin in lymphoid cancers. Thus, it seems that more clinical studies should introduce quercetin as a therapeutic, alone or in combination with other chemotherapy agents. Here, in this study, we reviewed the anticancer effects of quercetin and highlighted the potential therapeutic effects of quercetin in various types of lymphoma., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2021 Saiedeh Razi Soofiyani et al.)

Cancers are complex diseases orchestrated by a plethora of extrinsic and intrinsic factors. Research spanning over several decades has provided better understanding of complex molecular interactions responsible for the multifaceted nature of cancer. Recent advances in the field of next generation sequencing and functional genomics have brought us closer towards unravelling the complexities of tumor microenvironment (tumor heterogeneity) and deregulated signaling cascades responsible for proliferation and survival of tumor cells. Phytochemicals have begun to emerge as potent beneficial substances aimed to target deregulated signaling pathways. Isoflavonoid genistein is an essential phytochemical involved in regulation of key biological processes including those in different types of cancer. Emerging preclinical evidence have shown its anti-cancer, anti-inflammatory and anti-oxidant properties. Testing of this substance is in various phases of clinical trials. Comprehensive preclinical and clinical trials data is providing insight on genistein as a modulator of various signaling pathways both at transcription and translation levels. In this review we have explained the mechanistic regulation of several key cellular pathways by genistein. We have also addressed in detail various microRNAs regulated by genistein in different types of cancer. Moreover, application of nano-formulations to increase the efficiency of genistein is also discussed. Understanding the pleiotropic potential of genistein to regulate key cellular pathways and development of efficient drug delivery system will bring us a step towards designing better chemotherapeutics., (© 2021. The Author(s).)

Statins, a class of drugs for lowering serum LDL-cholesterol, have attracted attention because of their wide range of pleiotropic effects. An important but often neglected effect of statins is their role in the renin-angiotensin system (RAS) pathway. This pathway plays an integral role in the progression of several diseases including hypertension, heart failure, and renal disease. In this paper, the role of statins in the blockade of different components of this pathway and the underlying mechanisms are reviewed and new therapeutic possibilities of statins are suggested.

The current coronavirus disease (COVID-19) outbreak is a significant threat to human health and the worldwide economy. Coronaviruses cause a variety of diseases, such as pneumonia-like upper respiratory tract illnesses, gastroenteritis, encephalitis, multiple organ failure involving lungs and kidneys which might cause death. Since the pandemic started there have been more than 107 million COVID-19 infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and ∼2.4 million deaths globally. SARS-CoV-2 is easily transmitted from person-to-person and has spread quickly across all continents. With the continued increase in morbidity and mortality caused by COVID-19, and the damage to the global economy, there is an urgent need for effective prevention and treatment strategies. The advent of safe and effective vaccines has been a significant step forward in the battle against COVID-19, however treatment of the symptoms associated with the disease still requires new anti-viral and anti-inflammatory drug therapies. To this end, scientists have been investigating available natural products that may be effective against SARS-CoV-2, with some products showing promise in fighting several viral infections. Since many natural products are dietary components or are prepared as dietary supplements people tend to consider them safer than synthetic drugs. For example, Traditional Chinese Medicines have been effectively utilized to treat SARS-CoV-2 infected patients with promising results. In this review, we summarize the current knowledge of COVID-19 therapies and the therapeutic potential of medicinal plant extracts and natural compounds for the treatment of several viral infections, with special emphasis on SARS-CoV-2 infection. Realistic strategies that can be employed for the effective use of bioactive compounds for anti-SARS-CoV-2 research are also provided., Competing Interests: The authors declare that the paper was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ayatollahi, Sharifi-Rad, Tsouh Fokou, Mahady, Ansar Rasul Suleria, Krishna Kapuganti, Gadhave, Giri, Garg, Sharma, Ribeiro, Rodrigues, Reiner, Taheri and Cruz-Martins.)

Background and Aims: Statins are the drugs of choice for decreasing elevated low-density lipoprotein cholesterol. Based mostly on animal studies and case reports, they are forbidden to pregnant women and in the preconception period because of their possible teratogenic effects, for which causality has never been proven. The aim of this study was to systematically review the existing studies and to perform a meta-analysis on this topic., Methods: The databases PubMed/MEDLINE, Scopus, and Web of Science were searched since the inception until May 16, 2020. The risk of bias for each clinical trial was evaluated using the Cochrane handbook criteria for systematic reviews. The National Institutes of Health (NIH) quality assessment tool was used for the evaluation of cohort and cross-sectional studies. Meta-analysis was performed on the extracted data. Heterogeneity was assessed using I 2 measure and Cochrane's Q statistic. We calculated a pooled estimate of odds ratio (OR) and 95% confidence intervals (CI) using a random-effects model., Results: 23 studies (nine cohort studies, six case reports, six case series, one population-based case-referent study and one clinical trial) with 1,276,973 participants were included in the systematic review and 6 of them (n = 1,267,240 participants) were included in meta-analysis. The results of the critical review did not suggest a clear-cut answer to the question whether statin treatment during pregnancy is associated with an increased rate of birth defects or not, while the results of the meta-analysis indicated that statin use does not increase birth defects [OR (95%CI): 1.48 (0.90, 2.42), p = 0.509], including cardiac anomalies [2.53 (0.81, 7.93), p = 0.112] and other congenital anomalies [1.19 (0.70, 2.03), p = 0.509)]., Conclusions: We observed no significant increase of birth defects after statin therapy. Thus, there is still no undoubtful evidence that statin treatment during pregnancy is teratogenic, and this issue still needs to be investigated, especially there are more and more pregnant women at high CVD risk that could have benefited from the statin therapy., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: Obesity is one of the major health problems worldwide. Morbid obesity (body mass index >40 kg/m 2 or over 35 with a comorbidity) is associated, apart from other diseases, with an increased risk of non-alcoholic fatty liver disease (NAFLD). Moreover, dyslipidemia is an important comorbidity that is frequently found in NAFLD patients. The aim of this study was to analyze whether serum lipids in morbidly obese patients are associated with the spectrum of NAFLD. Methods: Total serum cholesterol, LDL cholesterol, HDL cholesterol, non-HDL cholesterol, VLDL, and triglycerides were analyzed in 90 morbidly obese patients. The association of lipid profile parameters with histopathological, elastographic, and sonographic indices of NAFLD, non-alcoholic steatohepatitis (NASH), and liver fibrosis were explored. Results: The mean levels of serum total cholesterol, LDL-C, and non-HDL cholesterol in patients with positive histology for liver steatosis and NASH were significantly higher than those in patients with negative histology. None of the indices showed a strong association with NAFLD, NASH, or liver fibrosis after adjustment for potential confounders. Conclusion: A slight predictive value of lipid profile is not sufficiently enough to use solely as a non-invasive test in predicting NASH or liver fibrosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ganjooei, Jamialahmadi, Nematy, Jangjoo, Goshayeshi, Khadem-Rezaiyan, Reiner, Alidadi, Markin and Sahebkar.)

Background: European Action on Secondary and Primary Prevention by Intervention to Reduce Events (EUROASPIRE) V in primary care was carried out by the European Society of Cardiology EURObservational Research Programme in 2016-2018. The main objective was to determine whether the 2016 Joint European Societies' guidelines on cardiovascular disease prevention in people at high cardiovascular risk have been implemented in clinical practice., Methods: The method used was a cross-stional survey in 78 centres from 16 European countries. Patients without a history of atherosclerotic cardiovascular disease either started on blood pressure and/or lipid and/or glucose lowering treatments were identified and interviewed ≥ 6 months after the start of medication., Results: A total of 3562 medical records were reviewed and 2759 patients (57.6% women; mean age 59.0 ± 11.6 years) interviewed (interview rate 70.0%). The risk factor control was poor with 18.1% of patients being smokers, 43.5% obese (body mass index ≥30 kg/m2) and 63.8% centrally obese (waist circumference ≥88 cm for women, ≥102 cm for men). Of patients on blood pressure lowering medication 47.0% reached the target of <140/90 mm Hg (<140/85 mm Hg in people with diabetes). Among treated dyslipidaemic patients only 46.9% attained low density lipoprotein-cholesterol target of <2.6 mmol/l. Among people treated for type 2 diabetes mellitus, 65.2% achieved the HbA1c target of <7.0%., Conclusion: The primary care arm of the EUROASPIRE V survey revealed that large proportions of people at high cardiovascular disease risk have unhealthy lifestyles and inadequate control of blood pressure, lipids and diabetes. Thus, the potential to reduce the risk of future cardiovascular disease throughout Europe by improved preventive cardiology programmes is substantial., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Context: Elevated levels of lipoprotein (a) [Lp(a)] are an independent risk factor for premature cardiovascular disease (CVD). Flaxseed (Linum usitiatissimum L.) is a rich source of alpha-linolenic acid, phytoestrogens, and lignans and has been shown to improve several cardiovascular risk factors, although the overall effect on Lp(a) is unknown., Objective: The study intended to assess the impact of flaxseed on plasma Lp(a) levels through a meta-analysis of the results of randomized controlled trials (RCTs)., Design: PubMed-Medline, Scopus, Embase, and Google Scholar databases were searched using the following search terms in titles and abstracts: flaxseed OR Linum usitatissimum OR lignin OR linseed AND lipoprotein(a) OR lipoprotein (a) OR Lp(a) OR Lp (a)., Results: Of the 48 RCTs, 6 were eligible for inclusion, and the results suggested a significant decrease in plasma Lp(a) levels-standardized mean difference: -0.22, 95% confidence interval: -0.41 to -0.04, P = .017-following supplementation with flaxseed-containing products., Conclusions: This finding highlights the potential clinical significance of flaxseed supplementation for patients who are at risk of a high residual CVD despite intensive statin therapy, patients with hyperliporoteinemia(a), and patients who prefer natural remedies for CVD prevention in the context of a healthy lifestyle. Further RCTs are needed to establish the role of flaxseed-containing products on lowering Lp(a).

Atherosclerotic cardiovascular disease (ASCVD) and consequent acute coronary syndromes (ACS) are substantial contributors to morbidity and mortality across Europe. Much of these diseases burden is modifiable, in particular by lipid-lowering therapy (LLT). Current guidelines are based on the sound premise that with respect to low density lipoprotein cholesterol (LDL-C), "lower is better for longer", and the recent data have strongly emphasized the need of also "the earlier the better". In addition to statins, which have been available for several decades, the availability of ezetimibe and inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) are additional very effective approach to LLT, especially for those at very high and extremely high cardiovascular risk. LLT is initiated as a response to an individual's calculated risk of future ASCVD and is intensified over time in order to meet treatment goals. However, in real-life clinical practice goals are not met in a substantial proportion of patients. This Position Paper complements existing guidelines on the management of lipids in patients following ACS. Bearing in mind the very high risk of further events in ACS, we propose practical solutions focusing on immediate combination therapy in strict clinical scenarios, to improve access and adherence to LLT in these patients. We also define an 'Extremely High Risk' group of individuals following ACS, completing the attempt made in the recent European guidelines, and suggest mechanisms to urgently address lipid-medicated cardiovascular risk in these patients., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: Statins are pivotal to the secondary prevention of major adverse cardiovascular events, but some patients are statin-intolerant. We examined the effects of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab on the risk of major adverse cardiovascular events according to the intensity of background statin treatment., Methods and Results: The ODYSSEY OUTCOMES trial compared alirocumab with placebo in 18,924 patients with acute coronary syndrome and dyslipidaemia despite intensive or maximum-tolerated statin treatment (including no statin if intolerance was documented). The primary outcome (major adverse cardiovascular events) comprised coronary heart disease death, non-fatal myocardial infarction, ischaemic stroke, or unstable angina. Median follow-up was 2.8 years. Baseline statin treatment was high-intensity (88.8%), low/moderate-intensity (8.7%) or none (2.4%). Median baseline low-density lipoprotein cholesterol was 86, 89 and 139 mg/dL (P < 0.001) in these statin treatment categories, respectively. Alirocumab produced similar relative reductions in low-density lipoprotein cholesterol from baseline across statin treatment subgroups, but the mean absolute reductions differed (52.9, 56.7 and 86.1 mg/dL, respectively; P < 0.001). With placebo, the incidence of major adverse cardiovascular events was highest in the no statin subgroup (10.8%, 10.7% and 26.0% respectively). Alirocumab reduced major adverse cardiovascular events in each statin subgroup (hazard ratio 0.88, 95% confidence interval (CI) 0.80-0.96; 0.68, 0.49-0.94; and 0.65, 0.44-0.97, respectively; Pinteraction = 0.14) with a gradient of absolute risk reduction: 1.25%, 95% CI 0.34-2.16; 3.16%, 0.38-5.94; 7.97%, 0.42-15.51; Pinteraction = 0.106)., Conclusions: PCSK9 inhibition with alirocumab reduces the relative risk of major adverse cardiovascular events after acute coronary syndrome irrespective of background statin treatment. However, patients on no statin are at high absolute risk for recurrent major adverse cardiovascular events; alirocumab substantially reduces that risk. PCSK9 inhibition may be an important therapeutic strategy for statin-intolerant patients with acute coronary syndrome., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Lung cancer is one of the most common causes of cancer-related mortality in the 21 st century. Statins as inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase not only reduce the cholesterol levels in the blood and decrease the risk of cardiovascular disease but may also play an important role in the prevention and treatment of lung cancer. Statins have several antitumor properties including the ability to reduce cell proliferation and angiogenesis, decrease invasion and synergistic suppression of lung cancer progression. Statins induce tumor cell apoptosis by inhibition of downstream products such as small GTP-binding proteins, Rho, Ras and Rac, which are dependent on isoprenylation. Statins reduce angiogenesis in tumors by down-regulation of pro-angiogenic factors, such as vascular endothelial growth factor. In this review, the feasibility and efficacy of statins in the prevention and treatment of lung cancer are discussed., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2021 Termedia & Banach.)

Background: Preeclampsia is a serious complication of pregnancy which increases the morbidity and mortality of both the fetus and pregnant woman. It is characterized by imbalances in angiogenesis, inflammation and endothelial dysfunction which cause the development of hypertension and proteinuria, sometimes progressing into a multisystem disorder. The aim of this systematic review was to analyze all the available data on statins and preeclampsia., Method: MEDLINE/PubMed, OVID, EMBASE, Web of Sciences, and SCOPUS were searched from inception to May 5, 2020. Any study evaluating the effects of statins on women with preeclampsia or HELLP syndrome or who were at risk for it has been included as well as the studies on the placenta of preeclamptic women., Results: 12 articles which included 136 pregnant women and 35 placental samples from hypertensive and normotensive women were analyzed. They showed contradictory effects of statins on blood pressure in preeclampsia, on soluble FMS-like tyrosine kinase-1 (sFlt-1) as well as soluble endoglin (sEng). However, statins caused a significant dose-dependent reduction of sFlt-1 secretion from isolated cytotrophoblasts and an increased secretion of sEng (at least in some studies) in primary HUVECs and placental explants obtained from patients with preeclampsia. Statins also increased eNOS in preeclamptic placentas. Statins were beneficial for patients with antiphospholipid syndrome (APS) preventing preeclampsia and it seems that they might prevent complications of HELLP., Conclusion: It seems that statins might be beneficial for preventing or treating preeclampsia. Nevertheless, further studies are needed to provide definitive conclusions regarding these effects of statins., (Copyright © 2020 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

The prevalence of obesity, diabetes, arterial hypertension and cardiovascular and cerebrovascular diseases is increasing worldwide. Nowdays we are witnessing a pandemic of metabolic syndrome and obesity and an epidemic of these diseases in Croatia as well. Moreover, every second Croatian citizen dies because of cardiovascular diseases. Visceral obesity, diabetes, dyslipidemia and arterial hypertension tend to cluster forming a syndrome that we call metabolic syndrome. The concept of metabolic syndrome was defined several decades ago as visceral type of obesity, hypertriglyceridemia, low HDL-cholesterol, arterial hypertension and diabetes mellitus (insulin resistance). Most widely used definition is the one by National Education Cholesterol Program, NCEP - Adult treatment Panel III - ATP III . Therefore, visceral obesity is considered as one of the greatest risks for mortality worldwide. COVID pandemia increased the risk od deaths especially among patients with metabolic syndrome. Pandemia perpetuated several other socio-economical risk factors (stress, depression, physical inactivity, deviant behaviour...) which also strongly influence cardiovascular health. Unfortunately, SARS-COV-2 virus enters the host (human) cell using signaling pathways (ANG II Rc) known very well from the metabolic syndrome research and connecting those two entities predesponing these patients for a much worse prognosis when infected with SARS-COV-2 virus. To conclude - chronic obesity pandemia goes hand by hand with novel COVID-19 pandemia dramatiacally increasing the risk of severe morbidity and mortality.

Background: Atrial fibrillation (AF) occurring after cardiac surgery, post-operative AF (POAF), is a serious and common complication of this treatment. POAF may be life-threatening and the available preventive strategies are insufficient or are associated with significantly increased risk of adverse effects, especially in long-term use. Therefore, more appropriate treatment strategies are needed., Methods: In this paper, the efficacy, safety, and other aspects of using statins in the prevention of POAF focusing on their anti-inflammatory effects are reviewed., Results: Recent studies have suggested that inflammation has a significant role in POAF, from the first AF episode to its serious complications including stroke and peripheral embolism. On the other hand, statins, the most widely used medications in cardiovascular patients, have pleiotropic effects, including anti-inflammatory properties. Therefore, they may potentially be effective in POAF prevention. Statins, especially atorvastatin, appear to be an effective option for primary prevention of POAF, especially in patients who had coronary artery bypass grafting (CABG), a cardiac surgery treatment associated with inflammation in the heart muscle. However, several large studies, particularly with rosuvastatin, did not confirm the beneficial effect of statins on POAF. One large clinical trial reported higher risk of acute kidney injury (AKI) following high-dose rosuvastatin in Chinese population. In this study, rosuvastatin reduced the level of C-reactive protein (CRP) but did not reduce the rate of POAF., Conclusion: Further studies are required to find the most effective statin regimen for POAF prevention with the least safety concern and the highest health benefits.

With the global expansion of coronavirus disease 2019 (COVID-19) and the declaration of its outbreak as a Public Health Emergency of International Concern by the World Health Organization, there is an urgent need for vaccines and medicines to prevent and treat COVID-19. The responsible pathogen for the disease is the newly severe acute respiratory syndrome coronavirus (SARS-CoV) 2 belonging to the same family of viruses SARS-CoV and Middle East respiratory syndrome coronavirus that originally are zoonotic and have been associated with severe illness during the outbreaks in 2003 and 2012, respectively. The virulence of coronavirus strains is mainly associated with variations in surface proteins mediating cellular entry of the virus, which can help in finding effective therapeutic targets. In this review, we seek evidence showing the role of coronavirus spike protein (S-protein) and its potential cellular receptor, angiotensin-converting enzyme 2 (ACE2), during infection of coronaviruses, including the newly SARS-CoV-2 and its similar strain SARS-CoV. This review also discusses the therapeutic effect of inhibiting the renin-angiotensin system cascade, a target of ACE2, in patients having coronavirus with cardiovascular disease.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease which increases the lysosomal degradation of low density lipoprotein receptor (LDLR) resulting in elevated serum LDL-cholesterol levels. Elevated LDL-cholesterol is the main risk factor for cardiovascular disease (CVD). Antibodies to PCSK9 decrease LDL-cholesterol. Recent studies have suggested a direct relationship between PCSK9 and inflammation and the potential inhibitory effects of anti-inflammatory agents against this enzyme. Nutraceuticals are natural compounds, which have numerous anti-inflammatory and lipid-lowering effects. In this review we focus on anti-inflammatory substances and nutraceuticals, which are beneficial in treatment of dyslipidemia. We also reviewed the recent findings concerning the role of PCSK9 as the main target for molecular mechanisms of these substances.

Background and Aim: Peripheral artery disease (PAD) is associated with an increased risk of fatal and non-fatal coronary heart disease (CHD). The aims of the this study were 1) to investigate the prevalence of PAD and suspected PAD in a large population of established CHD patients, and 2) to assess the prevalence and control of risk factors in these patients as well health-related quality of life., Material and Methods: In the EUROASPIRE V survey, 8243 patients with documented CHD were recruited from 27 ESC member countries and were invited to attend a study visit. Patients were investigated using questionnaires, in-depth interviews and a clinical examination. Intermittent claudication (IC) was assessed using the Edinburgh Claudication Questionnaire. Patients without previously diagnosed PAD were suspected of having PAD if they were found to have IC., Results: Overall, 6.4% of the patients had already a confirmed diagnosis of PAD and another 6.3% were suspected of having PAD. Independent of age and gender, patients with previously diagnosed PAD were significantly more frequently current smokers, had the lowest smoking cessation rates, were less physically active, reported more often previously diagnosed diabetes and had significantly higher blood pressure levels, compared to patients without PAD. They had also significantly higher levels of serum triglycerides, lower HDL-C levels, and had more often renal insufficiency. In comparison with patients without PAD, those with suspected PAD demonstrated significantly higher smoking cessation rates but their obesity rates were significantly higher. In CHD patients with a history of PAD, the use of calcium channel blockers and diuretics was significantly higher than in patients without PAD. Compared to the latter group, the use of diuretics, anti-arrhythmics and anti-depressants in patients with suspected PAD was significantly higher. Moreover, patients with previously diagnosed PAD had significantly higher levels of anxiety and depression and reported a significantly worse health-related quality of life (HRQoL), in comparison with those without PAD. HRQoL levels were significantly reduced in patients with suspected PAD as well., Conclusion: In CHD patients without a previous diagnosis of PAD, IC is not infrequent. Diagnosed PAD was significantly associated with a worse CHD risk factor profile. Patients with known PAD as well as those with suspected PAD had a considerable loss of health-related quality of life. Therefore, physicians should consider to screen for IC in all their CHD patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The inverse relationship between low plasma high-density lipoprotein cholesterol (HDL-C) concentrations and increased risk of Atherosclerotic Cardiovascular Disease (ASCVD) is well-known. However, plasma HDL-C concentrations are highly variable in subjects with ASCVD. In clinical outcome trials, pharmacotherapies that increase HDL-C concentrations are not associated with a reduction in ASCVD events. A causal relationship between HDL-C and ASCVD has also been questioned by Mendelian randomization studies and genome-wide association studies of genetic variants associated with plasma HDL-C concentrations. The U-shaped association between plasma HDL-C concentrations and mortality observed in several epidemiological studies implicates both low and very high plasma HDL-C concentrations in the etiology of ASCVD and non- ASCVD mortality. These data do not collectively support a causal association between HDL-C and ASCVD risk. Therefore, the hypothesis concerning the association between HDL and ASCVD has shifted from focus on plasma concentrations to the concept of functionality, in particular cellular cholesterol efflux and HDL holoparticle transport. In this review, we focus on these new concepts and provide a new framework for understanding and testing the role of HDL in ASCVD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: This systematic review and meta-analysis of randomized controlled trials (RCTs) was performed to analyze the effects of flaxseed oil supplementation on biomarkers of inflammation and oxidative stress in patients with metabolic syndrome (MetS) and related disorders., Methods: Databases including PubMed, Scopus, EMBASE, Web of Science, and Cochrane Central library were searched until January 31 th , 2019., Results: 14 effect sizes from 12 studies were identified eligible to be included in current meta-analysis. Flaxseed supplementation resulted in a significant reduction in interleukin 6 (IL-6) (WMD: -0.22; 95% CI: -0.43, -0.01) and malondialdehyde (MDA) (WMD: -0.17; 95% CI: -0.31, -0.03) and a significant increase in total antioxidant capacity (TAC) levels (WMD: 137.25; 95% CI: 68.04, 206.47). Flaxseed oil supplementation did not affect other biomarkers of inflammation and oxidative stress., Conclusions: Overall, this meta-analysis demonstrated flaxseed oil supplementation decreased IL-6 and MDA levels, and increased TAC, but did not affect other biomarkers of inflammation and oxidative stress among patients with MetS and related disorders. This suggests that flaxseed oil supplementation may have played an indirect role in improved clinical symptoms in diseases with metabolic disorders., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Bladder cancer (BC) is a leading cause of death among urothelial malignancies that more commonly affect male population. Poor prognosis and resistance to chemotherapy are the two most important characteristics of this disease. PI3K/Akt/mTOR signaling pathway has been considered pivotal in the regulation of proliferation, migration, invasiveness, and metastasis. Deregulation of PI3K/Akt/mTOR signaling has been found in 40% of bladder cancers. Several microRNAs (miRNAs) have been reported to interact with the PI3K/Akt/mTOR signaling pathway with a different possible role in proliferation and apoptosis in bladder cancer. Thus, miRNAs can be used as potential biomarkers for BC. Natural compounds have been in the spotlight for the past decade due to their effective anti-proliferative capabilities. However, little is known of its possible effects in bladder cancer. The aim of this review is to discuss the interplay between PI3K/Akt/mTOR, miRNAs, and natural compounds and emphasize the importance of miRNAs as biomarkers and resveratrol, curcumin and paclitaxel as a possible therapeutic approach against bladder cancer.

Cardiovascular diseases (CVDs) are one of the most important causes for mortality worldwide. Elevated levels of total cholesterol, and particularly LDL-cholesterol (LDL-C) are the main risk factor for acute myocardial infarction (AMI) and ischemic heart disease. The risk of CVDs could be reduced by decreasing the elevated cholesterol levels. β-hydroxy β-methylglutaryl-CoA reductase (HMGCoAR) is the primary and rate-limiting enzyme in the cholesterol biosynthesis pathway. Recently, the crucial role of nutraceuticals in maintaining normal physiological function was established. Nutraceuticals play an important role in preventing several non-communicable diseases such as obesity, CVDs, cancer, diabetes, and reducing hyperlipidemia. Although the effect of nutraceuticals and herbal medicine on CVDs and dyslipidemia was previously investigated thoroughly, the effect of these natural products on HMGCoAR as one of the important enzymes involved in CVDs etiopathogenesis has not yet been investigated. Therefore, the major aim of this paper was to review the effects of nutraceuticals and medicinal plants on HMGCoAR. Results indicate that different types of natural foods, isolated nutrients, herbal products, and dietary supplements as nutraceuticals decrease the expression and activity of HMGCoAR. This review shows that medicinal plants and nutraceuticals could be used to decrease HMGCoAR activity as accessible and convenient and economical natural compounds to prevent dyslipidemia and CVDs., (© 2020 International Union of Biochemistry and Molecular Biology.)