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Information available on lipid clinics and patient support and advocacy groups, such as location and services provided, is limited or unknown to patients with dyslipidaemia and their family members who may also be affected, and non-specialist clinicians, hindering accessibility to appropriate healthcare. To overcome this, the European Atherosclerosis Society Familial Hypercholesterolemia Study Collaboration (EAS FHSC) led by Imperial College London has, in collaboration with the European FH Patient Network (FH Europe), developed FindMyLipidClinic.com, a global Directory of lipid clinics and patient support groups in 29 languages. Since its launch in 2020, around 4,000 visitors have conducted 12,000 searches across 1,100 locations, which may have retrieved up to 124 lipid clinics and 29 patient groups currently listed in 39 and 28 countries, respectively. Clinics and patient organisations not currently listed are encouraged to join this directory, and it would also benefit further from collaborations with other existing directories able to contribute.

We assessed the impact of the first wave of COVID-19 pandemic on non-COVID hospital admissions, non-COVID mortality, factors associated with non-COVID mortality, and changes in the profile of non-COVID patients admitted to hospital. We used the Spanish Minimum Basic Data Set with diagnosis grouped according to the Diagnostic Related Groups. A total of 10,594 patients (3% COVID-19; 97% non-COVID) hospitalised during the first wave in 2020 (27-February/07-June) were compared with those hospitalised within the same dates of 2017-2019 (average annual admissions: 14,037). We found a decrease in non-COVID medical (22%) and surgical (33%) hospitalisations and a 25.7% increase in hospital mortality among non-COVID patients during the first pandemic wave compared to pre-pandemic years. During the officially declared sub-period of excess mortality in the area (17-March/20-April, in-hospital non-COVID mortality was even higher (58.7% higher than the pre-pandemic years). Non-COVID patients hospitalised during the first pandemic wave (compared to pre-pandemic years) were older, more frequently men, with longer hospital stay and increased disease severity. Hospitalisation during the first pandemic wave in 2020, compared to hospitalisation during the pre-pandemic years, was an independent risk factor for non-COVID mortality (HR 1.30, 95% CI 1.07-1.57, p = 0.008), reflecting the negative impact of the pandemic on hospitalised patients., The authors acknowledge and thank the City Council of Seville and the Institute of Cartography and Statistics of Andalusia who provided data on mortality. Dr AJ Vallejo-Vaz acknowledges support from the "Programa Beatriz Galindo" from the Ministry of Universities, Government of Spain, and University of Seville, Spain.

[Background]: Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally., [Methods]: The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005., [Findings]: Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12∙0 years (IQR 5∙5–27∙0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 (64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14∙7 mmol/L (IQR 11∙6–18∙4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3∙93 mmol/L, IQR 2∙6–5∙8) versus non-highincome countries (9∙3 mmol/L, 6∙7–12∙7), with greater use of three or more lipid-lowering therapies (LLT; highincome 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high-income 21% vs non-high-income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24∙5 years (IQR 17∙0–34∙5) versus 37∙0 years (29∙0–49∙0) in high-income countries (adjusted hazard ratio 1∙64, 95% CI 1∙13–2∙38)., [Interpretation]: Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH., Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; and European Atherosclerosis Society

PURPOSE OF REVIEW: This review explores the concepts of monogenic and the so-called polygenic familial hypercholesterolemia and how the identification of familial hypercholesterolemia as a monogenic condition and its separation from polygenic primary hypercholesterolemia may have implications for clinical practice. RECENT FINDINGS: Through genetic testing, a mutation in any of the three known autosomal dominant familial hypercholesterolemia-causing genes is found in 60-80% of cases with a clinical diagnosis of definite familial hypercholesterolemia. As individuals with a polygenic basis for their hypercholesterolemia do not follow the same inheritance pattern observed in monogenic familial hypercholesterolemia, the use of family-based cascade screening in individuals with a polygenic origin is not recommend, as only 30% of relatives have an elevated LDL-C compared to the 50% in monogenic families. The presence of a causative monogenic mutation associates the highest cardiovascular risk vs. not having a mutation or having a polygenic background, providing prognostic information independent of LDL-C. It may also help assess intensity of interventions. Treatment adherence also seems to be higher after monogenic confirmation of hypercholesterolemia. SUMMARY: Knowledge about the genetic status of an individual with clinical familial hypercholesterolemia (monogenic vs. polygenic) can provide a more informed understanding to evaluating risk, managing disease and opportunities for screening strategies.

Introduction Greater recognition of a multi-factorial approach to risk factor control and use of guideline-recommended evidence-based therapies, including antiplatelets, have led to a decline in recurrent cardiovascular (CV) events among those with atherosclerotic CV disease (ASCVD). While residual risk still persists, recent evidence-based therapies have emerged which could further attenuate CV risk in these individuals, including novel drugs adjunct to antiplatelet therapies. Purpose The RESRISK study aims to quantify the residual atherothrombotic risk among a routine care cohort with ASCVD on guideline-recommended antiplatelet monotherapy (APMT). As a first step, we assessed the characteristics of participants at entry in the study, including risk factor burden, comorbidities and use of evidence-based medications. Methods A retrospective (2010–18) cohort of 758,325 patients with coronary (CAD) or peripheral artery disease (PAD) aged ≥18 years was derived from the UK Clinical Practice Research Datalink. Patients were selected if they were on recommended APMT according to ESC guidelines and NICE (aspirin for CAD; clopidogrel for PAD), were diagnosed with CAD/PAD prior to initiating APMT, and had ≥1 year of baseline data prior to index date (date of first APMT prescription). History of atrial fibrillation and haemorrhagic stroke led to exclusion. Results 174,210 patients with CAD (and no prior history of PAD) and 11,050 patients with PAD (and no prior history of CAD) met the inclusion criteria. Within the selection process for the PAD cohort, 51,114 patients were excluded due to being prescribed aspirin instead of clopidogrel. Baseline characteristics are shown in Table. Mean age was ∼70 years for both cohorts. While prevalence of hypertension was similar in both cohorts, presence of diabetes was 1.6 times higher in PAD patients. Stroke was 2.5 times more prevalent among PAD patients. The proportion of patients with systolic/diastolic blood pressure ≤130/≤85 mmHg were 41.6%/84.5% for CAD and 32.2%/80.6% for PAD (corresponding numbers for ≤140/≤90 mmHg were 67.8%/93.4% for CAD, and 58.8%/91.1% for PAD). Mean LDL-C was 2.4±0.9 and 2.6±1.1 mmol/L in CAD and PAD patients, with 10.7% and 9.5% of them, respectively, having an LDL-C Conclusions Among a contemporary cohort with ASCVD on guideline-recommended APMT, risk factor burden is high and attainment of guideline-recommended targets remains largely suboptimal. Prevalence of diabetes among PAD patients is particularly high. A large gap exists between guideline recommendations and guideline-recommended goal attainment. Greater attention to risk factor control and use of appropriate evidence-based therapy is required to reduce the potential risk of recurrent events among this high-risk population. Subsequent follow-up analysis with linkage to outcomes will provide quantification of the consequences of current practice on residual risk. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): All financial support for this research has been provided by Bayer plc. Table 1

Background and aims Several medications targeting PCSK9 reduce LDL-cholesterol (LDL-C) in heterozygous familial hypercholesterolemia (HeFH). We aimed to assess in patients diagnosed clinically as HeFH, whether LDL-C reduction varied by different therapeutic approaches to PCSK9-targeting or by the underlying genetic variant. Methods We conducted a random-effects meta-analysis of randomised clinical trials assessing PCSK9-targeting therapies, namely alirocumab, evolocumab and inclisiran, in patients with clinically diagnosed HeFH and restricted analyses to those patients in whom genotypic data were available. A search of MEDLINE and Embase identified eligible trials published between inception and June 29, 2020. We included trials of sufficient duration to allow for a stable treatment effect: ~12 weeks for monoclonal antibodies (mAbs) (alirocumab, evolocumab) and ~1 year for small interfering RNA (siRNA) (inclisiran). Single-moderator meta-regression comparing mean percentage LDL-C reduction between mAbs and siRNA as well as PCSK9-targeting therapies between different genotypes was used to assess heterogeneity. Results Eight trials of HeFH met our inclusion criteria, including 1887 genotyped patients. Among monogenic HeFH cases (N = 1347) the LDL-C reduction from baseline was 46.12% (95%CI 48.4-43.9) for siRNA and 50.4% (59.3-41.4) for mAbs compared to control, without evidence of significant heterogeneity between treatment (QM = 0.32, df = 1, p = 0.57). Irrespective of therapeutic approach to PCSK9-targeting, reductions in LDL-C were generally consistent across genetic variants (LDL-Receptor variants, LDL-Receptor variants of unknown significance, Apolipoprotein B variants, two variants and no variant) (QM = 8.3, df = 4, p = 0.08). Conclusions Among patients with HeFH, the LDL-C-lowering effect of PCSK9-targeting medications did not show statistical heterogeneity across different drug-classes and across genetic variants.

BACKGROUND AND AIMS: Trial evidence for the benefits of cholesterol-lowering is limited for familial hypercholesterolemia (FH) patients, since they have not been the focus of large outcome trials. We assess statin use in coronary artery disease (CAD) subjects with low-density lipoprotein cholesterol (LDL-C) ≥4.9 mmol/L with or without an FH phenotype. METHODS: The 4S trial randomized hypercholesterolemic CAD patients to simvastatin or placebo. We first stratified participants into baseline LDL-C

[Background and aims] We aimed to assess the prevalence of familial hypercholesterolaemia (FH) and to determine the incidence of cardiovascular events during a 10-year follow up in individuals with FH, compared to unaffected individuals in a working, middle-aged/young population., [Methods and results] 576,724 active workers (36 ± 10 years-old, 70% men) without cardiovascular disease were given regular health check-ups and followed for a median of 8.5 years (i.e., 4,123,927 person-years). The FH phenotype was defined according to validated low-density lipoprotein-cholesterol thresholds, adjusted for age and sex. The primary outcome was a first cardiovascular event, whether fatal or non-fatal. We found that 707 workers (0.12% or 1 in 816 individuals) met the criteria for a heterozygous FH phenotype. During the follow-up, cardiovascular events occurred in 23 of 707 (3.25%) subjects with the FH phenotype and in 3297 of 576,017 (0.57%) subjects without the FH phenotype (p, [Conclusions] Our findings confirmed the high incidence of cardiovascular disease in individuals with untreated FH. We showed that regular health check-ups in an active, and mostly young, working population could contribute to the early identification of FH. Therefore, this approach may provide an opportunity for early treatment., This work was supported by the Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional-FEDER (grant number PI12/02812), in 2012; by the Instituto de Salud Carlos III (grant number PI18/01809), in 2018; and by a grant awarded to the CTS-159 group of Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI).

[Objectives] Chronic diseases are the leading cause of disability globally. Most chronic disease management occurs in primary care with outcomes varying across primary care providers. Computerised clinical decision support systems (CDSS) have been shown to positively affect clinician behaviour by improving adherence to clinical guidelines. This study provides a summary of the available evidence on the effect of CDSS embedded in electronic health records on patient-reported and clinical outcomes of adult patients with chronic disease managed in primary care., [Design and eligibility criteria] Systematic review, including randomised controlled trials (RCTs), cluster RCTs, quasi-RCTs, interrupted time series and controlled before-and-after studies, assessing the effect of CDSS (vs usual care) on patient-reported or clinical outcomes of adult patients with selected common chronic diseases (asthma, chronic obstructive pulmonary disease, heart failure, myocardial ischaemia, hypertension, diabetes mellitus, hyperlipidaemia, arthritis and osteoporosis) managed in primary care., [Data sources] Medline, Embase, CENTRAL, Scopus, Health Management Information Consortium and trial register clinicaltrials.gov were searched from inception to 24 June 2020., [Data extraction and synthesis] Screening, data extraction and quality assessment were performed by two reviewers independently. The Cochrane risk of bias tool was used for quality appraisal., [Results] From 5430 articles, 8 studies met the inclusion criteria. Studies were heterogeneous in population characteristics, intervention components and outcome measurements and focused on diabetes, asthma, hyperlipidaemia and hypertension. Most outcomes were clinical with one study reporting on patient-reported outcomes. Quality of the evidence was impacted by methodological biases of studies., [Conclusions] There is inconclusive evidence in support of CDSS. A firm inference on the intervention effect was not possible due to methodological biases and study heterogeneity. Further research is needed to provide evidence on the intervention effect and the interplay between healthcare setting features, CDSS characteristics and implementation processes., [PROSPERO registration number] CRD42020218184.

Background The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally. Methods Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Data were assessed overall and by WHO regions, sex, and index versus non-index cases. Findings Of the 61 612 individuals in the registry, 42 167 adults (21 999 [53.6%] women) from 56 countries were included in the study. Of these, 31 798 (75.4%) were diagnosed with the Dutch Lipid Clinic Network criteria, and 35 490 (84.2%) were from the WHO region of Europe. Median age of participants at entry in the registry was 46.2 years (IQR 34.3-58.0); median age at diagnosis of familial hypercholesterolaemia was 44.4 years (32.5-56.5), with 40.2% of participants younger than 40 years when diagnosed. Prevalence of cardiovascular risk factors increased progressively with age and varied by WHO region. Prevalence of coronary disease was 17.4% (2.1% for stroke and 5.2% for peripheral artery disease), increasing with concentrations of untreated LDL cholesterol, and was about two times lower in women than in men. Among patients receiving lipid-lowering medications, 16 803 (81.1%) were receiving statins and 3691 (21.2%) were on combination therapy, with greater use of more potent lipid-lowering medication in men than in women. Median LDL cholesterol was 5.43 mmol/L (IQR 4.32-6.72) among patients not taking lipid-lowering medications and 4.23 mmol/L (3.20-5.66) among those taking them. Among patients taking lipid-lowering medications, 2.7% had LDL cholesterol lower than 1.8 mmol/L; the use of combination therapy, particularly with three drugs and with proprotein convertase subtilisin-kexin type 9 inhibitors, was associated with a higher proportion and greater odds of having LDL cholesterol lower than 1.8 mmol/L. Compared with index cases, patients who were non-index cases were younger, with lower LDL cholesterol and lower prevalence of cardiovascular risk factors and cardiovascular diseases (all p, Pfizer Independent Grant for Learning Change [16157823]; Amgen; Merck Sharp Dohme; Sanofi-Aventis; Daiichi Sankyo; Regeneron; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK; NIHR; Czech Ministry of Health [NU20-02-00261]; Canadian Institutes of Health Research; Austrian Heart Foundation; Tyrolean Regional Government; Gulf Heart Association, The EAS FHSC is an academic initiative that has received funding from a Pfizer Independent Grant for Learning & Change 2014 (16157823) and from investigator-initiated research grants to the European Atherosclerosis Society-Imperial College London from Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron. KKR acknowledges support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK. KID acknowledges support from a PhD Studentship from NIHR under the Applied Health Research programme for Northwest London, UK (the views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health). TF was supported by a grant from the Czech Ministry of Health (NU20-02-00261). JG receives support from the Canadian Institutes of Health Research. The Austrian Familial Hypercholesterolaemia registry has been supported by funds from the Austrian Heart Foundation and the Tyrolean Regional Government. The Gulf Familial Hypercholesterolaemia registry was done under the auspices of the Gulf Heart Association.

Aims Guidelines recommend targeting non-high-density lipoprotein cholesterol to reduce cardiovascular risk. We assessed the impact of baseline triglycerides on non-high-density lipoprotein cholesterol goal attainment in 10 phase 3 trials with alirocumab versus control ( n = 4983). Methods Trials were grouped into four pools based on alirocumab dose (75–150 mg every 2 weeks), control (placebo/ezetimibe) and statin use. Baseline triglyceride quintiles were built within each pool. Non-high-density lipoprotein cholesterol goal attainment (very high risk: Results Higher baseline triglycerides were associated with a worse cardiovascular risk profile. Low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol increased with higher triglycerides, but the magnitude in non-high-density lipoprotein cholesterol was three- to four-fold higher compared with the increase in low-density lipoprotein cholesterol. Non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol percentage reductions from baseline with alirocumab were similar regardless of baseline triglycerides. A greater proportion of alirocumab-treated patients attained non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol goals compared with placebo or ezetimibe. Unlike low-density lipoprotein cholesterol goal attainment, non-high-density lipoprotein cholesterol goal attainment significantly declined with increasing baseline triglycerides ( p Conclusion Individuals with increased triglycerides have higher non-high-density lipoprotein cholesterol levels and lower rates of non-high-density lipoprotein cholesterol goal attainment (unlike low-density lipoprotein cholesterol goal attainment). Alirocumab improves non-high-density lipoprotein cholesterol goal attainment in this population. These results highlight the impact of triglycerides on non-high-density lipoprotein cholesterol and the need for novel therapies targeting triglyceride-related pathways.

PURPOSE OF REVIEW: To review the recent evidence from observational/genetic/interventional studies addressing triglycerides and residual cardiovascular risk (CVRisk). RECENT FINDINGS: Large population-based and secondary prevention studies consistently show an association of higher triglycerides with increased CVRisk. This is compounded by genetic studies demonstrating an independent relationship between triglyceride raising or lowering genetic variants affecting triglyceride-rich lipoproteins (TRL) metabolism and CVRisk. Mendelian randomization analysis suggests the benefit of genetic lowering of triglycerides and LDL-cholesterol is similar per unit change in apolipoprotein-B. Among cholesterol-lowering trials, more intensive statin therapy produced greater CVRisk reductions in patients with higher TRL-cholesterol or triglycerides; proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition led to similar triglycerides reduction but greater non-HDL-C or apolipoprotein-B reductions than fibrates or fish oils. Regarding n-3 fatty acids, A Study of Cardiovascular Events in Diabetes (ASCEND) and Vitamin D and Omega-3 Trial (VITAL) primary prevention trials with eicosapentaenoic acid (EPA) and docosahexaenoic acid failed to demonstrate cardiovascular benefits, Conversely, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) using high-dose icosapent-ethyl (purified EPA) in primary (diabetes) and secondary prevention with hypertriglyceridemia showed significant cardiovascular events reductions (greater than expected by the observed triglycerides or apolipoprotein-B reductions, suggesting potential benefits through non-lipid pathways). SUMMARY: Evidence suggests higher triglycerides are a marker of CVRisk and may help identify patients who benefit from intensification of therapy. Moreover, genetic studies support a causal link between TRL/triglycerides and cardiovascular disease. Treatment with high-dose EPA may be of benefit in high-risk patients with hypertriglyceridemia to reduce CVRisk.

ImportanceFamilial hypercholesterolemia (FH) is an underdiagnosed and undertreated genetic disorder that leads to premature morbidity and mortality due to atherosclerotic cardiovascular disease. Familial hypercholesterolemia affects 1 in 200 to 250 people around the world of every race and ethnicity. the lack of general awareness of FH among the public and medical community has resulted in only 10% of the FH population being diagnosed and adequately treated. the World Health Organization recognized FH as a public health priority in 1998 during a consultation meeting in Geneva, Switzerland. the World Health Organization report highlighted 11 recommendations to address FH worldwide, from diagnosis and treatment to family screening and education. Research since the 1998 report has increased understanding and awareness of FH, particularly in specialty areas, such as cardiology and lipidology. However, in the past 20 years, there has been little progress in implementing the 11 recommendations to prevent premature atherosclerotic cardiovascular disease in an entire generation of families with FH. ObservationsIn 2018, the Familial Hypercholesterolemia Foundation and the World Heart Federation convened the international FH community to update the 11 recommendations. Two meetings were held: one at the 2018 FH Foundation Global Summit and the other during the 2018 World Congress of Cardiology and Cardiovascular Health. Each meeting served as a platform for the FH community to examine the original recommendations, assess the gaps, and provide commentary on the revised recommendations. the Global Call to Action on Familial Hypercholesterolemia thus represents individuals with FH, advocacy leaders, scientific experts, policy makers, and the original authors of the 1998 World Health Organization report. Attendees from 40 countries brought perspectives on FH from low-, middle-, and high-income regions. Tables listing country-specific government support for FH care, existing country-specific and international FH scientific statements and guidelines, country-specific and international FH registries, and known FH advocacy organizations around the world were created. Conclusions and RelevanceBy adopting the 9 updated public policy recommendations created for this document, covering awareness; advocacy; screening, testing, and diagnosis; treatment; family-based care; registries; research; and cost and value, individual countries have the opportunity to prevent atherosclerotic heart disease in their citizens carrying a gene associated with FH and, likely, all those with severe hypercholesterolemia as well. This guideline presents updated recommendations for management of familial hypercholesterolemia. (c) 2020 American Medical Association. All rights reserved., AmgenAmgen; Sanofi Regeneron Pharmaceuticals, Funding to support the 2 international meetings to achieve consensus was provided by Amgen and Sanofi Regeneron Pharmaceuticals.

Background: Mendelian randomization data suggest that the genetic determinants of lifetime higher triglyceride-rich lipoprotein-cholesterol (TRL-C) are causally related to cardiovascular disease and therefore a potential therapeutic target. The relevance of TRL-C among patients receiving statins is unknown. We assessed the relationship between TRL-C and cardiovascular risk, and whether this risk was modifiable among patients receiving statins in the TNT trial (Treating to New Targets). Methods: Patients with coronary heart disease and low-density lipoprotein cholesterol (LDL-C) 130 to 250 mg/dL entered an 8-week run-in phase with atorvastatin 10 mg/d (ATV10). After this period, participants with LDL-C Results: ATV10 reduced TRL-C 10.7% from an initial TRL-C of 33.9±16.6 mg/dL. ATV80 led to an additional 15.4% reduction. Cardiovascular risk factors positively correlated with TRL-C. Among patients receiving ATV10, higher TRL-C was associated with higher 5-year MACE rates (Q1=9.7%, Q5=13.8%; hazard ratio Q5-versus-Q1, 1.48; 95% confidence interval, 1.15–1.92; P -trendP P -homogeneity=0.0053); results were consistent for triglycerides ( P -homogeneity=0.0101) and directionally similar for non–high-density lipoprotein cholesterol ( P -homogeneity=0.1387). Last, in adjusted analyses, a 1 SD percentage reduction in TRL-C with atorvastatin resulted in a significant lower risk of MACE (hazard ratio, 0.93; 95% confidence interval, 0.86–1.00; P =0.0482) independent of the reduction in LDL-C and of similar magnitude to that per 1 SD lowering in LDL-C (hazard ratio, 0.89; 95% confidence interval, 0.83–0.95; P =0.0008). Conclusions: The present post hoc analysis from TNT shows that increased TRL-C levels are associated with an increased cardiovascular risk and provides evidence for the cardiovascular benefit of lipid lowering with statins among patients who have coronary heart disease with high TRL-C. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00327691.

BACKGROUND Preeclampsia (PE) is a hypertensive disorder of pregnancy characterized by hypertension and proteinuria. The HELLP syndrome is the most severe form of PE. The aim of the present study was to determine different potential biomarkers that may help us perform an early diagnosis of the disease, assess on the severity of the disease, and/or predict maternal or fetal adverse outcomes. METHODS We measured serum levels of total and fetal circulating cell-free DNA (cfDNA), soluble endoglin, soluble form of vascular endothelial growth factor receptor, and placental growth factor in a healthy control group of pregnant women (n = 26), patients with mild (n = 37) and severe PE (n = 25), and patients with HELLP syndrome (n = 16). RESULTS We observed a gradual and strong relationship between all the biomarkers mentioned and the range of severity of PE, with the highest levels in patients with HELLP syndrome. Nevertheless, only the values of total cfDNA were able to significantly differentiate severe PE and HELLP syndrome (20957 ± 2784 vs. 43184 ± 8647 GE/ml, P = 0.01). Receiver operating characteristic (ROC) curves were constructed (i) for the healthy group with respect to the groups with PE and (ii) for patients with PE with respect to the group with HELLP syndrome; sensitivity and specificity values at different cutoff levels were calculated in each case. The maximum ROC area under the curve value for PE and HELLP syndrome (with respect to controls) was 0.91 (P < 0.001). CONCLUSIONS The measured biomarkers of cell damage, angiogenesis, and antiangiogenesis may reflect the severity of PE, with higher levels in patients who develop HELLP syndrome. In addition, these biomarkers may also help predict adverse fetal and maternal outcomes.

Background and aims Guidelines recommend high-intensity statins for patients with atherosclerotic cardiovascular disease (ASCVD). Subgroups with comorbidities that increase cardiovascular risk, such as diabetes mellitus (DM), chronic kidney disease (CKD) or polyvascular disease (PoVD), may derive greater absolute benefit from addition of non-statin therapies. We assessed the relationship between lower low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events (MACE) risk reduction during alirocumab phase III ODYSSEY trials among these subgroups. Methods Patient data were pooled from nine trials comparing alirocumab with control (placebo/ezetimibe), predominantly on background maximally tolerated statin. Patients with baseline ASCVD were stratified into subgroups with DM, CKD or PoVD, or without comorbidities, and between-group relative and absolute benefits were compared. Results Among 3505 patients with ASCVD, 1573 had no comorbidities, 981 had DM, 660 had CKD and 943 had PoVD, with overlap between comorbidities; mean baseline LDL-C levels were 119 (ASCVD overall), 123, 117, 114 and 113 mg/dL, respectively. Overall, each 39 mg/dL lower on-study LDL-C was associated with a 25% lower MACE risk, hazard ratio 0.75 (95% confidence interval, 0.62–0.90, p = 0.0023), with a similar lower risk observed in each very high-risk subgroup (DM, CKD or PoVD; 30–35%) but not in the subgroup without these comorbidities (9%). Absolute benefits were greater for very high-risk subgroups; lowering LDL-C from 120 to 40 mg/dL would result in 2.76–4.35 fewer MACE/100 patient-years versus 0.3 for no comorbidities. Conclusions Among patients with ASCVD and mean baseline LDL-C >100 mg/dL, patients with DM, CKD or PoVD appeared to derive greater absolute cardiovascular benefits from further LDL-C reduction than those without.

Background and aims Elevated lipoprotein(a) [Lp(a)] levels are considered a causal factor for cardiovascular disease. In phase 3 ODYSSEY trials, alirocumab reduced levels of low-density lipoprotein cholesterol (LDL-C) and Lp(a), with concomitant reductions in the risk of major adverse cardiovascular events (MACE). We assessed whether lower on-study and greater percentage reductions in Lp(a) are associated with a lower risk of MACE. Methods Post-hoc analysis of data pooled from 10 phase 3 ODYSSEY trials comparing alirocumab with control (placebo or ezetimibe) in patients (n = 4983) with cardiovascular disease and/or risk factors, and hypercholesterolemia despite statin/other lipid-lowering therapies. Results Median (Q1, Q3) baseline Lp(a) levels were 23.5 (8.0, 67.0) mg/dL. Median Lp(a) changes from baseline with alirocumab were −25.6% vs. −2.5% with placebo (absolute reductions 6.8 vs. 0.5 mg/dL) in placebo-controlled trials, and −21.4% vs. 0.0% with ezetimibe (4.5 vs. 0.0 mg/dL) in ezetimibe-controlled trials. During follow-up (6699 patient-years), 104 patients experienced MACE. A 12% relative risk reduction in MACE per 25% reduction in Lp(a) (p=0.0254) was no longer significant after adjustment for LDL-C changes: hazard ratio per 25% reduction: 0.89 (95% confidence interval, 0.79–1.01; p=0.0780). In subgroup analysis, the association between Lp(a) reduction and MACE remained significant in a fully adjusted model among participants with baseline Lp(a) ≥50 mg/dL (p-interaction vs. Lp(a) Conclusions In this population, Lp(a) reductions were not significantly associated with MACE independently of LDL-C reductions. Reducing the risk of MACE by targeting Lp(a) may require greater reductions in Lp(a) with more potent therapies and/or higher initial Lp(a) levels.

Background European and American guidelines recommend different LDL-C goals for ASCVD patients. We simulated the residual CV risk for 2019 ESC/EAS versus 2018 ACC/AHA LDL-C goals (

Background In statin trials, men and women derived similar relative risk reductions in cardiovascular events per 39 mg/ dL low‐density lipoprotein cholesterol ( LDL ‐C) reduction. We explored whether lower LDL ‐C levels and greater LDL ‐C percentage reductions than those achieved with statins are associated with reduced major adverse cardiovascular event ( MACE ) rates in women as well as men. Methods and Results Data pooled from 10 phase 3 ODYSSEY randomized trials (n=4983) comparing alirocumab with control (placebo/ezetimibe) were assessed for association between 39 mg/dL lower on‐treatment LDL ‐C and percentage LDL ‐C change from baseline, and MACE risk by sex, using multivariable Cox regression. Mean baseline LDL ‐C was 135 mg/dL (women) and 121 mg/dL (men). Average on‐treatment LDL ‐C levels with alirocumab, ezetimibe, and placebo were 71, 114, and 134 mg/dL, respectively, in women (n=1882) and 52, 93, and 122 mg/dL, respectively, in men (n=3090). Overall, 36.5% and 58.7% of women and men, respectively, achieved on‐treatment LDL ‐C LDL ‐C was associated with a 33% and 22% lower risk of MACE in women ( P =0.0209) and men ( P =0.0307), respectively, with no significant between‐sex difference ( P for heterogeneity=0.4597). Results were similar when analyzed per 50% LDL ‐C reduction, 24% ( P =0.1094) and 29% ( P =0.0125) lower MACE risk in women and men, respectively ( P for heterogeneity=0.7499). Alirocumab was generally well tolerated in both sexes. Conclusions The present analysis reinforces the notion that both sexes derive a similar cardiovascular benefit from LDL ‐C lowering. Although women had slightly higher on‐treatment LDL ‐C than men, both sexes showed a similar lower MACE risk with lower LDL ‐C.

We thank Lowe et al for their interest in our recent study1 and the opportunity to offer further clarifications. Although we acknowledge the interest of the question raised by Lowe et al, we think they miss the main rationale and research question of our analysis,1 namely, to provide the only randomized controlled trial evidence in primary prevention for lipid lowering among individuals with low-density lipoprotein-cholesterol (LDL-C) >190 mg/dL, a level consistent with inherited or genetic dyslipidemia (primary hypercholesterolemia). Current guidelines cite that statins are likely to be beneficial for such patients, but they also acknowledge that there is no direct randomized controlled trial evidence to support these recommendations. Given ethical concerns that would be posed by giving placebo to patients with LDL-C >190 mg/dL, the WOSCOPS data offer the only option to answer this question.1 The authors cite that the unanswered question is, “Will providing statins to people at low risk of atherosclerosis cardiovascular disease lower …

Familial hypercholesterolaemia (FH) is a genetic disorder affecting the metabolism of low-density lipoprotein (LDL) particles, leading to high LDL-cholesterol levels maintained over time and higher risk of cardiovascular disease (CVD) early in life. Contemporary studies have challenged prior estimations of FH prevalence and suggest this condition to be more frequent than previously considered, with an overall prevalence rate of 1:200-300 individuals in the general population (1:160,000-300,000 for homozygous FH). However, prevalence of FH varies around the world. In part this is due to an artefact of approaches of detection and methods used to diagnose FH (e.g. lack of gold standard for diagnosis of FH, different criteria applied, availability of genetic testing). But also due to intrinsic characteristic of different populations, e.g. higher presence of founder effects or rates of consanguinity. Additionally, results from many regions are lacking and it is estimated that only a small percentage of subjects with FH would have been diagnosed overall. FH entails a significantly higher risk of CVD, reported to be higher than that estimated by conventional risk assessment tools for the general population. This risk is mainly driven by coronary heart disease. Despite this evidence, low rates of patients meet therapeutic targets for cardiovascular prevention, and implementation of therapy (high intensity statins, combination therapy) is needed. The introduction of novel lipid-lowering therapies may improve this situation. In the present review, we discuss the epidemiology of FH overall, with special attention to different aspects related to prevalence, cardiovascular risk and prognosis, and treatment of FH.

Aims Whether adverse effect of statins on glycaemic indices is common to all statins remains controversial and as yet data for pitavastatin are limited. We sought to assess the effects of pitavastatin on glycaemia and new-onset diabetes (NOD) in non-diabetic individuals using data from RCT pooled together by means of a meta-analysis. Materials and methods We searched Medline, Cochrane, Embase and clinical trials registries websites until November-2014 for ≥12-week follow-up placebo or statin-controlled RCT of pitavastatin that included participants without diabetes and reported on fasting blood glucose (FBG), HbA1c or NOD. We additionally sought studies by consulting with Kowa Ph. Ltd. The association of pitavastatin with the outcomes were estimated by random-effects meta-analyses. Heterogeneity was assessed by the I 2 statistic and sensitivity and subgroup analyses, and publication bias with funnel plots and Egger and Harbord Tests. Results 15 studies (approx. 1600 person-years) were included. No significant differences associated with pitavastatin (vs. control) were observed for FBG (MD −0.01 mg/dL [95%CI −0.77, 0.74], I 2 = 0%), HbA1c (MD −0.03% [95%CI −0.11, 0.05], I 2 = 43%) or NOD (RR 0.70 [95%CI 0.30, 1.61]; RD 0.0 [95%CI −0.004, 0.003]; I 2 = 0%). Sensitivity and subgroup analyses (including type of control [placebo or other statin], pitavastatin dose or follow-up] did not yield significant results. Potential publication bias may occur for NOD. Conclusions In the present meta-analysis pitavastatin did not adversely affect glucose metabolism or diabetes development compared with placebo or other statins.

Whilst low density lipoprotein cholesterol (LDL-C) is widely accepted as the principal lipid fraction associated with atherosclerosis, emerging evidence suggests a causal relationship between lifelong elevations in triglyceride rich lipoprotein cholesterol (TRL-C) and cardiovascular disease (CVD) in genetic studies. To provide further evidence for the potential relevance of TRL-C and atherosclerosis, we have evaluated the relationship between TRL-C and coronary artery calcium score (CAC). We included 3,845 (49.9±8.4 years, 54% women) subjects who had no prior history of CVD, were not using lipid-lowering medications and underwent CAC evaluation. We assessed the relationship between increasing fasting TRL-C and the graded increase in CAC and to what extent TRL-C were independently associated with CAC over and above LDL-C using logistic regression models. Overall 973 (25%) of the participants had a CAC >0, and 308 (8%) had a CAC > 100. The median TRL-C level was 22 (IQR: 16 - 32) mg/dL. Individuals with CAC> 0 had higher TRL-C levels than those with CAC=0 (p 0 had higher levels of LDL-C, non-high density lipoprotein cholesterol (non-HDL-C), and lower HDL-C (all p0 (p=0.01). In conclusion, in a large cohort of asymptomatic individuals, TRL-C was associated with subclinical atherosclerosis supporting a potentially causal role in CVD.

Background: Patients with primary elevations of low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL are at a higher risk of atherosclerotic cardiovascular disease as a result of long-term exposure to markedly elevated LDL-C levels. Therefore, initiation of statin therapy is recommended for these individuals. However, there is a lack of randomized trial evidence supporting these recommendations in primary prevention. In the present analysis, we provide hitherto unpublished data on the cardiovascular effects of LDL-C lowering among a primary prevention population with LDL-C ≥190 mg/dL. Methods: We aimed to assess the benefits of LDL-C lowering on cardiovascular outcomes among individuals with primary elevations of LDL-C ≥190 mg/dL without preexisting vascular disease at baseline. We performed post hoc analyses from the WOSCOPS (West of Scotland Coronary Prevention Study) randomized, placebo-controlled trial, and observational posttrial long-term follow-up, after excluding individuals with evidence of vascular disease at baseline. WOSCOPS enrolled 6595 men aged 45 to 64 years, who were randomly assigned to pravastatin 40 mg/d or placebo. In the present analyses, 5529 participants without evidence of vascular disease were included, stratified by LDL-C levels into those with LDL-C Results: Among 5529 individuals without vascular disease, pravastatin reduced the risk of coronary heart disease by 27% ( P =0.002) and major adverse cardiovascular events by 25% ( P =0.004) consistently among those with and without LDL-C ≥190 mg/dL ( P -interaction >0.9). Among individuals with LDL-C ≥190 mg/dL, pravastatin reduced the risk of coronary heart disease by 27% ( P =0.033) and major adverse cardiovascular events by 25% ( P =0.037) during the initial trial phase and the risk of coronary heart disease death, cardiovascular death, and all-cause mortality by 28% ( P =0.020), 25% ( P =0.009), and 18% ( P =0.004), respectively, over a total of 20 years of follow-up. Conclusions: The present analyses provide robust novel evidence for the short- and long-term benefits of lowering LDL-C for the primary prevention of cardiovascular disease among individuals with primary elevations of LDL-C ≥190 mg/dL.

HDL cholesterol efflux capacity and incident cardiovascular events Rohatgi et al N Engl J Med 2014;371:2383–2393. Although low levels of high-density lipoprotein cholesterol (HDL-C) represent a strong independent risk marker inversely associated with cardiovascular disease (CVD), large interventional trials have failed to translate the increases in HDL-C into reductions in cardiovascular events. As HDL plasma levels represent a pool of the different HDL subfractions, which may vary in their structure and function, its levels may not capture adequately the dynamic process of reverse cholesterol transport. This has led attention to be focused on markers of HDL function, for example, cholesterol efflux capacity, further supported by a recent population-based cohort study that has related it with incident atherosclerotic cardiovascular events, suggesting HDL hypothesis may need to be revisited. HDL particles are responsible for the reverse cholesterol transport, the physiological mechanism by which the cholesterol in peripheral tissues and cells is transferred to the liver for biliary excretion.1,2 Reverse cholesterol transport is considered an important atheroprotective mechanism because it facilitates the removal of excess cholesterol from lipid-laden macrophages in the arterial wall and the subsequent reduction in the proinflammatory responses; in its first steps, the reverse cholesterol transport requires HDL particles to act as extracellular acceptors of cholesterol from these cells.1,2 The cholesterol efflux capacity (CEC), that is, the ability of HDL particles to accept cholesterol esters from cholesterol-loaded macrophages, represents, therefore, a key process within the mechanism of reverse cholesterol transport.1,2 In animal models, cholesterol efflux can modulate the severity of atherosclerosis, and in humans, CEC has been related to prevalent coronary artery disease independently of HDL-C levels in cross-sectional studies.3 In a recent article published by Rohatgi et al in the New England Journal of Medicine , CEC was for …

Background Increased plasma levels of circulating cell-free DNA (c-f DNA) have been recently described in diseases related to ischemia and/or hypoxia. Preeclampsia (PCL) is a hypertensive disorder of pregnancy, of unknown origin, where a defective placentation resulting in placental ischemia plays an important role. HELLP syndrome (haemolysis, elevated liver enzymes, and low platelet count) is the most serious form of PCL. The origin of the disease is unknown, and there are no markers to help us to make an early diagnosis of disease or to predict patients who are at risk of suffering serious complications. Methods We measured circulating c-f DNA levels in a group of control pregnant women (n = 20), patients with mild PCL (n = 9), patients with severe PCL (n = 24), and patients with HELLP syndrome (n = 8). Results Values of circulating c-f DNA were 333.59 ± 64.3 ng/ml in control subjects; 635.11 ± 111.7 ng/ml in patients with mild PCL; 1,264.63 ± 127.1 ng/ml in patients with severe PCL, and 1,595.95 ± 269.8 ng/ml in patients with HELPP syndrome. (P 950 ng/ml had a sensitivity and specificity for detecting severe PCL and/or HELLLP syndrome of 0.71 and 0.93, respectively. Conclusions As far as we know, this is the first report of increased c-f DNA levels in HELLP syndrome. In this preliminary report, we have observed a gradual and strong relation between c-f DNA levels and range of severity of PCL, with it the highest in patients with HELLP syndrome. Further studies are needed for evaluating the utility of this technique in hypertensive disorders of pregnancy and, particularly, in HELLP syndrome.

Aims Apolipoprotein A-1 (ApoA-1), based on epidemiology, is inversely associated with cardiovascular (CV) events. Human carriers of the ApoA-1 Milano variant have a reduced incidence of CV disease. Regression of atherosclerotic plaque burden was previously observed on intravascular ultrasound (IVUS) with ETC-216, a predecessor of MDCO-216. MDCO-216, a complex of dimeric ApoA-1 Milano and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, is being developed to reduce atherosclerotic plaque burden and CV events. We investigated the efficacy and safety of a single infusion of MDCO-216 in healthy volunteers and in patients with coronary artery disease (CAD). Methods and results Twenty-four healthy volunteers and 24 patients with documented CAD received a 2-h infusion of MDCO-216 in a randomized, placebo controlled, single ascending dose study. Five cohorts of healthy volunteers and four cohorts of CAD patients received ApoA-1 Milano doses ranging from 5 to 40 mg/kg. Subjects were followed for 30 days. Dose-dependent increases in ApoA-1, phospholipid, and pre-beta 1 HDL and decreases in ApoE were observed. Prominent and sustained increases in triglyceride, and decreases in HDL-C, endogenous ApoA-1 and ApoA-II occurred at doses >20 mg/kg and profound increases in ABCA1-mediated cholesterol efflux were observed. Other lipid and lipoprotein parameters were generally unchanged. MDCO-216 was well tolerated. Conclusions MDCO-216-modulated lipid parameters profoundly increased ABCA1-mediated cholesterol efflux and was well tolerated. These single-dose data support further development of this agent for reducing atherosclerotic disease and subsequent CV events.

Flow-mediated dilation (FMD) of the brachial artery reflects endothelium-dependent vasodilator function; since it correlates with coronary endothelial function, its reduction could predict cardiovascular events. Several studies have investigated the potential impact of fibrates therapy on endothelial function, but clinical findings have not been fully consistent. We aimed to conduct a meta-analysis of randomized placebo-controlled trials in order to clarify whether fibrate therapy could improve endothelial function. A systematic search in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases was performed to identify randomized placebo-controlled trials investigating the effect of fibrates on endothelial function as estimated by FMD. A random-effects model and generic inverse variance method were used for meta-analysis. Sensitivity analysis, risk of bias evaluation, and publication bias assessment were carried out using standard methods. Random-effects meta-regression was used to evaluate the impact of treatment duration on the estimated effect size. Fifteen trials with a total of 556 subjects met the eligibility criteria. Fibrate therapy significantly improves FMD (weighted mean difference [WMD]: 1.64%, 95% CI: 1.15, 2.13, p < 0.001) and the result was confirmed in both subgroups with treatment durations ≤8 weeks (WMD: 1.35%, 95% CI: 0.85, 1.86, p < 0.001) and >8 weeks (WMD: 2.55%, 95% CI: 1.21, 3.89, p

WOS: 000393031600001, PubMed ID: 27939304, Background: The potential for global collaborations to better inform public health policy regarding major non-hypercholesterolaemia (FH), a common genetic disorder associated with premature cardiovascular disease, is yet to be reliably ascertained using similar approaches. The European Atherosclerosis Society FH Studies Collaboration (EAS FHSC) is a new initiative of international stakeholders which will help establish a global FH registry to generate large-scale, robust data on the burden of FH worldwide. Methods: The EAS FHSC will maximise the potential exploitation of currently available and future FH data (retrospective and prospective) by bringing together regional/national/international data sources with access to individuals with a clinical and/or genetic diagnosis of heterozygous or homozygous FH. A novel bespoke electronic platform and FH Data Warehouse will be developed to allow secure data sharing, validation, cleaning, pooling, harmonisation and analysis irrespective of the source or format. Standard statistical procedures will allow us to investigate cross-sectional associations, patterns of real-world practice, trends over time, and analyse risk and outcomes (e.g. cardiovascular outcomes, all-cause death), accounting for potential confounders and subgroup effects. Conclusions: The EAS FHSC represents an excellent opportunity to integrate individual efforts across the world to tackle the global burden of FH. The information garnered from the registry will help reduce gaps in knowledge, inform best practices, assist in clinical trials design, support clinical guidelines and policies development, and ultimately improve the care of FH patients. (C) 2016 Elsevier Ireland Ltd., Pfizer Independent Grant for Learning Change [16157823]; AmgenAmgen; MSD; Sanofi-AventisSanofi-Aventis; Latvian State Research Programme BIOMEDICINE; Czech RepublicCzech Republic Government [MZ CR AZV 15-28277A, 16-29084A], The present project has received support from a Pfizer Independent Grant for Learning & Change 2014 (No: 16157823) and from investigator initiated unrestricted research grants to the European Atherosclerosis Society from Amgen, MSD, and Sanofi-Aventis. The project in Latvia was supported by the Latvian State Research Programme BIOMEDICINE. The project in Czech Republic was partly supported by grants MZ CR AZV 15-28277A and 16-29084A.

Endothelial function can be measured by the level of reactive vasodilation due to a transient ischemia caused by a blood pressure cuff on the arm, measured using Laser-Doppler flowmetry. This device has software that provides various parameters that can measure the magnitude of this response, but there are no general agreements with regard to which of them is the best to use. In this study, we analyze which of the parameters obtained using this technique is better to discriminate between patients with coronary artery disease (CAD) and healthy controls.We analyzed 40 patients with proven CAD and 60 healthy controls. We studied the hyperemic response to the ischemia in the forearm using a Laser-Doppler flowmeter.The most important differences between patients and controls were determined considering the area of hyperemia, which was 2.6 times higher in healthy controls than that in patients (754.9±566.4 vs 1981.3±1156.3 perfusion units per second, P0.001). To diagnose the disease, a cutoff point of 860 perfusion units per second had a sensitivity of 0.82 and a specificity of 0.97. This is probably because the area of hyperemia measures at the same time speed, intensity, and duration of the hyperemic response.The area of hyperemia was the parameter with a higher sensitivity and specificity for identification of patients with CAD. Nevertheless, further studies are needed to confirm the usefulness of this parameter, obtained using a noninvasive test, to assess the presence of subclinical coronary heart disease.

Introduction: While triglycerides (TG) are associated with cardiovascular disease, most studies suggests that non-fasting TG drives this effect, whereas the role of fasting TG is less well established. Hypothesis: We have evaluated whether triglyceride-derived markers (log-transformed TG [lnTG], non-HDL, TG/HDL ratio) and HDL independently predict subclinical coronary artery disease as measured by the coronary artery calcium score (CAC). Methods: We included 2911 (50.3±8.5 years, 54% women) participants from the ELSA-Brasil study who had no prior history of CVD, were not currently using lipid-lowering medications and underwent CAC evaluation. We analyzed the independent association of triglyceride-derived markers (lnTG, non-HDL, TG/HDL ratio) and HDL with CAC using logistic regression. Results: Among the 2911 participants, 759 (26%) had a CAC >0, and 247 (8.5%) had a CAC > 100. The median triglycerides level was 112 (IQR: 80 -162). Individuals with CAC>0 had higher TG levels than those with CAC=0 (p Conclusions: In a large cohort of asymptomatic individuals, measures associated with fasting TG were associated with CAC score. Even after adjustment for clinical risk factors, BMI and hsCRP, measures associated with TG (lnTG, non-HDL and TG/HDL ratio) all remained independent predictors of CAC, while HDL did not. This suggests that TG may potentially be an independent target for therapy to reduce residual cardiovascular risk.

SummaryElevated plasma levels of the pro-thrombotic and pro-inflammatory factor plasminogen activator inhibitor-1 (PAI-1) may contribute to the pathogenesis of atherosclerotic cardiovascular disease. Beyond their lipid-lowering effect, statins have been shown to modulate plasma PAI-1 levels but evidence from individual randomised controlled trials (RCTs) is controversial. Therefore, we aimed to assess the potential effects of statin therapy on plasma PAI-1 concentration through a meta-analysis of RCTs. We searched Medline and SCOPUS databases (up to October 3, 2014) to identify RCTs investigating the effect of statin therapy on plasma PAI-1 concentrations. We performed random-effects meta-analysis and assessed heterogeneity (I2 test, subgroup and sensitivity analyses) and publication bias (funnel plot, Egger and “trim and fill” tests). Sixteen RCTs (comprising 19 treatment arms) were included and pooled analyses showed a significant effect of statins in reducing plasma PAI-1 concentrations (weighted mean difference WMD: –15.72 ng/ml, 95 % confidence interval [CI]: –25.01, –6.43,). In subgroup analysis, this effect remained significant in with lipophilic statins (atorvastatin and simvastatin) (WMD: –21.32 ng/ml, 95 % CI: –32.73, –9.91, I2=99 %) and particularly atorvastatin (WMD: –20.88 ng/mL, 95 % CI: –28.79, –12.97, I2=97 %). In the meta-regression analysis, the impact of statins on PAI-1 did not correlate with the administered dose, duration of treatment and changes in plasma LDL-cholesterol concentrations. Finally, evidence of publication bias was observed. In conclusion, taking into account the limit of heterogeneity between studies, the present meta-analysis suggests that statin therapy (mainly atorvastatin) significantly lowers plasma PAI-1 concentrations.

Non-HDL cholesterol represents the pro-atherogenic, apo-B-containing lipoprotein fraction of circulating lipids, and represents a secondary target for CVD prevention in people with diabetes. We therefore assessed the proportion of individuals with diabetes and CVD who attain a non-HDL-C goal of2.6 mmol/L, the extent to which triglycerides influence this goal attainment, and their relationship with HDL-C and triglyceride-rich lipoproteins (TRL).Of 2674 diabetic subjects with baseline CVD in the Hungarian MULTI-GAP programme (mean age 64.8 years, mean HbA1c 7.2%), an LDL-C goal1.8 and non-HDL-C goal2.6 mmol/L was attained in 13.5% and 17.7% individuals, respectively. Non-HDL-C goal attainment declined at higher triglyceride concentrations; and graphically this relationship appeared to be continuously and inversely associated with triglyceride concentrations. In contrast, the relationship between LDL-C goal attainment was inversely and continuously associated with triglyceride levels up to about 2.5 mmol/L, after which the graphical appearance plateaued such that no further difference in LDL-C were observed beyond triglyceride levels of 2.5 mmol/L. With increasing triglyceride concentrations, non-HDL-C increased continuously, HDL-C decreased initially but later plateaued (at 1.5-2.0 [men] or 2.0-2.5 mmol/L [women]), LDL-C levels plateaued at about 2.0-2.5 mmol/L, and TRL-cholesterol (non-HDL-C minus LDL-C) rose continuously. In multivariable-adjusted models, elevated triglyceride concentrations, non-specialist care and uncontrolled blood pressure were inversely associated with non-HDL-C goal attainment. Triglyceride levels were more strongly associated with non-HDL-C than with LDL-C goal attainment (ORs per 1-SD increase in log-triglycerides was 0.74, 95% CI 0.61-0.89, for LDL-C goal attainment, and 0.49, 95% CI 0.38-0.61, for non-HDL-C goal attainment).Non-HDL-C goal attainment was suboptimal in people with diabetes and co-existing CVD. This was most marked at higher triglyceride levels, possibly due to higher levels of TRL.

Familial Hypercholesterolaemia (FH) is the commonest autosomal co-dominantly inherited condition affecting man. It is caused by mutation in one of three genes, encoding the low-density lipoprotein (LDL) receptor, or the gene for apolipoprotein B (which is the major protein component of the LDL particle), or in the gene coding for PCSK9 (which is involved in the degradation of the LDL-receptor during its cellular recycling). These mutations result in impaired LDL metabolism, leading to life-long elevations in LDL-cholesterol (LDL-C) and development of premature atherosclerotic cardiovascular disease (ASCVD) [1], [2] and [3]. If left untreated, the relative risk of premature coronary artery disease is significantly higher in heterozygous patients than unaffected individuals, with most untreated homozygotes developing ASCVD before the age of 20 and generally not surviving past 30 years [2], [3], [4] and [5]. Although early detection and treatment with statins and other LDL-C lowering therapies can improve survival, FH remains widely underdiagnosed and undertreated [1], thereby representing a major global public health challenge.