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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-high-income countries (9·3 mmol/L, 6·7-12·7), with greater use of three or more lipid-lowering therapies (LLT; high-income 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. FUNDING: Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; and European Atherosclerosis Society.
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Hipercolesterolemia Familiar Homozigota/complicações , Hipercolesterolemia Familiar Homozigota/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Hipercolesterolemia Familiar Homozigota/genética , Humanos , Masculino , Sistema de Registros , Estudos Retrospectivos , Adulto JovemRESUMO
PURPOSE OF REVIEW: We reviewed current and future therapeutic options for patients with homozygous familial hypercholesterolemia (HoFH) and place this evidence in context of an adaptable treatment algorithm. RECENT FINDINGS: Lowering LDL-C levels to normal in patients with HoFH is challenging, but a combination of multiple lipid-lowering therapies (LLT) is key. Patients with (near) absence of LDL receptor expression are most severely affected and frequently require regular lipoprotein apheresis on top of combined pharmacologic LLT. Therapies acting independently of the LDL receptor pathway, such as lomitapide and evinacumab, are considered game changers for many patients with HoFH, and may reduce the need for lipoprotein apheresis in future. Liver transplantation is to be considered a treatment option of last resort. Headway is being made in gene therapy strategies, either aiming to permanently replace or knock out key lipid-related genes, with first translational steps into humans being made. Cardiovascular disease risk management beyond LDL-C, such as residual Lp(a) or inflammatory risk, should be evaluated and addressed accordingly in HoFH. SUMMARY: Hypercholesterolemia is notoriously difficult to control in most patients with HoFH, but multi-LLT, including newer drugs, allows reduction of LDL-C to levels unimaginable until a few years ago. Cost and availability of these new therapies are important future challenges to be addressed.
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Anticolesterolemiantes , Hipercolesterolemia Familiar Homozigota , Hiperlipoproteinemia Tipo II , Humanos , Hiperlipoproteinemia Tipo II/terapia , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/farmacologia , LDL-Colesterol/genética , Receptores de LDL/genética , Algoritmos , HomozigotoRESUMO
PURPOSE OF REVIEW: The current review describes the development, clinical relevance and potential caveats of polygenic risk scores (PRS) for LDL cholesterol (LDL-C). RECENT FINDINGS: In recent years, a large number of common variants have been shown to have a small effect on LDL-C levels. The aggregate effect of all of these variants on LDL-C levels can be captured in a PRS and an elevated number of LDL-C increasing common variants is considered to be a cause of high LDL-C levels in patients with familial hypercholesterolemia (FH) without a large effect, rare mutation. PRS do not only serve as a tool in diagnostics, but are also helpful in cardiovascular disease (CVD) risk prediction. Moreover, PRS modulate CVD risk even in patients without a monogenic FH. However, future larger scale PRS directly aimed at CVD risk may serve as more sensitive tools to identify individuals with severely increased CVD risk. SUMMARY: LDL-C PRS help explain part of hypercholesterolemia in a proportion of dyslipidemic patients that do not have monogenic FH. Nevertheless, the CVD risk conferred by current PRS does not appear to match that of monogenic FH. LDL-C PRS are currently not widely used in clinical care.
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Doenças Cardiovasculares , LDL-Colesterol , Testes Genéticos , Herança Multifatorial , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , LDL-Colesterol/sangue , Fatores de Risco de Doenças Cardíacas , Humanos , Fatores de RiscoRESUMO
PURPOSE OF REVIEW: Apolipoprotein C-III (ApoC-III) and angiopoietin like protein 3 (angptl3) have emerged as key regulators of triglyceride metabolism. Based on Mendelian randomisation studies, novel therapeutic strategies inhibiting these proteins using monoclonal antibodies or gene silencing techniques might reduce residual cardiovascular disease (CVD) risk in dyslipidemic patients. This article aims to review the role of apoC-III and angptl3 in triglyceride metabolism and combine early clinical evidence of CVD reducing potential of these new therapeutic targets. RECENT FINDINGS: Angptl3 inhibition by mAb or antisense therapy has recently completed phase I and II studies, respectively and demonstrate robust apolipoprotein B (apoB) lowering up to 46%. Volanesorsen is an antisense therapy approved for patients with extremely elevated plasma triglyceride levels in which it showed no consistent apoB reduction. However, the GalNAc-conjugated oligonucleotide showed moderate (up to â¼30%) apoB reduction in a phase 1/2a dose-finding study. SUMMARY: Angptl3 and apoC-III are novel targets in lipoprotein metabolism that reduce triglycerides when inhibited. The expected CVD risk reduction may be mediated through reduced triglyceride-rich lipoprotein particle number, reflected by apoB, rather than triglyceride reduction per se. Limited human evidence shows that apoC-III and angptl3 inhibition both potently lower triglycerides, but since angptl3 inhibition reduces apoB more robustly it may be expected to confer more favorable CVD risk reduction.
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Proteínas Semelhantes a Angiopoietina/genética , Apolipoproteína C-III/genética , Doenças Cardiovasculares/tratamento farmacológico , Triglicerídeos/genética , Proteína 3 Semelhante a Angiopoietina , Proteínas Semelhantes a Angiopoietina/antagonistas & inibidores , Apolipoproteína C-III/antagonistas & inibidores , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Humanos , Hipertrigliceridemia/tratamento farmacológico , Hipertrigliceridemia/genética , Hipertrigliceridemia/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Oligonucleotídeos Antissenso/uso terapêutico , Triglicerídeos/antagonistas & inibidores , Triglicerídeos/metabolismoRESUMO
Importance: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic condition characterized by extremely increased low-density lipoprotein (LDL) cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Heterozygous familial hypercholesterolemia (HeFH) is more common than HoFH, and women with HeFH are diagnosed later and undertreated compared to men; it is unknown whether these sex differences also apply to HoFH. Objective: To investigate sex differences in age at diagnosis, risk factors, lipid-lowering treatment, and ASCVD morbidity and mortality in patients with HoFH. Design, Setting, and Participants: Sex-specific analyses for this retrospective cohort study were performed using data from the HoFH International Clinical Collaborators (HICC) registry, the largest global dataset of patients with HoFH, spanning 88 institutions across 38 countries. Patients with HoFH who were alive during or after 2010 were eligible for inclusion. Data entry occurred between February 2016 and December 2020. Data were analyzed from June 2022 to June 2023. Main Outcomes and Measures: Comparison between women and men with HoFH regarding age at diagnosis, presence of risk factors, lipid-lowering treatment, prevalence, and onset and incidence of ASCVD morbidity (myocardial infarction [MI], aortic stenosis, and combined ASCVD outcomes) and mortality. Results: Data from 389 women and 362 men with HoFH from 38 countries were included. Women and men had similar age at diagnosis (median [IQR], 13 [6-26] years vs 11 [5-27] years, respectively), untreated LDL cholesterol levels (mean [SD], 579 [203] vs 596 [186] mg/dL, respectively), and cardiovascular risk factor prevalence, except smoking (38 of 266 women [14.3%] vs 59 of 217 men [27.2%], respectively). Prevalence of MI was lower in women (31 of 389 [8.0%]) than men (59 of 362 [16.3%]), but age at first MI was similar (mean [SD], 39 [13] years in women vs 38 [13] years in men). Treated LDL cholesterol levels and lipid-lowering therapy were similar in both sexes, in particular statins (248 of 276 women [89.9%] vs 235 of 258 men [91.1%]) and lipoprotein apheresis (115 of 317 women [36.3%] vs 118 of 304 men [38.8%]). Sixteen years after HoFH diagnosis, women had statistically significant lower cumulative incidence of MI (5.0% in women vs 13.7% in men; subdistribution hazard ratio [SHR], 0.37; 95% CI, 0.21-0.66) and nonsignificantly lower all-cause mortality (3.0% in women vs 4.1% in men; HR, 0.76; 95% CI, 0.40-1.45) and cardiovascular mortality (2.6% in women vs 4.1% in men; SHR, 0.87; 95% CI, 0.44-1.75). Conclusions and Relevance: In this cohort study of individuals with known HoFH, MI was higher in men compared with women yet age at diagnosis and at first ASCVD event were similar. These findings suggest that early diagnosis and treatment are important in attenuating the excessive cardiovascular risk in both sexes.
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Aterosclerose , Hipercolesterolemia Familiar Homozigota , Infarto do Miocárdio , Humanos , Feminino , Masculino , Adolescente , LDL-Colesterol , Estudos de Coortes , Estudos Retrospectivos , Caracteres SexuaisRESUMO
BACKGROUND: Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by extremely high plasma LDL cholesterol from birth, causing atherosclerotic cardiovascular disease at a young age. Lipoprotein apheresis in combination with lipid-lowering drugs effectively reduce LDL cholesterol, but long-term health outcomes of such treatment are unknown. We aimed to investigate the long-term cardiovascular outcomes associated with lipoprotein apheresis initiated in childhood or adolescence. METHODS: In this cohort study, data were drawn from the HoFH International Clinical Collaboration (HICC) and the international registry for Children with Homozygous Hypercholesterolemia on Lipoprotein Apheresis (CHAIN). An overall cohort included patients diagnosed with HoFH aged 0-18 years who were alive and in follow-up between Jan 1, 2010, and Nov 8, 2021, and whose high plasma LDL cholesterol concentrations made them eligible for lipoprotein apheresis. To compare cardiovascular outcomes, patients who initiated lipoprotein apheresis in childhood (lipoprotein apheresis group) and patients who only received lipid-lowering drugs (pharmacotherapy-only group) were matched by sex and untreated plasma LDL cholesterol concentrations. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischaemic stroke, percutaneous coronary intervention, coronary artery bypass grafting, aortic valve replacement, peripheral artery disease, carotid endarterectomy, angina pectoris, and supra-aortic or aortic stenosis (collectively referred to as atherosclerotic cardiovascular disease), for which survival analyses were performed in the matched cohort. Cox regression analyses were used to compare disease-free survival between cohorts and to calculate hazard ratio (HR) and 95% CI adjusted for sex, age at diagnosis, untreated plasma LDL cholesterol concentration, and number of lipid-lowering therapies other than lipoprotein apheresis. FINDINGS: The overall cohort included 404 patients with a median age at diagnosis of 6·0 years (IQR 3·0-9·5) and median untreated plasma LDL cholesterol of 17·8 mmol/L (14·7-20·8). The matched cohorts included 250 patients (125 patients per group), with a median untreated LDL cholesterol of 17·2 mmol/L (14·8-19·7). Mean reduction in plasma LDL cholesterol concentrations between baseline and final follow-up was greater in the lipoprotein apheresis group (-55% [95% CI -60 to -51] vs -31% [-36 to -25]; p<0·0001). Patients in the lipoprotein apheresis group had longer atherosclerotic cardiovascular disease-free survival (adjusted HR 0·52 [95% CI 0·32-0·85]) and longer cardiovascular death-free survival (0·0301 [0·0021-0·4295]). Cardiovascular death was more common in the pharmacotherapy-only group than in the lipoprotein apheresis group (ten [8%] vs one [1%]; p=0·010), whereas median age at coronary artery bypass grafting was lower in the lipoprotein apheresis group than in the pharmacotherapy-only group (15·0 years [IQR 12·0-24·0] vs 30·5 years [19·0-33·8]; p=0·037). INTERPRETATION: Among patients with HoFH, lipoprotein apheresis initiated during childhood and adolescence is associated with reduced long-term risk of atherosclerotic cardiovascular disease and death, and clear benefits of early initiation of high-frequency treatment on reducing plasma cholesterol were found. Consensus recommendations are now needed to guide more widespread and timely use of lipoprotein apheresis for children with HoFH, and research is required to further optimise treatment and ensure benefits of early and aggressive treatment delivery are balanced against effects on quality of life. FUNDING: Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; European Atherosclerosis Society; and the US National Heart, Lung, and Blood Institute, National Institutes of Health.
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Remoção de Componentes Sanguíneos , Doenças Cardiovasculares , Hiperlipoproteinemia Tipo II , Sistema de Registros , Humanos , Feminino , Masculino , Hiperlipoproteinemia Tipo II/terapia , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/complicações , Criança , Remoção de Componentes Sanguíneos/métodos , Adolescente , Pré-Escolar , Seguimentos , Doenças Cardiovasculares/prevenção & controle , Lactente , LDL-Colesterol/sangue , Lipoproteínas/sangue , Estudos de Coortes , Resultado do Tratamento , HomozigotoRESUMO
Objectives: Individuals with familial hypercholesterolemia (FH) are at an increased risk for coronary artery disease (CAD). While prior research has shown variability in coronary artery calcification (CAC) among those with FH, studies with small sample sizes and single-center recruitment have been limited in their ability to characterize CAC and plaque burden in subgroups based on age and sex. Understanding the spectrum of atherosclerosis may result in personalized risk assessment and tailored allocation of costly add-on, non-statin lipid-lowering therapies. We aimed to characterize the presence and burden of CAC and coronary plaque on computed tomography angiography (CTA) across age- and sex-stratified subgroups of individuals with FH who were without CAD at baseline. Methods: We pooled 1,011 patients from six cohorts across Brazil, France, the Netherlands, Spain, and Australia. Our main measures of subclinical atherosclerosis included CAC ranges (i.e., 0, 1-100, 101-400, >400) and CTA-derived plaque burden (i.e., no plaque, non-obstructive CAD, obstructive CAD). Results: Ninety-five percent of individuals with FH (mean age: 48 years; 54% female; treated LDL-C: 154 mg/dL) had a molecular diagnosis and 899 (89%) were on statin therapy. Overall, 423 (42%) had CAC=0, 329 (33%) had CAC 1-100, 160 (16%) had CAC 101-400, and 99 (10%) had CAC >400. Compared to males, female patients were more likely to have CAC=0 (48% [n = 262] vs 35% [n = 161]) and no plaque on CTA (39% [n = 215] vs 26% [n = 120]). Among patients with CAC=0, 85 (20%) had non-obstructive CAD. Females also had a lower prevalence of obstructive CAD in CAC 1-100 (8% [n = 15] vs 18% [n = 26]), CAC 101-400 (32% [n = 22] vs 40% [n = 36]), and CAC >400 (52% [n = 16] vs 65% [n = 44]). Female patients aged 50-59 years were less likely to have obstructive CAD in CAC >400 (55% [n = 6] vs 70% [n = 19]). Conclusion: In this large, multi-national study, we found substantial age- and sex-based heterogeneity in CAC and plaque burden in a cohort of predominantly statin-treated individuals with FH, with evidence for a less pronounced increase in atherosclerosis among female patients. Future studies should examine the predictors of resilience to and long-term implications of the differential burden of subclinical coronary atherosclerosis in this higher risk population.
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Homozygous familial hypercholesterolemia (HoFH) is a rare, potentially life-limiting, inherited disorder of lipoprotein metabolism characterized by extremely high low-density lipoprotein cholesterol levels. When both parents have heterozygous FH, there is a 25% chance they will conceive a child with HoFH. Here we describe our clinical experience with two such prospective parent couples who were counseled regarding reproductive options and prenatal testing for HoFH. These cases showcase how, in consultation with a molecular geneticist and pediatric cardiologist, parents may be informed of the prognosis and treatment outlook of HoFH based on the FH-variants carried, to ultimately make personal decisions on reproductive options. One couple opted for prenatal testing and termination of pregnancy in case HoFH was found, while the other accepted the risk without testing. We review the available literature on preconception counseling for HoFH and provide practical guidance to clinicians counseling at-risk couples. Optimal counseling of prospective parents may help prevent future physical and psychological problems for both parent and child.
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Hipercolesterolemia Familiar Homozigota , Hiperlipoproteinemia Tipo II , Humanos , Criança , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Fenótipo , Estudos Prospectivos , Aconselhamento , HomozigotoRESUMO
BACKGROUND AND AIMS: Lipoprotein(a) (Lp(a)) is an LDL-like particle whose plasma levels are largely genetically determined. The impact of measuring Lp(a) in patients with clinical familial hypercholesterolemia (FH) referred for genetic testing is largely unknown. We set out to evaluate the contribution of (genetically estimated) Lp(a) in a large nation-wide referral population of clinical FH. METHODS: In 1504 patients referred for FH genotyping, we used an LPA genetic instrument (rs10455872 and rs3798220) as a proxy for plasma Lp(a) levels. The genetic Lp(a) proxy was used to correct LDL-cholesterol and reclassify patients with clinical FH based on Dutch Lipid Criteria Network (DLCN) scoring. Finally, we used estimated Lp(a) levels to reclassify ASCVD risk using the SCORE and SMART risk scores. RESULTS: LPA SNPs were more prevalent among mutation-negative compared with mutation-positive patients (296/1280 (23.1%) vs 35/224 (15.6%), p = 0.016). Among patients with genetically defined high Lp(a) levels, 9% were reclassified to the DLCN category 'unlikely FH' using Lp(a)-corrected LDL-cholesterol (LDL-Ccor) and all but one of these patients indeed carried no FH variant. Furthermore, elevated Lp(a) reclassified predicted ASCVD risk into a higher category in up to 18% of patients. CONCLUSIONS: In patients referred for FH molecular testing, we show that taking into account (genetically estimated) Lp(a) levels not only results in reclassification of probability of genetic FH, but also has an impact on individual cardiovascular risk evaluation. However, to avoid missing the diagnosis of an FH variant, clear thresholds for the use of Lp(a)-cholesterol adjusted LDL-cholesterol levels in patients referred for genetic testing of FH must be established.
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Arteriosclerose , Hiperlipoproteinemia Tipo II , Humanos , Lipoproteína(a) , Hiperlipoproteinemia Tipo II/genética , LDL-Colesterol , Testes Genéticos/métodos , Fatores de RiscoRESUMO
Emerging studies in the literature describe an association between high-fat, low-carbohydrate diets and severe hypercholesterolemia consistent with the levels observed in patients with (homozygous) familial hypercholesterolemia (FH). High levels of low-density lipoprotein cholesterol (LDL-C) may result from the reduced clearance of LDL particles from the circulation, the increased production of their precursor, or a combination of both. The increased intake of (saturated) fat and cholesterol, combined with limited to no intake of carbohydrates and fiber, are the main features of diets linked to hypercholesterolemia. However, several observations in previous studies, together with our observations from our lipid clinic, do not provide a definitive pathophysiological explanation for severe hypercholesterolemia. Therefore, we review these findings and possible pathophysiological explanations as well as opportunities for future research. Altogether, clinicians should rule out high-fat, low-carbohydrate diets as a possible cause for hypercholesterolemia in patients presenting with clinical FH in whom no mutation is found and discuss dietary modifications to durably reduce LDL-C levels and cardiovascular disease risk.
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Dislipidemias , Hipercolesterolemia , Hiperlipidemias , Hiperlipoproteinemia Tipo II , Humanos , LDL-Colesterol , Colesterol , Dieta com Restrição de Carboidratos , Ácidos Graxos , Carboidratos da Dieta , Gorduras na DietaRESUMO
Background ANGPTL3 (angiopoietin-like protein 3) is an acknowledged crucial regulator of lipid metabolism by virtue of its inhibitory effect on lipoprotein lipase and endothelial lipase. It is currently unknown whether and to which lipoproteins ANGPTL3 is bound and whether the ability of ANGPTL3 to inhibit lipase activity is affected by binding to lipoproteins. Methods and Results Incubation of ultracentrifugation-isolated low-density lipoprotein (LDL) and high-density lipoprotein (HDL) fractions from healthy volunteers with recombinant ANGPTL3 revealed that ANGPTL3 associates with both HDL and LDL particles ex vivo. Plasma from healthy volunteers and a patient deficient in HDL was fractionated by fast protein liquid chromatography, and ANGPTL3 distribution among lipoprotein fractions was measured. In healthy volunteers, ≈75% of lipoprotein-associated ANGPTL3 resides in HDL fractions, whereas ANGPTL3 was largely bound to LDL in the patient deficient in HDL. ANGPTL3 activity was studied by measuring lipolysis and uptake of 3H-trioleate by brown adipocyte T37i cells. Unbound ANGPTL3 did not suppress lipase activity, but when given with HDL or LDL, ANGPTL3 suppressed lipase activity by 21.4±16.4% (P=0.03) and 25.4±8.2% (P=0.006), respectively. Finally, in a subset of the EPIC (European Prospective Investigation into Cancer) Norfolk study, plasma HDL cholesterol and amount of large HDL particles were both positively associated with plasma ANGPTL3 concentrations. Moreover, plasma ANGPTL3 concentrations showed a positive association with incident coronary artery disease (odds ratio, 1.25 [95% CI, 1.01-1.55], P=0.04). Conclusions Although ANGPTL3 preferentially resides on HDL, its activity was highest once bound to LDL particles.
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Lipoproteínas HDL , Lipoproteínas , Humanos , Proteínas Semelhantes a Angiopoietina , Estudos Prospectivos , Lipase/metabolismo , Angiopoietinas , Triglicerídeos , Proteína 3 Semelhante a AngiopoietinaRESUMO
Importance: Lipoprotein(a) (Lp[a]) concentrations are a highly heritable and potential causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Recent consensus statements by the European Atherosclerosis Society and American Heart Association recommend screening of relatives of individuals with high Lp(a) concentrations, but the expected yield of this approach has not been quantified in large populations. Objective: To measure the prevalence of high Lp(a) concentrations among first- and second-degree relatives of individuals with high Lp(a) concentrations compared with unrelated participants. Design, Setting, and Participants: In this cross-sectional analysis, pairs of first-degree (n = 19â¯899) and second-degree (n = 9715) relatives with measured Lp(a) levels from the UK Biobank study and random pairs of unrelated individuals (n = 184â¯764) were compared. Data for this study were collected from March 2006 to August 2010 and analyzed from December 2021 to August 2023. Exposure: Serum Lp(a) levels, with a high Lp(a) level defined as at least 125 nmol/L. Main Outcome and Measure: Concordance of clinically relevant high Lp(a) levels in first- and second-degree relatives of index participants with high Lp(a) levels. Results: A total of 52 418 participants were included in the analysis (mean [SD] age, 57.3 [8.0] years; 29 825 [56.9%] women). Levels of Lp(a) were correlated among pairs of first-degree (Spearman ρ = 0.45; P < .001) and second-degree (Spearman ρ = 0.22; P < .001) relatives. A total of 1607 of 3420 (47.0% [95% CI, 45.3%-48.7%]) first-degree and 514 of 1614 (31.8% [95% CI, 29.6%-34.2%]) second-degree relatives of index participants with high Lp(a) levels also had elevated concentrations compared with 4974 of 30â¯258 (16.4% [95% CI, 16.0%-16.9%]) pairs of unrelated individuals. The concordance in high Lp(a) levels was generally consistent among subgroups (eg, those with prior ASCVD, postmenopausal women, and statin users). The odds ratios for relatives to have high Lp(a) levels if their index relative had a high Lp(a) level compared with those whose index relatives did not have high Lp(a) levels were 7.4 (95% CI, 6.8-8.1) for first-degree relatives and 3.0 (95% CI, 2.7-3.4) for second-degree relatives. Conclusions and Relevance: The findings of this cross-sectional study suggest that the yield of cascade screening of first-degree relatives of individuals with high Lp(a) levels is over 40%. These findings support recent recommendations to use this approach to identify additional individuals at ASCVD risk based on Lp(a) concentrations.
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Aterosclerose , Lipoproteína(a) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aterosclerose/epidemiologia , Estudos Transversais , Lipoproteína(a)/sangue , Estudos Prospectivos , Fatores de RiscoRESUMO
Background: Heterozygous familial hypercholesterolemia (HeFH) is a monogenic disorder characterized by increased circulating low-density lipoprotein cholesterol and accelerated atherosclerosis. Even among this high-risk group, prior studies note considerable variability in risk of coronary artery disease (CAD). Objectives: The purpose of this study was to evaluate the cumulative impact of many common DNA variants-as quantified by a polygenic score-on incident CAD among individuals carrying a HeFH variant. Methods: We analyzed data from a prospective cohort study of 1,315 individuals who carried a HeFH variant and 1,315 matched family noncarriers derived from a nationwide screening program in the Netherlands, with subsequent replication in 151,009 participants of the UK Biobank. Results: Despite identification and lipid management within the Dutch screening program, 84 (6.4%) of HeFH variant carriers developed CAD as compared to 45 (3.4%) of matched family members (median follow-up 10.2 years, HR 1.88, 95% CI: 1.31-2.70). Among HeFH variant carriers, a polygenic score was associated with CAD with an effect size similar to low-density lipoprotein cholesterol - HR of 1.35 (95% CI: 1.07-1.70) and 1.41 (95% CI: 1.17-1.70) per standard deviation increase, respectively. When compared to noncarriers, CAD risk increased from 1.24-fold (95% CI: 0.64-2.34) to 3.37-fold (95% CI: 2.11-5.36) across quintiles of the polygenic score. A similar risk gradient, 1.36-fold (95% CI: 0.65-2.85) to 2.88-fold (95% CI: 1.59-5.20), was observed in 429 carriers in the UK Biobank. Conclusions: In 2 cohort studies involving 1,744 individuals with genetically confirmed HeFH - the largest study to date - risk of CAD varied according to polygenic background, in some cases approaching the risk observed in noncarriers.
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BACKGROUND AND AIMS: Low-density lipoprotein cholesterol (LDL-C) levels vary in patients with familial hypercholesterolemia (FH) and can be explained by a single deleterious genetic variant or by the aggregate effect of multiple, common small-effect variants that can be captured in a polygenic score (PS). We set out to investigate the contribution of a previously published PS to the inter-individual LDL-C variation and coronary artery disease (CAD) risk in patients with a clinical FH phenotype. METHODS: First, in a cohort of 628 patients referred for genetic FH testing, we evaluated the distribution of a PS for LDL-C comprising 12 genetic variants. Next, we determined its association with coronary artery disease (CAD) risk using UK Biobank data. RESULTS: The mean PS was higher in 533 FH-variant-negative patients (FH/M-) compared with 95 FH-variant carriers (1.02 vs 0.94, p < 0.001). 39% of all patients had a PS equal to the top 20% from a population-based reference cohort and these patients were less likely to carry an FH variant (OR 0.22, 95% CI 0.10-0.48) compared with patients in the lowest 20%. In UK Biobank data, the PS explained 7.4% of variance in LDL-C levels and was associated with incident CAD. Addition of PS to a prediction model using age and sex and LDL-C did not increase the c-statistic for predicting CAD risk. CONCLUSIONS: This 12-variant PS was higher in FH/M- patients and associated with incident CAD in UK Biobank data. However, the PS did not improve predictive accuracy when added to the readily available characteristics age, sex and LDL-C, suggesting limited discriminative value for CAD.
Assuntos
Hipercolesterolemia , Hiperlipoproteinemia Tipo II , LDL-Colesterol/genética , Heterozigoto , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/epidemiologia , Hipercolesterolemia/genética , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Hiperlipoproteinemia Tipo II/genética , Herança Multifatorial , Fatores de RiscoRESUMO
BACKGROUND AND AIMS: Thrombosis is a major driver of adverse outcome and mortality in patients with Coronavirus disease 2019 (COVID-19). Hypercoagulability may be related to the cytokine storm associated with COVID-19, which is mainly driven by interleukin (IL)-6. Plasma lipoprotein(a) [Lp(a)] levels increase following IL-6 upregulation and Lp(a) has anti-fibrinolytic properties. This study investigated whether Lp(a) elevation may contribute to the pro-thrombotic state hallmarking COVID-19 patients. METHODS: Lp(a), IL-6 and C-reactive protein (CRP) levels were measured in 219 hospitalized patients with COVID-19 and analyzed with linear mixed effects model. The baseline biomarkers and increases during admission were related to venous thromboembolism (VTE) incidence and clinical outcomes in a Kaplan-Meier and logistic regression analysis. RESULTS: Lp(a) levels increased significantly by a mean of 16.9 mg/dl in patients with COVID-19 during the first 21 days after admission. Serial Lp(a) measurements were available in 146 patients. In the top tertile of Lp(a) increase, 56.2% of COVID-19 patients experienced a VTE event compared to 18.4% in the lowest tertile (RR 3.06, 95% CI 1.61-5.81; p < 0.001). This association remained significant after adjusting for age, sex, IL-6 and CRP increase and number of measurements. Increases in IL-6 and CRP were not associated with VTE. Increase in Lp(a) was strongly correlated with increase in IL-6 (r = 0.44, 95% CI 0.30-0.56, p < 0.001). CONCLUSIONS: Increases in Lp(a) levels during the acute phase of COVID-19 were strongly associated with VTE incidence. The acute increase in anti-fibrinolytic Lp(a) may tilt the balance to VTE in patients hospitalized for COVID-19.
Assuntos
COVID-19 , Tromboembolia Venosa , Humanos , Lipoproteína(a) , Projetos Piloto , Fatores de Risco , SARS-CoV-2 , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiologiaRESUMO
BACKGROUND: Familial hypercholesterolemia is characterised by high low-density lipoprotein-cholesterol levels and is caused by a pathogenic variant in LDLR, APOB or PCSK9. We investigated which proportion of suspected familial hypercholesterolemia patients was genetically confirmed, and whether this has changed over the past 20 years in The Netherlands. METHODS: Targeted next-generation sequencing of 27 genes involved in lipid metabolism was performed in patients with low-density lipoprotein-cholesterol levels greater than 5 mmol/L who were referred to our centre between May 2016 and July 2018. The proportion of patients carrying likely pathogenic or pathogenic variants in LDLR, APOB or PCSK9, or the minor familial hypercholesterolemia genes LDLRAP1, ABCG5, ABCG8, LIPA and APOE were investigated. This was compared with the yield of Sanger sequencing between 1999 and 2016. RESULTS: A total of 227 out of the 1528 referred patients (14.9%) were heterozygous carriers of a pathogenic variant in LDLR (80.2%), APOB (14.5%) or PCSK9 (5.3%). More than 50% of patients with a Dutch Lipid Clinic Network score of 'probable' or 'definite' familial hypercholesterolemia were familial hypercholesterolemia mutation-positive; 4.8% of the familial hypercholesterolemia mutation-negative patients carried a variant in one of the minor familial hypercholesterolemia genes. The mutation detection rate has decreased over the past two decades, especially in younger patients in which it dropped from 45% in 1999 to 30% in 2018. CONCLUSIONS: A rare pathogenic variant in LDLR, APOB or PCSK9 was identified in 14.9% of suspected familial hypercholesterolemia patients and this rate has decreased in the past two decades. Stringent use of clinical criteria algorithms is warranted to increase this yield. Variants in the minor familial hypercholesterolemia genes provide a possible explanation for the familial hypercholesterolemia phenotype in a minority of patients.
Assuntos
Hiperlipoproteinemia Tipo II , Pró-Proteína Convertase 9 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Hiperlipoproteinemia Tipo II/genética , Fenótipo , Pró-Proteína Convertase 9/genética , Receptores de LDL/genéticaRESUMO
INTRODUCTION: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality. High plasma low-density lipoprotein cholesterol (LDL-C) levels are a key CVD-risk factor. Triglyceride-rich remnant particles and lipoprotein(a) (Lp[a]) are also causally related to CVD. Consequently, therapeutic strategies for lowering LDL-C and triglyceride levels are widely used in routine clinical practice; however, specific Lp(a) lowering agents are not available. Many patients do not achieve guideline-recommended lipid levels with currently available therapies; hence, novel targets and treatment modalities are eagerly sought. AREAS COVERED: We discuss the milestones on the trajectory toward the full application of gene-based therapies in daily clinical practice. We describe the different methods, ranging from antisense oligonucleotides to liver-directed gene therapy and Crispr-cas9 modification to target the pivotal players in lipid metabolism: PCSK9, APOB, ANGPTL3, Lp(a), LDLR, and apoC-III. EXPERT OPINION: While acknowledging their different stages of development, gene-based therapies are likely to invoke a paradigm shift in lipid management because they allow us to target previously undruggable targets. Moreover, their low dosing frequency, high target selectivity, and relatively predictable adverse event profile are considered major advantages over current lipid-lowering therapies.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Terapia Genética/métodos , Hipercolesterolemia/terapia , Animais , Sistemas CRISPR-Cas/genética , Doenças Cardiovasculares/etiologia , Fatores de Risco de Doenças Cardíacas , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/genética , Metabolismo dos Lipídeos/genética , Oligonucleotídeos Antissenso/administração & dosagemRESUMO
BACKGROUND AND AIMS: Statins suppress hepatic mRNA expression of ANGPTL3 encoding angiopoietin-like 3 in healthy subjects, but it is unknown if plasma ANGPTL3 concentrations are affected by statins prescribed to hypercholesterolemic patients in clinical practice. We therefore investigated the effect of statin treatment on plasma ANGPTL3 concentrations in hypercholesterolemic patients. In addition, we explored the underlying mechanism by which statins regulate ANGPTL3 in vitro. METHODS: Plasma ANGPTL3 concentrations were measured in 93 genetically confirmed familial hypercholesterolemia (FH) patients who were using statin therapy and 61 statin naïve FH patients. Moreover, concentrations were measured in 14 hypercholesterolemic patients who discontinued their statin treatment for 4 weeks. In vitro studies were performed with Huh7 human hepatoma cells. RESULTS: Plasma ANGPTL3 concentrations were 15% lower in statin treated FH patients compared to statin naïve FH patients (145 (120-193) vs. 167 (135-220) ng/ml, p = 0.012). Statin discontinuation resulted in a 21% (p<0.001) increase of plasma ANGPTL3 concentrations. Simvastatin reduced ANGPTL3 mRNA expression and ANGPTL3 secretion of Huh7 cells. Liver X receptor (LXR) activation with T0901317 increased ANGPTL3 mRNA expression and ANGPTL3 secretion by 6- and 3-fold, respectively. Adding simvastatin did not mitigate this effect but adding the LXR antagonist GSK2230 to simvastatin-incubated Huh7 cells diminished simvastatin-induced reductions in ANGPTL3 mRNA expression and ANGPTL3 secretion. Simvastatin reduced intracellular oxysterol concentrations. Oxysterols are endogenous LXR ligands, implying that simvastatin suppresses ANGPTL3 secretion via reduced oxysterol-mediated LXR activation. CONCLUSIONS: Statins lower plasma ANGPTL3 concentrations in hypercholesterolemic patients, likely due to decreased oxysterol-mediated LXR activation.