Publications by authors named "Antonio J Vallejo-Vaz"

34 Publications

LDL-cholesterol lowering and clinical outcomes in hypercholesterolemic subjects with and without a familial hypercholesterolemia phenotype: Analysis from the secondary prevention 4S trial.

Atherosclerosis 2021 03 12;320:1-9. Epub 2021 Jan 12.

Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United Kingdom.

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 <4.9 and ≥ 4.9 mmol/L; next, based on the DLCN criteria for FH, the latter group was stratified into four subgroups by presence of none, one or both of "premature CAD" and "family history of CAD". Participants having both are defined as having an FH phenotype.

Results: 2267 and 2164 participants had LDL-C <4.9 and ≥ 4.9 mmol/L, respectively. Mortality endpoints and major coronary events (MCE) were significantly reduced with simvastatin versus placebo in both groups over 5.4 years, but the latter derived greater absolute risk reductions (ARR) (4.1-4.3% for mortality endpoints, versus 2.5-2.8%). LDL-C reductions were similar among the 4 subgroups with levels ≥4.9 mmol/L. Participants with FH phenotype (n = 152) appeared to derive greater relative benefits with simvastatin than the other three subgroups (all-cause death: 84% relative risk reduction, p = 0.046; MCE: 55% reduction, p = 0.0297); statistical interaction was non-significant. Participants with FH phenotype derived greater ARR than any other group with simvastatin versus placebo (all-cause mortality: 6.6% ARR; MCE 13.2%; versus 3.8% and 8.3%, respectively, among participants with LDL-C ≥4.9 mmol/L but without features suggestive of FH).

Conclusions: The FH phenotype appeared to be associated with greater clinical benefits from a given magnitude of LDL-C reduction as compared to individuals without FH phenotype.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.01.003DOI Listing
March 2021

Prevalence of Familial Hypercholesterolemia Among the General Population and Patients With Atherosclerotic Cardiovascular Disease: A Systematic Review and Meta-Analysis.

Circulation 2020 Jun 29;141(22):1742-1759. Epub 2020 May 29.

Imperial Center for Cardiovascular Disease Prevention (P.H., K.I.D., C.A.T.S., K.K.R., A.J.V.-V.), Imperial College London, UK.

Background: Contemporary studies suggest that familial hypercholesterolemia (FH) is more frequent than previously reported and increasingly recognized as affecting individuals of all ethnicities and across many regions of the world. Precise estimation of its global prevalence and prevalence across World Health Organization regions is needed to inform policies aiming at early detection and atherosclerotic cardiovascular disease (ASCVD) prevention. The present study aims to provide a comprehensive assessment and more reliable estimation of the prevalence of FH than hitherto possible in the general population (GP) and among patients with ASCVD.

Methods: We performed a systematic review and meta-analysis including studies reporting on the prevalence of heterozygous FH in the GP or among those with ASCVD. Studies reporting gene founder effects and focused on homozygous FH were excluded. The search was conducted through Medline, Embase, Cochrane, and Global Health, without time or language restrictions. A random-effects model was applied to estimate the overall pooled prevalence of FH in the general and ASCVD populations separately and by World Health Organization regions.

Results: From 3225 articles, 42 studies from the GP and 20 from populations with ASCVD were eligible, reporting on 7 297 363 individuals/24 636 cases of FH and 48 158 patients/2827 cases of FH, respectively. More than 60% of the studies were from Europe. Use of the Dutch Lipid Clinic Network criteria was the commonest diagnostic method. Within the GP, the overall pooled prevalence of FH was 1:311 (95% CI, 1:250-1:397; similar between children [1:364] and adults [1:303], =0.60; across World Health Organization regions where data were available, =0.29; and between population-based and electronic health records-based studies, =0.82). Studies with ≤10 000 participants reported a higher prevalence (1:200-289) compared with larger cohorts (1:365-407; <0.001). The pooled prevalence among those with ASCVD was 18-fold higher than in the GP (1:17 [95% CI, 1:12-1:24]), driven mainly by coronary artery disease (1:16; [95% CI, 1:12-1:23]). Between-study heterogeneity was large (>95%). Tests assessing bias were nonsignificant (>0.3).

Conclusions: With an overall prevalence of 1:311, FH is among the commonest genetic disorders in the GP, similarly present across different regions of the world, and is more frequent among those with ASCVD. The present results support the advocacy for the institution of public health policies, including screening programs, to identify FH early and to prevent its global burden.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044795DOI Listing
June 2020

Familial hypercholesterolemia: is it time to separate monogenic from polygenic familial hypercholesterolemia?

Curr Opin Lipidol 2020 06;31(3):111-118

Imperial Centre for Cardiovascular Disease Prevention (ICCP), Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, UK.

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.
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http://dx.doi.org/10.1097/MOL.0000000000000675DOI Listing
June 2020

Triglyceride concentrations and non-high-density lipoprotein cholesterol goal attainment in the ODYSSEY phase 3 trials with alirocumab.

Eur J Prev Cardiol 2020 10 23;27(15):1663-1674. Epub 2020 Feb 23.

Imperial Centre for Cardiovascular Disease Prevention, Imperial College, UK.

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 ( = 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: <100 mg/dl; moderate/high risk: <130 mg/dl), low-density lipoprotein cholesterol goal attainment (very high risk: <70 mg/dl; moderate/high risk: <100 mg/dl) and changes from baseline in lipid parameters were assessed at Week 24 among baseline triglyceride quintiles.

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 ( < 0.05 for trend tests). A single standard deviation increase in baseline log(triglycerides) was significantly associated with lower odds ratios of attaining non-high-density lipoprotein cholesterol goals in the different pools and treatment (alirocumab/placebo/ezetimibe) groups, unlike low-density lipoprotein cholesterol goal attainment.

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.
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http://dx.doi.org/10.1177/2047487320905185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549294PMC
October 2020

Triglycerides and residual risk.

Curr Opin Endocrinol Diabetes Obes 2020 04;27(2):95-103

Imperial Centre for Cardiovascular Disease Prevention (ICCP), Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, UK.

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.
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http://dx.doi.org/10.1097/MED.0000000000000530DOI Listing
April 2020

Reducing the Clinical and Public Health Burden of Familial Hypercholesterolemia: A Global Call to Action.

JAMA Cardiol 2020 02;5(2):217-229

Familial Hypercholesterolemia Foundation, Pasadena, California.

Importance: Familial 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.

Observations: In 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 Relevance: By 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.
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http://dx.doi.org/10.1001/jamacardio.2019.5173DOI Listing
February 2020

Associations between lower levels of low-density lipoprotein cholesterol and cardiovascular events in very high-risk patients: Pooled analysis of nine ODYSSEY trials of alirocumab versus control.

Atherosclerosis 2019 09 12;288:85-93. Epub 2019 Jul 12.

Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA.

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.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.07.008DOI Listing
September 2019

Lipoprotein(a) reductions from PCSK9 inhibition and major adverse cardiovascular events: Pooled analysis of alirocumab phase 3 trials.

Atherosclerosis 2019 09 8;288:194-202. Epub 2019 Jun 8.

Cardiovascular Medicine Innovation, Brigham and Women's Hospital, Boston, MA, USA.

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) < 50 mg/dL: 0.0549).

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.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.06.896DOI Listing
September 2019

Lower On-Treatment Low-Density Lipoprotein Cholesterol and Major Adverse Cardiovascular Events in Women and Men: Pooled Analysis of 10 ODYSSEY Phase 3 Alirocumab Trials.

J Am Heart Assoc 2018 09;7(18):e009221

1 Imperial Centre for Cardiovascular Disease Prevention Department of Primary Care and Public Health Imperial College London United Kingdom.

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 <50 mg/dL. Each 39 mg/dL lower 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.
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http://dx.doi.org/10.1161/JAHA.118.009221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222947PMC
September 2018

: Reducing Risk in Familial Hypercholesterolaemia and Severe Dyslipidaemia: Novel Drugs Targeting PCSK9.

Eur Cardiol 2018 Aug;13(1):7-8

Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London London, UK.

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http://dx.doi.org/10.15420/ecr.2018.13.1.GE3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159434PMC
August 2018

Epidemiology of familial hypercholesterolaemia: Community and clinical.

Atherosclerosis 2018 10;277:289-297

Imperial Centre for Cardiovascular Disease Prevention (ICCP), Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United Kingdom.

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.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.06.855DOI Listing
October 2018

Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC).

Atherosclerosis 2018 10;277:234-255

Imperial Centre for Cardiovascular Disease Prevention (ICCP), Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United Kingdom.

Background And Aims: Management of familial hypercholesterolaemia (FH) may vary across different settings due to factors related to population characteristics, practice, resources and/or policies. We conducted a survey among the worldwide network of EAS FHSC Lead Investigators to provide an overview of FH status in different countries.

Methods: Lead Investigators from countries formally involved in the EAS FHSC by mid-May 2018 were invited to provide a brief report on FH status in their countries, including available information, programmes, initiatives, and management.

Results: 63 countries provided reports. Data on FH prevalence are lacking in most countries. Where available, data tend to align with recent estimates, suggesting a higher frequency than that traditionally considered. Low rates of FH detection are reported across all regions. National registries and education programmes to improve FH awareness/knowledge are a recognised priority, but funding is often lacking. In most countries, diagnosis primarily relies on the Dutch Lipid Clinics Network criteria. Although available in many countries, genetic testing is not widely implemented (frequent cost issues). There are only a few national official government programmes for FH. Under-treatment is an issue. FH therapy is not universally reimbursed. PCSK9-inhibitors are available in ∼2/3 countries. Lipoprotein-apheresis is offered in ∼60% countries, although access is limited.

Conclusions: FH is a recognised public health concern. Management varies widely across countries, with overall suboptimal identification and under-treatment. Efforts and initiatives to improve FH knowledge and management are underway, including development of national registries, but support, particularly from health authorities, and better funding are greatly needed.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.08.051DOI Listing
October 2018

Triglyceride-Rich Lipoprotein Cholesterol and Risk of Cardiovascular Events Among Patients Receiving Statin Therapy in the TNT Trial.

Circulation 2018 08;138(8):770-781

Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, United Kingdom (A.J.V.-V., K.K.R.).

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 <130 mg/dL entered the randomized phase with ATV10 (n=5006) versus atorvastatin 80 mg/d (ATV80, n=4995). The primary end point was coronary heart disease death, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke (major adverse cardiovascular events [MACE]). TRL-C was calculated as total cholesterol minus high-density lipoprotein cholesterol minus LDL-C. The effect of atorvastatin on TRL-C was assessed during the run-in phase (ATV10) and randomized phase (ATV80 versus ATV10). The risk of MACE was assessed across quintiles (Q) of baseline TRL-C (and, for comparison, by baseline triglycerides and non-high-density lipoprotein cholesterol) during the randomized period. Last, the association between TRL-C changes with atorvastatin and cardiovascular risk was assessed by multivariate Cox regression.

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-trend<0.0001). ATV80 (versus ATV10) did not significantly alter the risk of MACE in Q1-Q2, but significantly reduced risk in Q3-Q5 (relative risk reduction, 29%-41%; all P<0.0250), with evidence of effect modification ( 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.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.032318DOI Listing
August 2018

Low-Density Lipoprotein Cholesterol Lowering for the Primary Prevention of Cardiovascular Disease Among Men With Primary Elevations of Low-Density Lipoprotein Cholesterol Levels of 190 mg/dL or Above: Analyses From the WOSCOPS (West of Scotland Coronary Prevention Study) 5-Year Randomized Trial and 20-Year Observational Follow-Up.

Circulation 2017 Nov 6;136(20):1878-1891. Epub 2017 Sep 6.

Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, United Kingdom (A.J.V.-V., K.K.R.).

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 <190 mg/dL (n=2969; mean LDL-C 178±6 mg/dL) and those with LDL-C ≥190 mg/dL (n=2560; mean LDL-C 206±12 mg/dL). The effect of pravastatin versus placebo on coronary heart disease and major adverse cardiovascular events were assessed over the 4.9-year randomized controlled trial phase and on mortality outcomes over a total of 20 years of follow-up.

Results: Among 5529 individuals without vascular disease, pravastatin reduced the risk of coronary heart disease by 27% (=0.002) and major adverse cardiovascular events by 25% (=0.004) consistently among those with and without LDL-C ≥190 mg/dL (-interaction >0.9). Among individuals with LDL-C ≥190 mg/dL, pravastatin reduced the risk of coronary heart disease by 27% (=0.033) and major adverse cardiovascular events by 25% (=0.037) during the initial trial phase and the risk of coronary heart disease death, cardiovascular death, and all-cause mortality by 28% (=0.020), 25% (=0.009), and 18% (=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.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.027966DOI Listing
November 2017

Total and Fetal Circulating Cell-Free DNA, Angiogenic, and Antiangiogenic Factors in Preeclampsia and HELLP Syndrome.

Am J Hypertens 2017 Jul;30(7):673-682

Laboratorio de Hipertensión Arterial e Hipercolesterolemia, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.

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.
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http://dx.doi.org/10.1093/ajh/hpx024DOI Listing
July 2017

Relation of Fasting Triglyceride-Rich Lipoprotein Cholesterol to Coronary Artery Calcium Score (from the ELSA-Brasil Study).

Am J Cardiol 2017 05 10;119(9):1352-1358. Epub 2017 Feb 10.

Center for Clinical and Epidemiological Research, University Hospital, University of São Paulo School of Medicine, São Paulo, Brazil; University of São Paulo School of Medicine, São Paulo, Brazil.

Although low-density lipoprotein cholesterol (LDL-C) is widely accepted as the principal lipid fraction associated with atherosclerosis, emerging evidence suggests a causal relation 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 relation between TRL-C and coronary artery calcium (CAC) score. We included 3,845 subjects (49.9 ± 8.4 years, 54% women) who had no history of CVD, were not using lipid-lowering medications, and underwent CAC evaluation. We assessed the relation 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 mg/dL (IQR 16 to 32). Subjects with CAC >0 had higher TRL-C levels than those with CAC = 0 (p <0.001). Similarly, subjects with CAC >0 had higher levels of LDL-C, non-high-density lipoprotein cholesterol, and lower high-density lipoprotein cholesterol (all p <0.001). After multivariate adjustment, log-transformed TRL-C remained associated with the presence and severity of CAC (all p <0.05). When TRL-C was added to models that contained demographic factors and conventional lipids, it significantly improved the model to predict the presence of CAC >0 (p = 0.01). In conclusion, in a large cohort of asymptomatic subjects, TRL-C was associated with subclinical atherosclerosis supporting a potentially causal role in CVD.
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http://dx.doi.org/10.1016/j.amjcard.2017.01.033DOI Listing
May 2017

Pooling and expanding registries of familial hypercholesterolaemia to assess gaps in care and improve disease management and outcomes: Rationale and design of the global EAS Familial Hypercholesterolaemia Studies Collaboration.

Atheroscler Suppl 2016 Dec 7;22:1-32. Epub 2016 Dec 7.

Imperial Centre for Cardiovascular Disease Prevention (ICCP), School of Public Health, Imperial College London, London, UK.

Background: The potential for global collaborations to better inform public health policy regarding major non-communicable diseases has been successfully demonstrated by several large-scale international consortia. However, the true public health impact of familial 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.
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http://dx.doi.org/10.1016/j.atherosclerosissup.2016.10.001DOI Listing
December 2016

Promoting high-density lipoprotein function via intravenous infusion: the rebirth of apoA-I Milano?

Eur Heart J Cardiovasc Pharmacother 2016 01 10;2(1):30-1. Epub 2015 Dec 10.

Department of Primary Care and Public Health, Imperial Centre for Cardiovascular Disease Prevention, School of Public Health, Imperial College London, Reynolds building, St Dunstan's road, W6 8RP, London, UK

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http://dx.doi.org/10.1093/ehjcvp/pvv042DOI Listing
January 2016

Fibrate therapy and flow-mediated dilation: A systematic review and meta-analysis of randomized placebo-controlled trials.

Pharmacol Res 2016 09 15;111:163-179. Epub 2016 Jun 15.

Geriatric Department, Campus Bio-Medico University and Teaching Hospital, Rome, Italy.

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<0.001). When the analysis was stratified according to the fibrate type, a significant effect was observed with fenofibrate but not with gemfibrozil, though difference between the two subgroups was not significant. Meta-analysis of data from trials where nitrate mediated dilation (NMD) was available did not suggest a significant change in NMD following treatment with fibrates. The results of this meta-analysis suggest that fibrates may exert beneficial effects on endothelial function, even over a short-term treatment course.
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http://dx.doi.org/10.1016/j.phrs.2016.06.011DOI Listing
September 2016

Impact of statin therapy on plasma levels of plasminogen activator inhibitor-1. A systematic review and meta-analysis of randomised controlled trials.

Thromb Haemost 2016 07 24;116(1):162-71. Epub 2016 Mar 24.

GianLuca Colussi, MD, Clinica Medica, University of Udine, University Hospital, Building 8, 1st floor, 33100 Udine, Italy, Tel.: +39 0432 559 804, Fax: +39 0432 559 490, E-mail:

Elevated 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.
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http://dx.doi.org/10.1160/TH15-10-0770DOI Listing
July 2016

Novel Biomarkers in Heart Failure Beyond Natriuretic Peptides - The Case for Soluble ST2.

Eur Cardiol 2015 Jul;10(1):37-41

Cardiovascular Sciences, Cardiovascular and Cell Sciences Research Institute, St George's University of London, London, UK.

Despite more effective management of heart failure over the past few decades, its burden as a chronic disease has grown and is expected to continue to rise, representing a major health problem for years to come. Having reliable tools for early diagnosis and risk stratification can help managing the condition more efficiently. In this context, the interest for biomarkers has increased considerably in the last years following the useful clinical role of B-type natriuretic peptides. These biomarkers have been extensively studied and have become established diagnostic and prognostic biomarkers in heart failure. Despite their usefulness, limitations still remain a problem in clinical practice and the search for new biomarkers has therefore continued. Amongst the most promising newer biomarkers, soluble ST2 deserves further consideration. The present review will focus on the role of this new biomarker in the context of heart failure.
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http://dx.doi.org/10.15420/ecr.2015.10.01.37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159417PMC
July 2015

Effect of pitavastatin on glucose, HbA1c and incident diabetes: A meta-analysis of randomized controlled clinical trials in individuals without diabetes.

Atherosclerosis 2015 Aug 4;241(2):409-18. Epub 2015 Jun 4.

Department of Primary Care and Public Health, School of Public Health, Imperial College London, UK. Electronic address:

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.
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http://dx.doi.org/10.1016/j.atherosclerosis.2015.06.001DOI Listing
August 2015

The evolving role of CETP inhibition: beyond HDL cholesterol.

Lancet 2015 Aug 2;386(9992):412-4. Epub 2015 Jun 2.

Cardiovascular Sciences, Cardiovascular and Cell Sciences Research Institute, St George's University of London, London, UK.

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http://dx.doi.org/10.1016/S0140-6736(15)60608-0DOI Listing
August 2015

Non-HDL cholesterol goal attainment and its relationship with triglyceride concentrations among diabetic subjects with cardiovascular disease: A nationwide survey of 2674 individuals in Hungary.

Atherosclerosis 2015 Jul 30;241(1):62-8. Epub 2015 Apr 30.

Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, UK. Electronic address:

Aims: 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 of <2.6 mmol/L, the extent to which triglycerides influence this goal attainment, and their relationship with HDL-C and triglyceride-rich lipoproteins (TRL).

Methods And Results: 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 goal <1.8 and non-HDL-C goal <2.6 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).

Conclusion: 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.
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http://dx.doi.org/10.1016/j.atherosclerosis.2015.04.810DOI Listing
July 2015

Cholesterol efflux capacity as a novel biomarker for incident cardiovascular events: has high-density lipoprotein been resuscitated?

Circ Res 2015 May;116(10):1646-8

From the Cardiovascular Sciences Department, Cardiovascular and Cell Sciences Research Institute, St George's University of London, London, UK (A.J.V.V.); and Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, UK (K.K.R.).

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http://dx.doi.org/10.1161/CIRCRESAHA.115.305938DOI Listing
May 2015

Obstructive sleep apnoea syndrome, endothelial function and markers of endothelialization. Changes after CPAP.

PLoS One 2015 27;10(3):e0122091. Epub 2015 Mar 27.

Laboratorio de Hipertensión Arterial e Hipercolesterolemia, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; Unidad Clínico Experimental de Riesgo Vascular (UCAMI), Hospital Virgen del Rocío, Sevilla, Spain.

Study Objectives: This study tries to assess the endothelial function in vivo using flow-mediated dilatation (FMD) and several biomarkers of endothelium formation/restoration and damage in patients with obstructive sleep apnoea (OSA) syndrome at baseline and after three months with CPAP therapy.

Design: Observational study, before and after CPAP therapy.

Setting And Patients: We studied 30 patients with apnoea/hypopnoea index (AHI) >15/h that were compared with themselves after three months of CPAP therapy. FMD was assessed non-invasively in vivo using the Laser-Doppler flowmetry. Circulating cell-free DNA (cf-DNA) and microparticles (MPs) were measured as markers of endothelial damage and the vascular endothelial growth factor (VEGF) was determined as a marker of endothelial restoration process.

Measurements And Results: After three month with CPAP, FMD significantly increased (1072.26 ± 483.21 vs. 1604.38 ± 915.69 PU, p< 0.005) cf-DNA and MPs significantly decreased (187.93 ± 115.81 vs. 121.28 ± 78.98 pg/ml, p<0.01, and 69.60 ± 62.60 vs. 39.82 ± 22.14 U/μL, p<0.05, respectively) and VEGF levels increased (585.02 ± 246.06 vs. 641.11 ± 212.69 pg/ml, p<0.05). These changes were higher in patients with more severe disease. There was a relationship between markers of damage (r = -0.53, p<0.005) but not between markers of damage and restoration, thus suggesting that both types of markers should be measured together.

Conclusions: CPAP therapy improves FMD. This improvement may be related to an increase of endothelial restoration process and a decrease of endothelial damage.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122091PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376903PMC
February 2016

Maternal body-mass index and cord blood circulating endothelial colony-forming cells.

J Pediatr 2014 Mar 5;164(3):566-571. Epub 2013 Dec 5.

Department of Cardiac Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA.

Objective: Endothelial colony-forming cells (ECFCs) are a subset of circulating endothelial progenitor cells that are particularly abundant in umbilical cord blood. We sought to determine whether ECFC abundance in cord blood is associated with maternal body-mass index (BMI) in nonpathologic pregnancies.

Study Design: We measured the level of ECFCs in the cord blood of neonates (n = 27) born from non-obese healthy mothers with nonpathologic pregnancies and examined whether ECFC abundance correlated with maternal BMI. We also examined the effect of maternal BMI on ECFC phenotype and function using angiogenic and vasculogenic assays.

Results: We observed variation in ECFC abundance among subjects and found a positive correlation between prepregnancy maternal BMI and ECFC content (r = 0.51, P = .007), which was independent of other obstetric factors. Despite this variation, ECFC phenotype and functionality were deemed normal and highly similar between subjects with maternal BMI <25 kg/m(2) and BMI between 25-30 kg/m(2), including the ability to form vascular networks in vivo.

Conclusions: This study underlines the need to consider maternal BMI as a potential confounding factor for cord blood levels of ECFCs in future comparative studies between healthy and pathologic pregnancies.
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http://dx.doi.org/10.1016/j.jpeds.2013.10.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943964PMC
March 2014