Search

Objective: The optimal management of patients with asymptomatic carotid stenosis (AsxCS) is enduringly controversial. We updated our 2021 Expert Review and Position Statement, focusing on recent advances in the diagnosis and management of patients with AsxCS., Methods: A systematic review of the literature was performed up to August 1, 2023, using PubMed/PubMed Central, EMBASE and Scopus. The following keywords were used in various combinations: "asymptomatic carotid stenosis," "carotid endarterectomy" (CEA), "carotid artery stenting" (CAS), and "transcarotid artery revascularization" (TCAR). Areas covered included (i) improvements in best medical treatment (BMT) for patients with AsxCS and declining stroke risk, (ii) technological advances in surgical/endovascular skills/techniques and outcomes, (iii) risk factors, clinical/imaging characteristics and risk prediction models for the identification of high-risk AsxCS patient subgroups, and (iv) the association between cognitive dysfunction and AsxCS., Results: BMT is essential for all patients with AsxCS, regardless of whether they will eventually be offered CEA, CAS, or TCAR. Specific patient subgroups at high risk for stroke despite BMT should be considered for a carotid revascularization procedure. These patients include those with severe (≥80%) AsxCS, transcranial Doppler-detected microemboli, plaque echolucency on Duplex ultrasound examination, silent infarcts on brain computed tomography or magnetic resonance angiography scans, decreased cerebrovascular reserve, increased size of juxtaluminal hypoechoic area, AsxCS progression, carotid plaque ulceration, and intraplaque hemorrhage. Treatment of patients with AsxCS should be individualized, taking into consideration individual patient preferences and needs, clinical and imaging characteristics, and cultural, ethnic, and social factors. Solid evidence supporting or refuting an association between AsxCS and cognitive dysfunction is lacking., Conclusions: The optimal management of patients with AsxCS should include BMT for all individuals and a prophylactic carotid revascularization procedure (CEA, CAS, or TCAR) for some asymptomatic patient subgroups, additionally taking into consideration individual patient needs and preference, clinical and imaging characteristics, social and cultural factors, and the available stroke risk prediction models. Future studies should investigate the association between AsxCS with cognitive function and the role of carotid revascularization procedures in the progression or reversal of cognitive dysfunction., Competing Interests: Disclosures J.F.M. is co-Principal Investigator for the Clinical Coordinating Center of the CREST-2 multicenter randomized clinical trial (U01NS080168) and Principal Investigator of the Long-term Observational Extension of participants in the CREST-2 randomized clinical trial (C2LOE; U01NS119169). M.L.S. is the Principal Investigator of the ROADSTER-3 trial and is the Chair of the TCAR Surveillance Program in the Vascular Quality Initiative. L.H.B., P.J.N., and M.M.B. are co-Principal Investigators for the 2nd European Carotid Surgery Trial (ECST-2). P.S. is a consultant for Silk Road, Philips, Surmodics, Medtronic, Boston Scientific, Cagent, and LimFlow. E.A.S. has received research grants from the Food & Drug Administration (FDA), SCAI, BD, Boston Scientific, Cook, Laminate Medical, Medtronic, Philips, and NIH/NHLBIK23HL150290. He has received Consulting/Speaker fees from Abbott, Bayer, BD, Boston Scientific, Cook, Cordis, Heartflow, Inari, InfraRedx, Medtronic, Philips, RapidAI, Shockwave, and VentureMed. D.P.M. has given talks, acted as a consultant or attended conferences sponsored by Amgen and Novo Nordisk. B.K.L. is co-Principal Investigator of the CREST-2 multicenter randomized clinical trial (U01NS080168), Principal Investigator of the CREST-2 Registry (C2R; NCT02240862) and Principal Investigator for the Asymptomatic Carotid Stenosis and Cognitive Function Study (ACCOF; CX001621). The other authors have no conflicts of interest., (Copyright © 2023 Society for Vascular Surgery. All rights reserved.)

Objective: Despite the publication of various national/international guidelines, several questions concerning the management of patients with asymptomatic (AsxCS) and symptomatic (SxCS) carotid stenosis remain unanswered. The aim of this international, multi-specialty, expert-based Delphi Consensus document was to address these issues to help clinicians make decisions when guidelines are unclear., Methods: Fourteen controversial topics were identified. A three-round Delphi Consensus process was performed including 61 experts. The aim of Round 1 was to investigate the differing views and opinions regarding these unresolved topics. In Round 2, clarifications were asked from each participant. In Round 3, the questionnaire was resent to all participants for their final vote. Consensus was reached when ≥75% of experts agreed on a specific response., Results: Most experts agreed that: (1) the current periprocedural/in-hospital stroke/death thresholds for performing a carotid intervention should be lowered from 6% to 4% in patients with SxCS and from 3% to 2% in patients with AsxCS; (2) the time threshold for a patient being considered "recently symptomatic" should be reduced from the current definition of "6 months" to 3 months or less; (3) 80% to 99% AsxCS carries a higher risk of stroke compared with 60% to 79% AsxCS; (4) factors beyond the grade of stenosis and symptoms should be added to the indications for revascularization in AsxCS patients (eg, plaque features of vulnerability and silent infarctions on brain computed tomography scans); and (5) shunting should be used selectively, rather than always or never. Consensus could not be reached on the remaining topics due to conflicting, inadequate, or controversial evidence., Conclusions: The present international, multi-specialty expert-based Delphi Consensus document attempted to provide responses to several unanswered/unresolved issues. However, consensus could not be achieved on some topics, highlighting areas requiring future research., Competing Interests: Disclosures D.P.M. has given talks, acted as a consultant or attended conferences sponsored by Amgen and Novo Nordisk. J.F.M. receives funding from the United States National Institute of Neurologic Disorders and Stroke for work related to running the CREST-2 clinical trial (U01NS080168) and the CREST-2 Long-term Observational Extension study (U01NS119169). E.A.S. has received research grants from the United States Food and Drug Administration, BD, Boston Scientific, Cook, CSI, Laminate Medical, Medtronic and Philips; has received consulting/speaking fees from Abbott, Bayer, BD, Boston Scientific, Cook, Cordis, CSI, Inari, Infraredx, Medtronic, Philips, Shockwave and VentureMed. H.-H.E. is a local Principal Investigator for the ROADSTER 2 trial and a scientific committee member of SPACE-1, SPACE-2 and ACST-2. T.R. is funded by grants from the National Institutes of Health (R01 MD012467, R01 NS029993, R01NS040807, 1U24NS107267), and the National Center for Advancing Translational Sciences (UL1 TR002736, KL2 TR002737). J.S.M. has received institutional research grants from Abbott, Cook, Endologix, Gore and Medtronic., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Carotid artery atherosclerosis is highly prevalent in the general population and is a well-established risk factor for acute ischemic stroke. Although the morphological characteristics of vulnerable plaques are well recognized, there is a lack of consensus in reporting and interpreting carotid plaque features., Objectives: The aim of this paper is to establish a consistent and comprehensive approach for imaging and reporting carotid plaque by introducing the Plaque-RADS (Reporting and Data System) score., Methods: A panel of experts recognized the necessity to develop a classification system for carotid plaque and its defining characteristics. Using a multimodality analysis approach, the Plaque-RADS categories were established through consensus, drawing on existing published reports., Results: The authors present a universal classification that is applicable to both researchers and clinicians. The Plaque-RADS score offers a morphological assessment in addition to the prevailing quantitative parameter of "stenosis." The Plaque-RADS score spans from grade 1 (indicating complete absence of plaque) to grade 4 (representing complicated plaque). Accompanying visual examples are included to facilitate a clear understanding of the Plaque-RADS categories., Conclusions: Plaque-RADS is a standardized and reliable system of reporting carotid plaque composition and morphology via different imaging modalities, such as ultrasound, computed tomography, and magnetic resonance imaging. This scoring system has the potential to help in the precise identification of patients who may benefit from exclusive medical intervention and those who require alternative treatments, thereby enhancing patient care. A standardized lexicon and structured reporting promise to enhance communication between radiologists, referring clinicians, and scientists., Competing Interests: Funding Support and Author Disclosures The views expressed in this paper are those of the authors and do not reflect the official policy of the Department of Army/Navy/Air Force, Department of Defense, or U.S. Government. The identification of specific products or scientific instrumentation does not constitute endorsement or implied endorsement on the part of the author, Department of Defense, or any component agency. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Non-Alcoholic Fatty Liver Disease (NAFLD) is a common condition affecting around 10-25% of the general adult population, 15% of children, and even > 50% of individuals who have type 2 diabetes mellitus. It is a major cause of liver-related morbidity, and cardiovascular (CV) mortality is a common cause of death. In addition to being the initial step of irreversible alterations of the liver parenchyma causing cirrhosis, about 1/6 of those who develop NASH are at risk also developing CV disease (CVD). More recently the acronym MAFLD (Metabolic Associated Fatty Liver Disease) has been preferred by many European and US specialists, providing a clearer message on the metabolic etiology of the disease. The suggestions for the management of NAFLD are like those recommended by guidelines for CVD prevention. In this context, the general approach is to prescribe physical activity and dietary changes the effect weight loss. Lifestyle change in the NAFLD patient has been supplemented in some by the use of nutraceuticals, but the evidence based for these remains uncertain. The aim of this Position Paper was to summarize the clinical evidence relating to the effect of nutraceuticals on NAFLD-related parameters. Our reading of the data is that whilst many nutraceuticals have been studied in relation to NAFLD, none have sufficient evidence to recommend their routine use; robust trials are required to appropriately address efficacy and safety., Competing Interests: Declaration of Competing Interest Manfredi Rizzo: speakers bureau: Amgen, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Meda, Mylan, Merck Sharp & Dohme, Novo Nordisk, Roche Diagnostics, Sanofi, and Servier; consultant to Amgen, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Meda, Mylan, Merck Sharp & Dohme, Novo Nordisk, Roche Diagnostics, Sanofi, and Servier; Medical and Scientific Advisor, Europe East and South at Novo Nordisk; Peter E. Penson has received honoraria and/or travel reimbursement for events sponsored by AKCEA, Amgen, AMRYT, Link Medical, Mylan, Napp, Sanofi; Niki Katsiki; Dimitri P. Mikhailidis has given talks, acted as a consultant or attended conferences sponsored by Amgen and Novo Nordisk; Peter P. Toth: speakers bureau: Amgen, Esperion, Kowa, Merck, Novo-Nordisk; consultant to Amarin, bio89, Kowa, Merck, Resverlogix, Theravance; Maciej Banach: speakers bureau: Amgen, Herbapol, Kogen, KRKA, Polpharma, Mylan/Viatris, Novartis, Novo-Nordisk, Sanofi-Aventis, Teva, Zentiva; consultant to Amgen, Daichii Sankyo, Esperion, Freia Pharmaceuticals, Novartis, Novo-Nordisk, Polfarmex, Sanofi-Aventis; Grants from Amgen, Mylan/Viatris, Sanofi and Valeant; CMO at Nomi Biotech Corporation Ltd.; all other authors have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Current guidelines do not recommend screening for asymptomatic carotid artery stenosis (AsxCS). The rationale behind this recommendation is that detection of AsxCS may lead to an unnecessary carotid intervention. In contrast, screening for abdominal aortic aneurysms is strongly recommended., Methods: A critical analysis of the literature was performed to evaluate the implications of detecting AsxCS., Results: Patients with AsxCS are at high risk for future stroke, myocardial infarction and vascular death. Population-wide screening for AsxCS should not be recommended. Additionally, screening of high-risk individuals for AsxCS with the purpose of identifying candidates for a carotid intervention is inappropriate. Instead, selective screening for AsxCS should be considered and should be viewed as an opportunity to identify individuals at high risk for atherosclerotic cardiovascular disease and future cardiovascular events for the timely initiation of intensive medical therapy and risk factor modification., Conclusions: Although mass screening should not be recommended, there are several arguments suggesting that selective screening for AsxCS should be considered. The rationale supporting such selective screening is to optimize risk factor control and to initiate intensive medical therapy for prevention of future cardiovascular events, rather than to identify candidates for an intervention., Competing Interests: Declaration of Competing Interest All authors are members of the Faculty Advocating Collaborative and Thoughtful Carotid Artery Treatments (FACTCATS; available at www.FACTCATS.org) with the shared goal of optimizing stroke prevention. The views of particular FACTCATS do not necessarily reflect the views of other FACTCATS., (Copyright © 2022 Elsevier B.V. All rights reserved.)

There is considerable evidence that patients with inflammatory conditions are at higher risk of developing cardiovascular (CV) disease including carotid artery stenosis. CV disease accounts for 35-50% of the excess mortality in patients with inflammatory diseases such as rheumatoid arthritis, with cerebrovascular disease being the second leading cause of death. We review current evidence regarding the association of inflammatory conditions and specifically carotid artery disease. Clinical epidemiological observations suggest that mechanisms other than classic risk factors may promote accelerated atherogenesis in rheumatoid and other inflammatory arthritis and carotid artery disease is increased in individuals with these conditions. Additional studies to better understand the underlying mechanisms and targeted strategies to mitigate such risk are indicated. For now, lifestyle modifications, aggressive treatment of risk factors and lipid lowering therapy in appropriate individuals is indicated., Competing Interests: Conflict of Interest None declared for Tayana Rodriguez, Angelical Lehker and Debabrata Mukherjee. Dimitri P Mikhailidis has given talks, acted as a consultant or attended conferences sponsored by Amgen and Novo Nordisk., (Copyright © 2021 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Proteins play a crucial role in metabolism, in maintaining fluid and acid-base balance and antibody synthesis. Dietary proteins are important nutrients and are classified into: 1) animal proteins (meat, fish, poultry, eggs and dairy), and, 2) plant proteins (legumes, nuts and soy). Dietary modification is one of the most important lifestyle changes that has been shown to significantly decrease the risk of cardiovascular (CV) disease (CVD) by attenuating related risk factors. The CVD burden is reduced by optimum diet through replacement of unprocessed meat with low saturated fat, animal proteins and plant proteins. In view of the available evidence, it has become acceptable to emphasize the role of optimum nutrition to maintain arterial and CV health. Such healthy diets are thought to increase satiety, facilitate weight loss, and improve CV risk. Different studies have compared the benefits of omnivorous and vegetarian diets. Animal protein related risk has been suggested to be greater with red or processed meat over and above poultry, fish and nuts, which carry a lower risk for CVD. In contrast, others have shown no association of red meat intake with CVD. The aim of this expert opinion recommendation was to elucidate the different impact of animal vs vegetable protein on modifying cardiometabolic risk factors. Many observational and interventional studies confirmed that increasing protein intake, especially plant-based proteins and certain animal-based proteins (poultry, fish, unprocessed red meat low in saturated fats and low-fat dairy products) have a positive effect in modifying cardiometabolic risk factors. Red meat intake correlates with increased CVD risk, mainly because of its non-protein ingredients (saturated fats). However, the way red meat is cooked and preserved matters. Thus, it is recommended to substitute red meat with poultry or fish in order to lower CVD risk. Specific amino acids have favourable results in modifying major risk factors for CVD, such as hypertension. Apart from meat, other animal-source proteins, like those found in dairy products (especially whey protein) are inversely correlated to hypertension, obesity and insulin resistance., Competing Interests: Conflict of interest Maciej Banach: speakers bureau: Abbott/Mylan, Abbott Vascular, Actavis, Akcea, Amgen, Biofarm, KRKA, MSD, Sanofi-Aventis, Servier and Valeant; consultant to Abbott Vascular, Akcea, Amgen, Daichii Sankyo, Esperion, Lilly, MSD, Resverlogix, Sanofi-Aventis; Grants from Sanofi and Valeant; Dimitri P. Mikhailidis: has given talks and attended conferences sponsored by Amgen, Novo Nordisk and Libytec; Gani Bajraktari: speakers bureau: KRKA, Bosnalijek, Novartis, LEK-Sandoz, Boston-Scientific, Trepharm and Alkaloid; consultant to Novartis; Michael Y. Henein, Fjolla Zhubi-Bakija, Ibadete Bytyçi, Zarife Rexhaj and Esra Zhubi, have no conflict of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: We evaluated the association of egg consumption with liver tests (LTs) and non-alcoholic fatty liver disease (NAFLD). This relationship is poorly documented., Methods: The National Health and Nutrition Examination Survey (NHANES, 2005-2010) database was used. Analysis of covariance, adjusted linear and logistic regression models were used., Results: Of the 14,369 participants, 46.8% were men and 45.2% had NAFLD. After correction for several variables including: age, gender, race, education, poverty to income ratio, alcohol intake, energy intake, smoking, and physical activity - fatty liver index (FLI), serum aspartate aminotransferase (AST) alanine aminotransferase (ALT) were 36.9, 25.8 (U/L) and 23.9 (U/L), respectively, in the first tertile (T1) reaching 68.7, 34.9 and 36.5, respectively, in the third tertile (T3) (p < 0.001 for all comparisons). In the model with same covariates, there was significant positive linear relationship between FLI (standard β coefficient (β): 0.196), AST (β: 0.099) and ALT (β: 0.112) with egg consumption and participants in the highest tertile (T3) of egg consumption had 11% higher chance of NAFLD compared with T1 (odds ratio: 1.11 and 95% confidence interval: 1.07-1.17). Of note, after more correction for triglycerides, hypertension and diabetes, the significant link between egg consumption and LTs and/or NAFLD attenuated and disappeared., Conclusion: Our findings highlight the adverse role of egg consumption on LTs and likelihood of NAFLD. These associations seem to be attributable to cardio-metabolic risk factors. These findings require confirmation to improve our understanding of the role of egg consumption in the pathogenesis of NAFLD., Competing Interests: Conflict of Interest DPM has given talks and attended conferences sponsored by MSD, AstraZeneca and Libytec. The other authors have no conflict of interest to declare., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Associations between dietary fats and mortality are unclear., Methods: We evaluated the relationship between quartiles of total fat, mono-unsaturated (MUFA), polyunsaturated (PUFA) and saturated fatty acid (SFA) consumption, and all-cause, coronary heart disease (CHD), stroke, and type 2 diabetes (T2D)-associated mortality in 24,144 participants from the National Health and Nutrition Examination Surveys (NHANES) 1999-2010. We added our results to a meta-analysis based on searches until November 2018., Results: In fully adjusted Cox-proportional hazard models in our prospective study, there was an inverse association between total fat (HR: 0.90, 95% confidence interval 0.82, 0.99, Q4 vs Q1) and PUFA (0.81, 0.78-0.84) consumption and all-cause mortality, whereas SFA were associated with the increased mortality (1.08, 1.04-1.11). In the meta-analysis of 29 prospective cohorts (n = 1,164,029) we found a significant inverse association between total fat (0.89, 0.82-0.97), MUFA (0.94, 0.89-0.99) and PUFA (0.89, 0.84-0.94) consumption and all-cause mortality. No association was observed between total fat and CVD (0.93, 0.80-1.08) or CHD mortality (1.03 0.99-1.09). A significant association between SFA intake and CHD mortality (1.10, 1.01-1.21) was observed. Neither MUFA nor PUFA were associated with CVD or CHD mortality. Inverse associations were observed between MUFA (0.80, 0.67-0.96) and PUFA (0.84, 0.80-0.90) intakes and stroke mortality., Conclusions: We showed differential associations of total fat, MUFA and PUFA with all-cause mortality, but not CVD or CHD mortalities. SFA was associated with higher all-cause mortality in NHANES and with CHD mortality in our meta-analysis. The type of fat intake appears to be associated with important health outcomes., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Conventional observational studies have suggested that 25-hydroxyvitamin D (25(OH)D) is inversely associated with telomere shortening. We aimed to apply two-sample Mendelian randomization (MR) to assess the causal association between serum 25(OH) D and telomere length (TL)., Methods: MR was implemented by using summary-level data from the largest genome-wide association studies (GWAS) on vitamin D (n = 73 699) and TL (n = 37 684). Inverse variance weighted method (IVW) was used to estimate the causal estimates. Weighted median (WM)-based method, and MR-Egger, leave-one-out were applied as sensitivity analysis., Results: The results of MR demonstrated no effect of 25(OH)D on TL (IVW = β:-0.104, p = 0.219, WM = β:-0.109, p = 0.188; MR Egger = β:-0.127, p = 0.506). None of the 25(OH)D-related single nucleotide polymorphisms (SNPs) were significantly associated with TL. Heterogeneity tests did not detect heterogeneity. Furthermore, MR pleiotropy residual sum and outlier (MR-PRESSO) did not highlight any outliers (p = 0.424). Results of leave-one-out method demonstrated that the links are not driven because of the single SNPs., Conclusions: Our study does not support any causal effect of 25(OH) D on TL., Competing Interests: Declaration of interest All authors have no conflict of interest to declare., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Acute and chronic physical exercises may enhance the development of statin-related myopathy. In this context, the recent (2019) guidelines of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) for the management of dyslipidemias recommend that, although individuals with dyslipidemia should be advised to engage in regular moderate physical exercise (for at least 30 min daily), physicians should be alerted with regard to myopathy and creatine kinase (CK) elevation in statin-treated sport athletes. However it is worth emphasizing that abovementioned guidelines, previous and recent ESC/EAS consensus papers on adverse effects of statin therapy as well as other previous attempts on this issue, including the ones from the International Lipid Expert Panel (ILEP), give only general recommendations on how to manage patients requiring statin therapy on regular exercises. Therefore, these guidelines in the form of the Position Paper are the first such an attempt to summary existing, often scarce knowledge, and to present this important issue in the form of step-by-step practical recommendations. It is critically important as we might observe more and more individuals on regular exercises/athletes requiring statin therapy due to their cardiovascular risk., Competing Interests: Declaration of Competing Interest NK has given talks, attended conferences and participated in trials sponsored by Amgen, Astra Zeneca, Bausch Health, Boehringer Ingelheim, Elpen, MSD, Mylan, Novo Nordisk, Sanofi and Servier; GB has given talks and attended conferences sponsored by KRKA, Trepharm, Bosnalijek, Akaloid and Novartis; AC has received honoraria as scientific consultant from Meda-Mylan, Menarini International and Sharper; EB - consulting/presentation: Amgen, Genfit, MSD, Sanofi-Regeneron, Aegerion, Chiesi, Rottapharm, Lilly, Ionis pharmaceuticals, Servier, Mylan and Akcea; FA has given talks, attended conferences and participated in trials sponsored by Amgen, AMRYT Pharma and Sanofi; 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, Freia Pharmaceuticals, Esperion, Lilly, MSD, Polfarmex, Resverlogix, Sanofi-Aventis; Grants from Sanofi and Valeant; All other authors have nothing to declare. #International Lipid Expert Panel (ILEP) Experts (alphabetically): Fahad Alnouri (Cardiovascular Prevention Unit, Adult Cardiology Department. Prince Sultan Cardiac Centre Riyadh, Saudi Arabia), Fahma Amar (Unit of Diabetes &Metabolism, Alexandria University, Alexandria, Egypt), Atanas G. Atanasov (Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Jastrzebiec, Poland; Department of Pharmacognosy, University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Digital Health and Patient Safety, Medical University of Vienna, Vienna, Austria; Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria), Gani Bajraktari (Institute of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden; Clinic of Cardiology, University Clinical Centre of Kosovo, Prishtina, Kosovo; Medical Faculty, University of Prishtina, Prishtina, Kosovo), Maciej Banach (Department of Hypertension, Medical University of Lodz, Poland; Polish Mother’s Memorial Hospital Research Institute (PMMHRI), Lodz, Poland, Cardiovascular Research Centre, University of Zielona-Gora, Zielona-Gora, Poland), Marcin A. Bartlomiejczyk (Department of Hypertension, Medical University of Lodz, Poland; Polish Mother’s Memorial Hospital Research Institute (PMMHRI), Lodz, Poland), Bojko Bjelakovic (Clinic of Pediatrics, Clinical Center, Nis, Faculty of Medicine, University of Nis, Serbia), Eric Bruckert (Pitié-Salpetrière Hospital and Sorbonne University, Cardio metabolic Institute, Paris, France), Agata Bielecka-Dabrowa (Polish Mother’s Memorial Hospital Research Institute (PMMHRI), Lodz, Poland), Alberto Cafferata (Facultad de Medicina, Instituto Universitario de Ciencias de la Salud, Fundación H.A. Barceló, Argentina), Richard Ceska (Third Department of Medicine - Department of Endocrinology and Metabolism of the First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic), Arrigo F.G. Cicero (Atherosclerosis and Hypertension Research Group, Medical and Surgical Sciences Department, University of Bologna, Bologna, Italy), Xavier Collet (Institute of Metabolic and Cardiovascular Diseases, Inserm, Toulouse, France), Olivier Descamps (Department of Internal Medicine, Centres Hospitaliers Jolimont, Haine Saint-Paul, Belgium; Department of Cardiology, Cliniques Universitaires Saint-Luc, Bruxells, Belgium), Nair Devaki (Department of Clinical Biochemistry, the Royal Free London NHS Foundation Trust, Pond Street, London, UK), Dragan Djuric (Institute of Medical Physiology "Richard Burian" Faculty of Medicine, University of Belgrade, Belgrade, Serbia), Ronen Durst (Cardiology Department, Hadassah Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel), Marat V. Ezhov (National Cardiology Research Center, Moscow, Russia), Zlatko Fras (Preventive Cardiology Unit, Department of Vascular Medicine, Division of Medicine, University Medical Centre Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia), Dan Gaita (Institutul de Boli Cardiovasculare, Universitatea de Medicina si Farmacie Victor Babes din Timisoara, Romania), Stephan von Haehling (Department of Cardiology and Pneumology, Heart Center Göttingen, University of Göttingen Medical Center, Georg-August-University, Göttingen, Germany), Adrian V. Hernandez (Health Outcomes, Policy, and Evidence Synthesis (HOPES) Group, University of Connecticut/Hartford Hospital Evidence-Based Practice Center, Hartford, CT, USA; Vicerrectorado de Investigación, Universidad San Ignacio de Loyola (USIL), Lima, Peru), Steven R. Jones (the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD, USA), Jacek Jozwiak (Department of Family Medicine and Public Health Faculty of Medicine University of Opole, Opole, Poland), Nona Kakauridze (Department of Internal Medicine, Faculty of Medicine, Tbilisi State Medical University, Tbilisi, Georgia), Niki Katsiki (Second Department of Propaedeutic Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital, Thessaloniki, Greece), Amit Khera (Division of Cardiology, UT Southwestern, Dallas, TX, USA), Karam Kostner (Mater Hospital, University of Queensland, St Lucia, QLD, Australia), Raimondas Kubilius (Department of Rehabilitation, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania), Gustavs Latkovskis (Institute of Cardiology and Regenerative Medicine, Faculty of Medicine, University of Latvia, Riga, Latvia; Pauls Stradins Clinical University Hospital, Riga, Latvia), G.B. John Mancini (Department of Medicine, Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada), A. David Marais (Chemical Pathology Division of the Department of Pathology, University of Cape Town Health Science Faculty, Cape Town, South Africa), Seth S. Martin (Ciccarone Center for Prevention of Heart Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA), Julio Acosta Martinez (Medico Cardiologo de la Policlinica Metropolitana, Carcass, Venezuela), Mohsen Mazidi (Department of Twin Research and Genetic Epidemiology, King's College London, St Thomas' Hospital, Strand, London, UK), Dimitri P. Mikhailidis (Department of Clinical Biochemistry, Royal Free Campus, University College London Medical School, University College London (UCL), London, UK), Erkin Mirrakhimov (Kyrgyz State Medical Academy, Bishkek, Kyrgyzstan), Andre R. Miserez (diagene Research Institute, Reinach, Switzerland; President of Swiss Society of Familial Forms of Hypercholesterolemia (SSFH), Breitenbach, Switzerland; University of Basel, Basel, Switzerland), Olena Mitchenko (Dyslipidaemia Department, Institute of Cardiology AMS of Ukraine, Ukraine; Ukrainian Atherosclerosis Society), Patrick Moriarty (Division of Clinical Pharmacology, Division of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA), Seyed Mohammad Nabavi (Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran), Demosthenes B. Panagiotakos (School of Health Science and Education, Department of Nutrition and Dietetics, Harokopio University of Athens, Athens, Greece), György Paragh (University of Debrecen Faculty of Medicine, Department of Internal Medicine, Debrecen, Hungary), Daniel Pella (1 st Department of Internal Medicine, Faculty of Medicine, Pavol Jozef Safarik University, Košice, Slovakia), Peter E. Penson (School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK), Zaneta Petrulioniene (Vilnius University Faculty of Medicine, Vilnius, Lithuania; Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania), Matteo Pirro (Department of Medicine, University of Perugia, Perugia, Italy), Arman Postadzhiyan (Bulgarian Society of Cardiology, Medical University of Sofia, Sofia, Bulgaria), Raman Puri (I P Apollo Hospital, New Delhi, India), Ashraf Reda (Menoufia University, President of EAVA), Željko Reiner (University Hospital Center Zagreb, Department of Internal Medicine, School of Medicine, University of Zagreb, Zagreb, Croatia), Jemaa Riadh (Laboratory of Biochemistry, Faculty of Medicine of Tunis, Rabta Hospital, University of Tunis El Manar, Tunis, Tunisia), Dimitri Richter (Cardiac Department, Euroclinic, Athens, Greece), Manfredi Rizzo (Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy), Massimiliano Ruscica (Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy), Amirhossein Sahebkar (Biotechnology Research Center, Pharmaceutical Technology Institute, Neurogenic Inflammation Research Center, and School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran), Naveed Sattar (Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK), Maria-Corina Serban (Department of Functional Sciences, Discipline of Pathophysiology, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania), Abdulla M.A Shehab (Medical Education Department, United Arab Emirates University, Al Ain, United Arab Emirates), Aleksandr B. Shek (Department of Ischemic Heart Disease and Atherosclerosis, Republican Specialised Center of Cardiology, Tashkent, Uzbekistan), Cesare R. Sirtori (Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano Centro Dislipidemie, Grande Ospedale Metropolitano, Niguarda Ca'Granda President, Fondazione Carlo Sirtori), Claudia Stefanutti (Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy), Tomasz Tomasik (Department of Family Medicine, Chair of Internal Medicine and Gerontology, Jagiellonian University Medical College, Krakow, Poland), Peter P. Toth (The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD, USA), Margus Viigimaa (Tallinn University of Technology, North Estonia Medical Centre, Tallinn, Estonia), Dragos Vinereanu (Cardiology Department, University and Emergency Hospital, Bucharest, Romania, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania), Branislav Vohnout (Institute of Nutrition, Faculty of Nursing and Health Professional Studies and Coordination Centre for Familial Hyperlipoproteinemias, Slovak Medical University in Bratislava, Bratislava, Slovakia; Institute of Epidemiology, School of Medicine, Comenius University, Bratislava, Slovakia), Michal Vrablik (1 st Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic), Nathan D. Wong (Department of Medicine, School of Medicine University of California, Irvine, CA, USA; Heart Disease Prevention Program, Division of Cardiology, University of California, Irvine, California, USA), Hung-I Yeh (Department of Medicine, Mackay Medical College, Taipei, Taiwan; Cardiovascular Division, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan), Jiang Zhisheng (Institute of Cardiovascular Disease, University of South China, Hengyang, Hunan, China), Andreas Zirlik (University Heart Centre Freiburg University, Department of Cardiology and Angiology I, Faculty of Medicine, University of Freiburg, Freiburg, Germany). With the official endorsement of: Association of Cardiologists of the Republic of Uzbekistan, Baltic Society of Atherosclerosis, Chinese Atherosclerosis Society, College of Family Physicians in Poland, Croatian Atherosclerosis Society, Czech Society for Atherosclerosis, Egyptian Association for Endocrinology, Diabetes and Atherosclerosis (EAEDA), French Atherosclerosis Society, Hellenic Atherosclerosis Society, Hellenic Lipidology Society, Hungarian Atherosclerosis Society, International Natural Product Sciences Taskforce (INPST), Israeli Society for Treatment and Prevention of Atherosclerosis, Italian Nutraceuticals Society (SINut), Italian Society for Cardiovascular Prevention (SIPREC), Kosovo Society of Cardiology, Kyrgyz Atherosclerosis Society, Latvian Society of Cardiology, Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group, Lithuanian Heart Association, Mighty Medic, Polish Lipid Association (PoLA), Romanian National Forum for Prevention, Romanian Society of Cardiology, Russian National Atherosclerosis Society, Saudi Group for Cardiovascular Prevention and Rehabilitation of the Saudi Heart Association, Serbian Association for Arteriosclerosis, Thrombosis and Vascular Biology Research (SAATVBR), Slovak Association of Atherosclerosis, Slovenian Society of Cardiology, Society of Endocrine and Metabolic Disease of South Africa, Society on Sarcopenia, Cachexia and Wasting Disorders, South African Heart Association, Swiss Society for Familial forms of Hypercholesterolemia (SSFH), Tunisian Association of Study and Research on Atherosclerosis, Ukrainian Atherosclerosis Society, Very Large Database of Lipids (VLDL)., (Copyright © 2020. Published by Elsevier Ltd.)

Background and Aims: There is considerable controversy regarding the link between serum uric acid (SUA) and mortality. We prospectively evaluated the association between SUA and risk of total and cause specific (coronary heart disease [CHD], cerebrovascular and cancer) mortality by using the National Health and Nutrition Examination Surveys (NHANES, 1999-2010). Furthermore, a systematic review and meta-analysis of cohort studies was performed to investigate pooled associations of SUA with all-cause and cause-specific mortality., Methods: Vital status through December 31, 2011 was ascertained. PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases were searched (up to April 2018). Adjusted Cox proportional hazard regression models were used to determine the association between SUA and mortality. The DerSimonian-Laird method and generic inverse variance methods were used for quantitative data synthesis., Results: Overall, 21,025 individuals were included (mean age = 47.6 years, 48.7% men) and 3520 deaths occurred during the 144 months of follow-up. In adjusted models, individuals in the highest quartile of SUA had 10 and 8% greater risk of CHD and stroke mortality, whereas there was no link between SUA, all-cause and cancer mortality. The associations of CHD and stroke mortality with SUA were more pronounced in women and, among women, in those aged >50 years. Furthermore, all-cause mortality was positively and significantly related to SUA concentrations only in women. In the meta-analysis, SUA was shown to predict the risk of total (21%), CHD (24%) and stroke (29%) mortality. Furthermore, participants with a higher level of central adiposity had a greater risk of mortality from CHD and stroke for the same level of SUA., Conclusions: Our results highlight the adverse impact of SUA on mortality, particularity in older (>50 years) women. The clinical implications of these findings remain to be established in future trials., (Copyright © 2019. Published by Elsevier B.V.)

Background: The intake of dairy products has been thought to be associated with an increased risk of coronary heart diseases (CHD) and total mortality due to its relatively high content of saturated fat. However, reports on this association particularly among US adults are conflicting and controversial. Therefore, we used data from the 1999-2010 National Health and Nutrition Examination Surveys (NHANES) study to examine whether consumption of total dairy and dairy subgroups was associated with total and cause specific (CHD, cerebrovascular and cancer) mortality. Further we carried out a systematic review and meta-analysis of prospective studies to check for consistency with the NHANES findings., Methods: In the NHANES cohort vital status through December 31, 2011 was ascertained. Cox proportional hazard regression models were used to relate baseline dairy intake with all-cause and cause-specific mortality. For the systematic review PubMed, SCOPUS, Web of Science and Google Scholar databases were searched (up to December 2017). The DerSimonian-Laird method and generic inverse variance methods were used for quantitative data synthesis., Results: In the NHANES data set of 24,474 participants, 3520 deaths occurred during follow-up. In multivariate adjusted Cox models, total mortality risk was lower when comparing the top (Q4) with the lower (Q1) quartiles of total dairy (hazard ratio [HR] 0.98, 95% confidence interval [CI]: 0.95-0.99) and cheese (HR: 0.92, 95% CI: 0.87-0.97) consumption. Using a similar model, we have found a negative association between total dairy and milk consumption with risk of cerebrovascular mortality (HR: 0.96, 95% CI: 0.94-0.98, HR: 0.93, 95% CI: 0.91-0.96, respectively), while milk consumption was associated with increased CHD mortality (HR: 1.04, 95% CI: 1.02-1.06). The meta-analysis with 636,726 participants indicated a significant inverse association between fermented dairy products and total mortality (RR: 0.97, 95% CI: 0.96-0.99), while milk consumption was associated with higher CHD mortality (RR: 1.04, 95% CI: 1.01-1.05). These findings were robust in sensitivity analyses., Conclusions: Among American adults, higher total dairy consumption was associated with lower total and cerebrovascular mortality, while higher milk consumption was associated with higher risk of CHD. These findings do not support dogmatic public health advice to reduce total dairy fat consumption, although the association between milk consumption and CHD mortality requires further study., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Gender differences in the pathophysiology of atherosclerosis, cardiovascular risk factors, and diagnosis of coronary artery disease and valvular heart disease are well known. Such differences have also been outlined in the management and outcomes after acute coronary syndromes and valvular repair. Regarding the atherosclerotic process, pathological experimental studies suggest that plaque composition and burden may differ by gender. Female gender is associated with worse outcomes in the case of ischemic heart disease and, compared with men, women are less likely to undergo interventional cardiac procedures and sustain worse outcomes. In the setting of valvular heart disease (VHD), transcatheter aortic valve implantation (TAVI) and percutaneous edge-to-edge mitral valve repair are now well-established procedures with high success rates. In women with moderate to severe aortic stenosis, subgroup analyses in TAVI trials have demonstrated gender-related differences suggesting female gender as beneficial in terms of short-, mid-, and long-term outcomes. Similarly, several studies reported different procedural challenges and outcomes in males and females following surgical and percutaneous mitral valve repair. These diverse findings emphasize the necessity to provide gender-specific analyses of interventional methods. This review highlights gender differences in the epidemiology, pathophysiology, treatment options and clinical outcomes of the conditions mentioned above., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: Little is known about the role of liver enzymes as predictors of non-liver-related morbidity and mortality. The ideal cardiovascular health (CVH) score proposed by the American Heart Association (AHA) can be used to predict mortality and morbidity. We investigated the association of the CVH score with liver enzymes and the risk of non-alcoholic fatty liver disease (NAFLD) among US adults., Methods: By using the National Health and Nutrition Examination Survey database (cross-sectional), the CVH score was calculated as meeting ideal levels of the following components: 4 behaviors (smoking, body mass index, physical activity and diet adherence) and 3 factors (total cholesterol, blood pressure and fasting glucose)., Results: Individuals with a higher CVH score ("better CVH") had a more favorable profile of liver biomarkers. Adjusted (for age, gender, race, poverty to income ratio, education, marital status and alcohol intake) linear regression indicated significant and negative associations between liver biomarkers and CVH score: (β = -0.069, p < 0.001) for alanine aminotransferase, (β = -0.095, p < 0.001), aspartate aminotransferase, (β = -0.067, p < 0.001), alkaline phosphatase and (β = -0.125, p < 0.001) and fatty liver index. In the logistic regression, with the same confounders, individuals with a higher CVH score had 12% less likelihood of NAFLD compared with those with a lower score. Furthermore, each CVH metric separately was inversely linked to the risk of NAFLD., Conclusions: For the first time among US adults, our findings shed light on the role CVH on liver biomarkers., (Copyright © 2018. Published by Elsevier B.V.)

Background and Aims: We aimed to evaluate the link between inflammatory score [consisting of C-reactive protein (CRP) and white blood cells], serum uric acid (SUA) and atherogenic index of plasma (AIP) and the cardiovascular health (CVH) score., Methods: We used the cross-sectional National Health and Nutrition Examination Survey database. Statistical analyses accounted for the survey design and sample weights., Results: Overall, there were 23,004 participants (mean age = 47.2 years, 46.5% males). Participants with an ideal CVH level had the highest ratio of poverty to income (3.62%, p < 0.001), as well as lower levels of CRP, SUA and AIP (p < 0.001 for all comparisons). In adjusted linear regression, a significant negative association was observed between inflammatory score (β = -0.052, p < 0.001), SUA (β = -0.041, p < 0.001) and AIP (β = -0.039, p < 0.001) and CVH score, i.e. participants with a better (greater) CVH score had a lower inflammatory score. Results from adjusted logistic regression showed reduction in the likelihood of "high-risk atherosclerosis" (defined as AIP ≥0.21) [intermediate: odds ratio (OR) = 0.90, 95% confidence interval (CI):0.85-0.95, ideal: OR = 0.81, 95%CI: 0.74-0.88] and "high CVD risk" (defined as CRP ≥3 mg/l) [intermediate: OR = 0.86, 95%CI:0.73-0.98, ideal: OR = 0.82, 95%CI:0.69-0.95] across the categories of CVH., Conclusions: Our findings highlight that CVH metrics were associated with inflammatory score, SUA and AIP. Furthermore, participants with a better CVH score had a lower CVD risk. These results reinforce the importance of implementing healthy behaviours as proposed by the American Heart Association. If confirmed in clinical trials, this knowledge may have implications for CVD prevention and management., (Copyright © 2018. Published by Elsevier B.V.)

Recently, concerns regarding the safety of red yeast rice (RYR) have been raised after the publication of some case reports claiming toxicity. Since the previous meta-analyses on the effects of RYR were mainly focused on its efficacy to improve lipid profile and other cardiovascular parameters, we carried out a meta-analysis on safety data derived from the available randomized controlled clinical trials (RCTs). Primary outcomes were musculoskeletal disorders (MuD). Secondary outcomes were non-musculoskeletal adverse events (Non-MuD) and serious adverse events (SAE). Subgroups analyses were carried out considering the intervention (RYR alone or in association with other nutraceutical compounds), monacolin K administered daily dose (≤3, 3.1-5 or >5 mg/day), follow-up (>12 or ≤12 weeks), with statin therapy or statin-intolerance and type of control treatment (placebo or statin treatment). Data were pooled from 53 RCTs comprising 112 treatment arms, which included 8535 subjects, with 4437 in the RYR arm and 4303 in the control one. Monacolin K administration was not associated with increased risk of MuD (odds ratio (OR) = 0.94, 95% confidence interval (CI) 0.53,1.65). Moreover, we showed reduced risk of Non-MuD (OR = 0.59, 95%CI 0.50, 0.69) and SAE (OR = 0.54, 95%CI 0.46, 0.64) vs. control. Subgroups analyses confirmed the high tolerability profile of RYR. Furthermore, increasing daily doses of monacolin K were negatively associated with increasing risk of Non-MuD (slope: -0.10; 95%CI: -0.17, -0.03; two-tailed p < 0.01). Based on our data, RYR use as lipid-lowering dietary supplement seems to be overall tolerable and safe in a large kind of moderately hypercolesterolaemic subjects., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The health outcomes associated with extremely low or high plasma concentrations of high-density lipoprotein cholesterol (HDL-C) are not well documented mainly because of the small numbers of participants with such values included in the clinical trials., Objective: We prospectively investigated the association between extremely low and high HDL-C with: 1) the risk of overall, coronary heart disease (CHD), cerebrovascular and cancer mortality, and, 2) their link with inflammatory factors., Methods: Analysis was based on subjects ≥18 years old from the National Health and Nutrition Examination Surveys (NHANES). We categorized HDL-C levels as follows: [low HDL-C group ≤30 (extremely low), 30-40 (low), and ≥40 (reference)] [high HDL-C group = 40-80 (reference), 80-100 (high) and ≥100 mg/dl (extremely high). Cox proportional hazard regression models and analysis of covariance accounted for survey design, masked variance and sample weights., Results: After adjustment for age, race and sex, we found that the very low HDL-C category (<30 mg/dl) had a greater risk of total mortality (risk ratio [RR]: 3.00, 95%CI: 2.20-4.09). RR for CHD and stroke mortality was 2.00 and 2.53, respectively; there was no link between cancer and level of HDL-C (p = 0.235). The association between total mortality, CHD and stroke with the level of HDL-C attenuated but remained significant even after adjustment for demographics, dietary, cardiovascular risk factors and treatment for dyslipidemia (all p < 0.001). After adjustments, subjects with extremely high HDL-C levels had a higher risk of mortalities (all p < 0.001). Mexican-American ethnicity, subjects in the low level of HDL-C (30-40 mg/dl) category had higher risk of mortalities than those with a very low level (all p < 0.001). Concentration of C-reactive protein, fibrinogen and white blood count significantly decreased as the level of the HDL-C increased; these findings were robust after adjustment for demographics, dietary, cardiovascular risk factors and treatment for dyslipidemia (all p < 0.001); further subjects with extremely high HDL-C levels have a greater levels of inflammatory factors (all p < 0.001)., Conclusions: Both extremely low and high HDL-C levels were associated with greater risk of mortalities (total, CHD and stroke) and higher level of inflammatory factors, while there was no link between level of HDL-C and risk of cancer. Moreover, we found evidence of an HDL-C paradox in Mexican-American ethnicity participants., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The prevalence of non-alcoholic fatty liver disease (NAFLD) is rising. This increase may be associated with obesity. It has been suggested that trans-fatty acids (TFAs) play an important role in non-communicable diseases., Aim: We examined the link between liver tests, fatty liver index (FLI) and plasma TFAs. Furthermore, we evaluated the impact of adiposity on this link., Methods: The National Health and Nutrition Examination Survey (NHANES) was used to obtain the data on TFAs and liver function biomarkers. We took account of complex NHANES data, masked variance and weighting methodology., Results: Of the 4252 participants, 46.4% were men. The mean age was 50.6 years overall; 51.3 years for men and 49.8 years for women (p = 0.206). In a fully adjusted model (demographic and clinical factors), FLI increased as trans-9-hexadecenoic acid and trans-11-octadecenoic acid levels increased; FLI was 38.1 and 42.3 for the first quarter (Q1) of trans-9-hexadecenoic acid and trans-11-octadecenoic acid, respectively, reaching 65.1 and 69.3 for the highest quarters (Q4) (p < 0.001 for all comparisons). Multivariable logistic regression showed for all four studied TFAs, the likelihood of NAFLD (determined by FLI) increased with increasing TFAs levels (quartiles) in a stepwise manner (p < 0.001 for all comparisons). Based on moderation analysis, a strong impact of body mass index (BMI) on the link between FLI and TFAs was observed., Conclusions: Our results suggest a direct significant association between plasma TFAs, liver tests and NAFLD (assessed by FLI). Furthermore, BMI was shown to mediate this relationship. These findings highlight the importance of avoiding TFAs consumption in order to minimize cardiometabolic risk., (Copyright © 2018. Published by Elsevier B.V.)

Background and Aims: We investigated the association between Dietary Inflammatory Index (DII ® ) scores and cardio-metabolic risk factors singly and in combination as metabolic syndrome (MetS)., Methods: We used data from participants selected from the US National Health and Nutrition Examination Survey (NHANES). Analyses were restricted to participants with data available on dietary intake, biochemical data, and anthropometric measurements from 2005 to 2012. Statistical analyses used the SPSS ® Complex Samples v22.0 (IBM Corp, Armonk, NY) and accounted for the survey design and sample weights. Energy-adjusted-DII (E-DII ® ) expressed per 1000 kcal was calculated from 24-h dietary recalls. Of the 17,689 participants with evaluable data, 8607 (48.3%) were men. The mean age was 45.8 years in the overall sample, with men being slightly younger than women (44.9 vs. 46.5 years, p = 0.05)., Results: In multivariable-adjusted regression models, the odds of MetS, its components, as well as obesity, and elevated high-sensitivity C-reactive protein (hsCRP) increased across increasing quartiles of E-DII (p < 0.001). In age, sex, race, income-to-poverty ratio-adjusted models, these and other cardiovascular disease risk factors (triglycerides/high density lipoprotein cholesterol (HDL-C) ratio, apolipoprotein (B) and HbA1C) increased across quartiles of the E-DII (all p < 0.001), while HDL-C levels decreased (p < 0.001)., Conclusions: This study suggests associations between MetS, its components, subclinical inflammation, and the DII. These results reinforce the view that diet plays an important role in the occurrence of cardiovascular diseases., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Atherosclerosis usually develops at geometrically susceptible areas, despite the impact of systemic risk factors on the entire vascular system. The aim of our study was to investigate whether carotid bifurcation geometry as assessed by ultrasound is associated with early carotid atherosclerosis, regardless of the presence of known atherosclerotic risk factors., Material and Methods: A nonrandomized prospective study was undertaken, including subjects of both genders, aged 50-60 years, without known cardiovascular family history, and symptoms and/or signs of cardiovascular disease. Clinical assessment and ultrasound of the carotid bifurcation evaluating geometrical characteristics, ultrasonic biopsy score (UBS), intima-media thickness (IMT), and the presence of plaque were recorded., Results: Two hundred one subjects (95 men/106 women; mean age: 55 years) provided 286 carotid bifurcations associated with atherosclerotic risk factors and 114 without (one poor imaging). While UBS in the right common carotid artery (CCA) was higher in subjects with atherosclerotic risk factors but free of plaque (P = 0.035), larger diameter of the bulb (dBULB) (P < 0.001), lower ratios of internal carotid artery diameter + external carotid artery diameter/diameter of CCA ([dICA + dECA]/dCCA) (P = 0.004), and (dICA 2 + dECA 2 )/dCCA 2 (P = 0.025) were independently associated with higher CCA IMT. The presence of plaque among the total 400 carotid bifurcations was associated in the left and right CCA with lower values of bulb diameter/dCCA (dBULB/dCCA) (P = 0.014) and (dICA + dECA)/dCCA (P = 0.001), respectively. Among subjects without atherosclerotic risk factors (n = 114), the presence of plaque in the right CCA was associated with lower values of (dBULB + dECA)/dCCA (P = 0.001) and that in the left with lower values of dBULB/dCCA (P = 0.001)., Conclusions: Different dimensional ratios of the carotid bifurcation assessed by ultrasound are associated with the development of early carotid atherosclerosis independently from the presence of atherosclerotic risk factors. Carotid atherosclerotic process may be side dependent., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Statin intolerance is the inability to tolerate a dose of statin required to sufficiently reduce cardiovascular risk. With the five-step approach, more than 90% of these patients might be treated with statins. The principal approaches are to try not to discontinue statin therapy and to treat these patients as effectively as possible. New therapies with the proprotein convertase subtilisin-kexin type 9 inhibitors and bempedoic acid might be an effective response to these needs. In case of lack of achieved goal of the therapy nutraceuticals with confirmed low-density lipoprotein cholesterol reduction properties may be considered as a part of the lipid-lowering combination therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Statins are well-established low-density lipoprotein cholesterol-lowering drugs. Elevated apolipoprotein CIII (Apo CIII) levels are associated with elevated triglyceride-rich particles, which are also considered to be a possible risk factor for cardiovascular disease., Objective: The aim of this meta-analysis of randomized placebo-controlled clinical trials was to assess the effect of statins on Apo CIII concentrations., Methods: Randomized placebo-controlled trials investigating the impact of statin treatment on cholesterol lowering that include lipoprotein measurement were searched in PubMed, MEDLINE, Scopus, Web of Science, and Google Scholar databases (up to July 31, 2017). A random-effects model and generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. A weighted random-effects meta-regression was performed to evaluate the impact of potential confounders on Apo CIII concentrations., Results: This meta-analysis of data from 6 randomized placebo-controlled clinical trials (10 statin arms) involving 802 subjects showed that statin therapy significantly decreased circulating Apo CIII concentrations (weighted mean difference [WMD]: -2.71, 95% confidence interval [CI]: -3.74 to -1.68, P < .001; I 2 : 73.83%). The effect size was robust in the leave-one-out sensitivity analysis and not driven by any single study. Subgroup analysis showed a reduction of Apo CIII concentrations by atorvastatin (WMD: -4.74, 95% CI: -3.74 to -1.68, P = .002; I 2 : 84.02%), rosuvastatin (WMD: -2.68, 95% CI: -4.52 to -0.84, P = .004; I 2 : 0%), and lovastatin (WMD: -1.64, 95% CI: -2.22 to -1.07, P < .001; I 2 : 0%)., Conclusion: This meta-analysis suggests that statin treatment significantly reduces plasma Apo CIII levels., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Conflicting results suggest a link between serum uric acid (SUA), inflammation and glucose/insulin homeostasis; however, the role of adiposity in this relationship is not clear. Therefore, we evaluated the role of different adiposity factors, including central body mass index (BMI), peripheral waist circumference (WC), and visceral adiposity [visceral adipose tissue (apVAT)], on the association between SUA, inflammation and glucose/insulin homeostasis among US adults., Methods: Data were extracted from the 2005-2010 US National Health and Nutrition Examination Surveys. Overall, 16,502 participants were included in the analysis (mean age = 47.1 years, 48.2% men). Analysis of co-variance and "conceptus causal mediation" models were applied, while accounting for survey design., Results: Corrected models showed that subjects with higher SUA levels have a less favorable profile of inflammation and glucose/insulin homeostasis parameters (all p < 0.001). We found that all our potential mediators (BMI, WC and apVAT) had an impact (to various extents) on the link between variables, including serum C-reactive protein (CRP), apolipoprotein-B (apoB), insulin resistance markers, 2-h blood glucose (2hG) and triglyceride, and fasting blood glucose (FBG) (TyG) index (all p < .001), while none of the potential mediators (BMI, apVAT, WC) had an impact on the link between FBG and glycated hemoglobin with SUA (all p > 0.05). We have found that all of our mediators partially mediated the link between inflammation and glucose/insulin homeostasis parameters and SUA. Of note, apVAT fully mediated the association between SUA and 2hG., Conclusions: By applying advanced statistical techniques, we shed light on the complex link of SUA with inflammation and glucose/insulin homeostasis and quantify the role of adiposity factors in that link., (Copyright © 2017. Published by Elsevier B.V.)

Tibolone is a synthetic steroid with estrogenic, androgenic and progestogenic activity, but the evidence regarding its effects on fibrinogen and antithrombin III (ATIII) has not been conclusive. We assessed the impact of tibolone on fibrinogen and ATIII through a systematic review and meta-analysis of available randomized controlled trials (RCTs). The search included PUBMED, Web of Science, Scopus, and Google Scholar (up to January 31st, 2016) to identify controlled clinical studies investigating the effects of oral tibolone treatment on fibrinogen and ATIII. Overall, the impact of tibolone on plasma fibrinogen concentrations was reported in 10 trials comprising 11 treatment arms. Meta-analysis did not suggest a significant reduction of fibrinogen levels following treatment with tibolone (WMD: -5.38%, 95% CI: -11.92, +1.16, p=0.107). This result was robust in the sensitivity analysis and not influenced after omitting each of the included studies from meta-analysis. When the studies were categorized according to the duration of treatment, there was no effect in the subsets of trials lasting either <12months (WMD: -7.64%, 95% CI: -16.58, +1.29, p=0.094) or ≥12months (WMD: -0.62%, 95% CI: -8.40, +7.17, p=0.876). With regard to ATIII, there was no change following treatment with tibolone (WMD: +0.74%, 95% CI: -1.44, +2.93, p=0.505) and this effect was robust in sensitivity analysis. There was no differential effect of tibolone on plasma ATIII concentrations in trials with either <12months (WMD: +2.26%, 95% CI: -3.14, +7.66, p=0.411) or≥12months (WMD: +0.06%, 95% CI: -1.16, +1.28, p=0.926) duration. Consistent with the results of subgroup analysis, meta-regression did not suggest any significant association between the changes in plasma concentrations of fibrinogen (slope: +0.40; 95% CI: -0.39, +1.19; p=0.317) and ATIII (slope: -0.17; 95% CI: -0.54, +0.20; p=0.374) with duration of treatment. In conclusion, meta-analysis did not suggest a significant reduction of fibrinogen and ATIII levels following treatment with tibolone., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Smoking is an important risk factor for cardiovascular disease (CVD) morbidity and mortality. The impact of statin therapy on CVD risk by smoking status has not been fully investigated. Therefore we assessed the impact of statin therapy on CVD outcomes by smoking status through a systematic review of the literature and meta-analysis of available randomized controlled trials (RCTs). The literature search included EMBASE, ProQuest, CINAHL and PUBMED databases to 30 January 2016 to identify RCTs that investigated the effect of statin therapy on cumulative incidence of major CVD endpoints (e.g. non-fatal myocardial infarction, revascularization, unstable angina, and stroke). Relative risks (RR) ratios were calculated from the number of events in different treatment groups for both smokers and non-smokers. Finally 11 trials with 89,604 individuals were included. The number of smokers and non-smokers in the statin groups of the analyzed studies was 8826 and 36,090, respectively. The RR for major CV events was 0.73 (95% confidence interval [CI]: 0.67-0.81; p<0.001) in nonsmokers and 0.72 (95%CI: 0.64-0.81; p<0.001) in smokers. Moderate to high heterogeneity was observed both in non-smokers (I 2 =77.1%, p<0.001) and in smokers (I 2 =51.6%, p=0.024) groups. Smokers seemed to benefit slightly more from statins than non-smokers according to the number needed to treat (NNT) analysis (23.5 vs 26.8) based on RRs applied to the control event rates. The number of avoided events per 1000 individuals was 42.5 (95%CI: 28.9-54.6) in smokers and 37.3 (95%CI: 27.2-46.4) in non-smokers. In conclusion, this meta-analysis suggests that the effect of statins on CVD is similar for smokers and non-smokers, but in terms of NNTs and number of avoided events, smokers seem to benefit more although non-significantly., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Evidence about the optimal time of day at which to administer statins is lacking., Objective: The objective of this study is to synthesize evidence about effects of morning vs evening statin administration on lipid profile., Methods: We searched PubMed, SCOPUS, Web of Science, and Embase databases (from inception up to July 24, 2016) to identify the relevant studies. Mean differences (MDs) between the change scores in lipid parameters were pooled using a fixed-effect model., Results: Eleven articles with 1034 participants were eligible for the analysis. The pooled analysis comparing effects of morning vs evening administration of statins on plasma total cholesterol (TC; P = .10), high-density lipoprotein cholesterol (P = .90), and triglycerides (P = .45) was not statistically significant. Low-density lipoprotein cholesterol (LDL-C) lowering was statistically greater in the evening-dose group (MD: 3.24 mg/dL, 95% CI: 1.23-5.25, P = .002). Subgroup analysis according to statin half-lives showed that evening dose of statins was significantly superior to morning dose for lowering LDL-C in case of both short and long half-life statins (MD: 9.68 mg/dL, 95% CI: 3.32-16.03, P = .003 and MD: 2.53 mg/dL, 95% CI: 0.41-4.64, P = .02, respectively) and also for TC reduction in case of short half-life statins only (P = .0005)., Conclusions: LDL-C and TC lowering was significantly greater in the evening dose than in the morning dose in case of short-acting statins. Besides slight but significant effect on LDL-C, the efficacy of long-acting statins was equivalent for both regimens. Therefore, long-acting statins should be given at a time that will best aid compliance. Short-acting statins should be given in the evening., (Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background and Aims: The effect of statin therapy on plasma adiponectin levels has not been conclusively studied. Therefore, we aimed to evaluate this effect through a systematic review and meta-analysis of available randomized controlled trials (RCTs)., Methods: Quantitative data synthesis was performed using a random-effects model with weighted mean difference (WMD) and 95% confidence interval (CI) as summary statistics., Results: In 30 studies (43 study arms) with 2953 participants, a significant increase in plasma adiponectin levels was observed after statin therapy (WMD: 0.57 μg/mL, 95% CI: 0.18, 0.95, p = 0.004). In subgroup analysis, atorvastatin, simvastatin, rosuvastatin, pravastatin and pitavastatin were found to change plasma adiponectin concentrations by 0.70 μg/mL (95% CI: -0.26, 1.65), 0.50 μg/mL (95% CI: -0.44, 1.45), -0.70 μg/mL (95% CI: -1.08, -0.33), 0.62 μg/mL (95% CI: -0.12, 1.35), and 0.51 μg/mL (95% CI: 0.30, 0.72), respectively. With respect to duration of treatment, there was a significant increase in the subset of trials lasting ≥12 weeks (WMD: 0.88 μg/mL, 95% CI: 0.19, 1.57, p = 0.012) but not in the subset of <12 weeks of duration (WMD: 0.18 μg/mL, 95% CI: -0.23, 0.58, p = 0.390). Random-effects meta-regression suggested a significant association between statin-induced elevation of plasma adiponectin and changes in plasma low density lipoprotein cholesterol levels (slope: 0.04; 95% CI: 0.01, 0.06; p = 0.002)., Conclusions: The meta-analysis showed a significant increase in plasma adiponectin levels following statin therapy. Although statins are known to increase the risk for new onset diabetes mellitus, our data might suggest that the mechanism for this is unlikely to be due to a reduction in adiponectin expression., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Statin therapy may lower plasma lipid concentrations, but the evidence in HIV-infected patients is still unclear. Therefore, we aimed to investigate the impact of statin therapy on plasma lipid concentrations through a systematic review of the literature and meta-analysis of available randomized controlled trials (RCTs). The literature search included PUBMED, SCOPUS, Web of Science and Google Scholar up to October 30, 2015. The meta-analysis was performed using either a fixed-effects or random-effect model according to I(2) statistic. Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence interval (CI). Two investigators independently reviewed the title or abstract, further reviewed the full-texts and extracted information on study characteristics and study outcomes. Meta-analysis of 12 RCTs with 697 participants suggested significant reductions in plasma concentrations of low density lipoprotein (LDL) cholesterol (WMD: -0.72mmol/L [-27.8mg/dL], 95%CI: -1.04, -0.39, p<0.001; I(2)=85.7%), total cholesterol (WMD: -1.03mmol/L [-39.8mg/dL], 95%CI: -1.42, -0.64, p<0.001; I(2)=94.7%) and non-high density lipoprotein cholesterol (non-HDL-C) (WMD: -0.81mmol/L [-31.3mg/dl], 95%CI: -1.32, -0.30, p=0.002; I(2)=76.5%), and elevations in HDL-C (WMD: 0.072mmol/L [2.8mg/dL], 95%CI: 0.053, 0.092, p<0.001; I(2)=0%) following treatment with statins (mostly of moderate-intensity). No significant alteration in plasma triglycerides (TG) concentrations was found (WMD: -0.16mmol/L [-14.2mg/dL], 95%CI: -0.61, 0.29, p=0.475; I(2)=90.2%). All these effects were robust in sensitivity analysis, suggesting that the computed effect is not driven by any single study. In subgroup analysis, no significant difference was found among different statins in terms of changing plasma concentrations of LDL-C, HDL-C and TG. However, atorvastatin was found to be more efficacious in reducing plasma total cholesterol concentrations (p<0.001). In conclusion, the meta-analysis suggested significant reductions in plasma concentrations of LDL-C, total cholesterol and non-HDL-C, and elevations in HDL-C, but no significant alteration in plasma TG following treatment with statins., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Previous studies have suggested that for clinical purposes, subjects with fasting triglycerides (TGs) between 89-180 mg/dl (1-2 mmol/l) would benefit from postprandial TGs testing., Objective: To determine the postprandial TG response in 2 independent studies and validate who should benefit diagnostically from an oral-fat tolerance test (OFTT) in clinical practice., Methods: A population of 1002 patients with coronary heart disease (CHD) from the CORDIOPREV clinical trial and 1115 white US subjects from the GOLDN study underwent OFTTs. Subjects were classified into 3 groups according to fasting cut points of TGs to predict the usefulness of OFTT: (1) TG < 89 mg/dl (<1 mmol/l); (2) TG, 89-180 mg/dl (1-2 mmol/l); and (3) TG > 180 mg/dl (>2 mmol/l). Postprandial TG concentration at any point > 220 mg/dl (>2.5 mmol/l) has been pre-established as an undesirable postprandial response., Results: Of the total, 49% patients with CHD and 42% from the general population showed an undesirable response after the OFTT. The prevalence of undesirable postprandial TG in the CORDIOPREV clinical trial was 12.8, 50.3, and 89.7%, in group 1, 2, and 3, respectively (P < .001) and 11.2, 58.1, and 97.5% in group 1, 2, and 3, respectively (P < .001) in the GOLDN study., Conclusions: These two studies validate the predictive values reported in a previous consensus. Moreover, the findings of the CORDIOPREV and GOLDN studies show that an OFTT is useful to identify postprandial hyperlipidemia in subjects with fasting TG between 1-2 mmol/l (89-180 mg/dL), because approximately half of them have hidden postprandial hyperlipidemia, which may influence treatment. An OFTT does not provide additional information regarding postprandial hyperlipidemia in subjects with low TG (<1 mmol/l, <89 mg/dL) or increased TG (>2 mmol/l, >180 mg/dl)., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

We aimed to elucidate the role of vitamin D supplementation on adipokines through a systematic review and a meta-analysis of randomized placebo-controlled trials (RCTs). The search included PUBMED, Scopus, Web of Science and Google Scholar through July 1st, 2015. Finally we identified 9 RCTs and 484 participants. Meta-analysis of data from 7 studies did not find a significant change in plasma adiponectin concentrations following vitamin D supplementation (mean difference [MD]: 4.45%, 95%CI: -3.04, 11.93, p=0.244; Q=2.18, I(2)=0%). In meta-regression, changes in plasma adiponectin concentrations following vitamin D supplementation were found to be independent of treatment duration (slope: 0.25; 95%CI: -0.69, 1.19; p=0.603) and changes in serum 25-hydroxy vitamin D [25(OH)D] levels (slope: -0.02; 95%CI: -0.15, 0.12; p=0.780). Meta-analysis of data from 6 studies did not find a significant change in plasma leptin concentrations following vitamin D supplementation (MD: -4.51%, 95%CI: -25.13, 16.11, p=0.668; Q=6.41, I(2)=21.97%). Sensitivity analysis showed that this effect size is sensitive to one of the studies; removing it resulted in a significant reduction in plasma leptin levels (MD: -12.81%, 95%CI: -24.33, -1.30, p=0.029). In meta-regression, changes in plasma leptin concentrations following vitamin D supplementation were found to be independent of treatment duration (slope: -1.93; 95%CI: -4.08, 0.23; p=0.080). However, changes in serum 25(OH)D were found to be significantly associated with changes in plasma leptin levels following vitamin D supplementation (slope: 1.05; 95%CI: 0.08, 2.02; p=0.033). In conclusion, current data did not indicate a significant effect of vitamin D supplementation on adiponectin and leptin levels., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Several studies suggest differences between fibrates and statins in lowering plasma fibrinogen (Fib) concentrations, but the evidence is not definitive. Therefore, the aim of this meta-analysis of head-to-head randomized trials was to compare the efficacy of statins and fibrates on plasma Fib concentrations., Methods: The literature search included Medline, Scopus, and Web of Science up to February 1st, 2015, to identify head-to-head comparative randomized trials investigating the efficacy of fibrates vs statins on plasma Fib concentrations., Results: In total 22 trials with 2762 participants were included to the meta-analysis. Random-effect meta-analysis suggested a significantly greater effect of fibrates vs statins in lowering plasma Fib concentrations (weighted mean difference [WMD]: -40.7mg/dL, 95% confidence interval [CI]: -55.2, -26.3, p<0.001). When the analysis was stratified according to the type of fibrate administered, there were significant Fib-lowering effects with both bezafibrate (n=8 treatment arms; WMD: -23.7mg/dL, 95% CI: -41.8, -5.7, p=0.01) and fenofibrate (n=15 treatment arms; WMD: -43.7mg/dL, 95% CI: -61.3, -26.2, p<0.001). Overall, there was a numerically greater effect in the subgroup of trials with ≥12 weeks duration (n=17 treatment arms; WMD: -42.7mg/dL, 95% CI: -60.3, -25.1, p<0.001) compared with the subgroup of trials lasting <12 weeks (n=7 treatment arms; WMD: -36.7mg/dL, 95% CI: -52.0, -21.4, p<0.001)., Conclusions: Monotherapy with either fibrates or statins suggested a significantly greater effect of fibrates in lowering plasma Fib concentrations. According to these findings, mechanisms associated with fibrinogen metabolism might be responsible for the distinct effects of statins and fibrates in reducing cardiovascular endpoints., (Copyright © 2015. Published by Elsevier Ltd.)

Endothelial dysfunction is considered as an early change in atherogenesis. Raised levels of systemic inflammatory markers are associated with cardiovascular disease (CVD). Endocan (previously known as endothelial cell specific molecule-1, ESM-1), is a potential immunoinflammatory marker that may be linked to CVD. Endocan is released by vascular endothelial cells in several organs. Endocan may play an important role in regulating cell adhesion and raised plasma levels may reflect endothelial dysfunction. Endocan levels are elevated in conditions such as chronic kidney disease, renal transplant rejection, tumor progression and hypertension. Endocan is a potential inflammatory and CVD marker. Further studies are needed to assess the relevance of endocan in clinical practice., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Circulating lipoprotein (a) (Lp(a)) is a recognized risk factor for cardiovascular disease (CVD). Tibolone, a synthetic steroid, may lower Lp(a) levels; however, evidence of the effects of tibolone on Lp(a) still remain to be defined. Therefore, we investigated the effects of tibolone treatment on circulating Lp(a) levels in postmenopausal women., Methods: The search included PUBMED, Web of Science, Scopus, and Google Scholar (up to January 31st, 2015) to identify controlled clinical studies investigating the effects of oral tibolone treatment on Lp(a) levels in postmenopausal women. Random-effects meta-regression was performed using unrestricted maximum likelihood method for the association between calculated weighted mean difference (WMD) and potential moderators., Results: Meta-analysis of data from 12 trials (16 treatment arms) suggested a significant reduction of Lp(a) levels following tibolone treatment (WMD: -25.28%, 95% confidence interval [CI]: -36.50, -14.06; p < 0.001). This result was robust in the sensitivity analysis and its significance was not influenced after omitting each of the included studies from the meta-analysis. When the studies were categorized according to the tibolone dose, there were consistent significant reductions of Lp(a) in the subsets of studies with doses <2.5 mg/day (WMD: -17.00%, 95%CI: -30.22, -3.77; p < 0.012) and 2.5 mg/day (WMD: -29.18%, 95%CI: -45.02, -13.33; p < 0.001). Likewise, there were similar reductions in the subsets of trials with follow-up either <24 months (WMD: -26.79%, 95%CI: -38.40, -15.17; p < 0.001) or ≥24 months (WMD: -23.10%, 95%CI: -40.17, -6.03; p = 0.008)., Conclusions: This meta-analysis shows that oral tibolone treatment significantly lowers circulating Lp(a) levels in postmenopausal women. Further studies are warranted to explore the mechanism of this effect and the potential value and place of tibolone or its analogues in the treatment of elevated Lp(a) in individuals at risk of CVD., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Statin therapy may lower plasma coenzyme Q10 (CoQ10) concentrations, but the evidence as to the significance of this effect is unclear. We assessed the impact of statin therapy on plasma CoQ10 concentrations through the meta-analysis of available RCTs. The literature search included selected databases up to April 30, 2015. The meta-analysis was performed using either a fixed-effects or random-effect model according to I(2) statistic. Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence interval (CI). The data from 8 placebo-controlled treatment arms suggested a significant reduction in plasma CoQ10 concentrations following treatment with statins (WMD: -0.44 μmol/L, 95%CI: -0.52, -0.37, p<0.001). The pooled effect size was robust and remained significant in the leave-one-out sensitivity analysis. Subgroup analysis suggested that the impact of statins on plasma CoQ10 concentrations is significant for all 4 types of statins studied i.e. atorvastatin (WMD: -0.41 μmol/L, 95%CI: -0.53, -0.29, p<0.001), simvastatin (WMD: -0.47 μmol/L, 95% CI: -0.61, -0.33, p<0.001), rosuvastatin (WMD: -0.49 μmol/L, 95%CI: -0.67, -0.31, p<0.001) and pravastatin (WMD: -0.43 μmol/L, 95%CI: -0.69, -0.16, p=0.001). Likewise, there was no differential effect of lipophilic (WMD: -0.43 μmol/L, 95%CI: -0.53, -0.34, p<0.001) and hydrophilic statins (WMD: -0.47 μmol/L, 95%CI: -0.62, -0.32, p<0.001). With respect to treatment duration, a significant effect was observed in both subsets of trials lasting <12 weeks (WMD: -0.51 μmol/L, 95%CI: -0.64, -0.39, p<0.001) and ≥12 weeks (WMD: -0.40 μmol/L, 95%CI: -0.50, -0.30, p<0.001). The meta-analysis showed a significant reduction in plasma CoQ10 concentrations following treatment with statins. Further well-designed trials are required to confirm our findings and elucidate their clinical relevance., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

While risk scores are invaluable tools for adapted preventive strategies, a significant gap exists between predicted and actual event rates. Additional tools to further stratify the risk of patients at an individual level are biomarkers. A surrogate endpoint is a biomarker that is intended as a substitute for a clinical endpoint. In order to be considered as a surrogate endpoint of cardiovascular events, a biomarker should satisfy several criteria, such as proof of concept, prospective validation, incremental value, clinical utility, clinical outcomes, cost-effectiveness, ease of use, methodological consensus, and reference values. We scrutinized the role of peripheral (i.e. not related to coronary circulation) noninvasive vascular biomarkers for primary and secondary cardiovascular disease prevention. Most of the biomarkers examined fit within the concept of early vascular aging. Biomarkers that fulfill most of the criteria and, therefore, are close to being considered a clinical surrogate endpoint are carotid ultrasonography, ankle-brachial index and carotid-femoral pulse wave velocity; biomarkers that fulfill some, but not all of the criteria are brachial ankle pulse wave velocity, central haemodynamics/wave reflections and C-reactive protein; biomarkers that do no not at present fulfill essential criteria are flow-mediated dilation, endothelial peripheral arterial tonometry, oxidized LDL and dysfunctional HDL. Nevertheless, it is still unclear whether a specific vascular biomarker is overly superior. A prospective study in which all vascular biomarkers are measured is still lacking. In selected cases, the combined assessment of more than one biomarker may be required., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Objective: Raised plasma endothelin-1 (ET-1) levels may be a risk factor for vascular dysfunction and cardiovascular (CV) disease. This meta-analysis assessed the effect of statins on circulating ET-1 concentrations., Methods and Results: The search included PUBMED, Cochrane Library, Web of Science, Scopus, and EMBASE up to September 30, 2014 to identify randomized controlled trials (RCTs) with ET-1 measurement during statin therapy. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. Data from 15 RCTs showed that statin therapy significantly reduces plasma ET-1 concentrations (WMD: -0.30 pg/mL, 95%CI: -0.47, -0.13; p < 0.01). This effect was robust in sensitivity analysis, and not largely affected by the duration of statin therapy (<12 weeks - WMD: -0.51 pg/mL, 95%CI: -0.89, -0.14, p < 0.01; >12 week -WMD: -0.19 pg/mL, 95%CI: -0.36, -0.02; p < 0.05) or by dose of statins (<40 mg/day - WMD: -0.27 pg/mL, 95%CI: -0.49, -0.05; p = 0.01; >40 mg/day - WMD: -0.38 pg/mL, 95%CI: -0.68, -0.08; p = 0.01). Lipophilic (atorvastatin, simvastatin, fluvastatin, and cerivastatin - WMD: -0.34 pg/mL, 95%CI: -0.55, -0.13; p < 0.01), but not a hydrophilic statin (pravastatin - WMD: -0.18 pg/mL, 95%CI: -0.44 -0.08; p > 0.05) had a significant effect in promoting ET-1 reduction., Conclusions: Statin therapy significantly reduces circulating ET-1 concentrations, regardless of treatment duration or dose of statins. This effect of statins may be influenced by statin lipophilicity. There is a need to establish whether lowering ET-1 levels has a beneficial effect on CV events., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Vitamin D (vit D) deficiency may be associated with an increased risk of statin-related symptomatic myalgia in statin-treated patients. The aim of this meta-analysis was to substantiate the role of serum vitamin D levels in statin-associated myalgia., Methods: The search included PUBMED, Cochrane Library, Scopus, and EMBASE from January 1, 1987 to April 1, 2014 to identify studies that investigated the impact of vit D levels in statin-treated subjects with and without myalgia. Two independent reviewers extracted data on study characteristics, methods and outcomes. Quantitative data synthesis was performed using a fixed-effect model., Results: The electronic search yielded 437 articles; of those 20 were scrutinized as full texts and 13 studies were considered unsuitable. The final analysis included 7 studies with 2420 statin-treated patients divided into subgroups of patients with (n=666 [27.5%]) or without (n=1754) myalgia. Plasma vit D concentrations in the symptomatic and asymptomatic subgroups were 28.4±13.80ng/mL and 34.86±11.63ng/mL, respectively. The combination of data from individual observational studies showed that vit D plasma concentrations were significantly lower in patients with statin-associated myalgia compared with patients not manifesting this side effect (weighted mean difference -9.41ng/mL; 95% confidence interval: -10.17 to -8.64; p<0.00001)., Conclusions: This meta-analysis provides evidence that low vit D levels are associated with myalgia in patients on statin therapy. Randomized controlled trials are necessary to establish whether vitamin D supplementation reduces the risk for statin-associated myalgia., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)