Familial Hypercholesterolemia Patients Research Articles

Impact of cholesterol on proinflammatory monocyte production by the bone marrow.

AimPreclinical work indicates that low-density lipoprotein cholesterol (LDL-C) not only drives atherosclerosis by directing the innate immune response at plaque level but also augments proinflammatory monocyte production in the bone marrow (BM) compartment. In this study, we aim to unravel the impact of LDL-C on monocyte production in the BM compartment in human subjects.Methods and resultsA multivariable linear regression analysis in 12 304 individuals of the EPIC-Norfolk prospective population study showed that LDL-C is associated with monocyte percentage (β = 0.131 [95% CI: 0.036–0.225]; P = 0.007), at the expense of granulocytes (β = −0.876 [95% CI: −1.046 to −0.705]; P < 0.001). Next, we investigated whether altered haematopoiesis could explain this monocytic skewing by characterizing CD34+ BM haematopoietic stem and progenitor cells (HSPCs) of patients with familial hypercholesterolaemia (FH) and healthy normocholesterolaemic controls. The HSPC transcriptomic profile of untreated FH patients showed increased gene expression in pathways involved in HSPC migration and, in agreement with our epidemiological findings, myelomonocytic skewing. Twelve weeks of cholesterol-lowering treatment reverted the myelomonocytic skewing, but transcriptomic enrichment of monocyte-associated inflammatory and migratory pathways persisted in HSPCs post-treatment. Lastly, we link hypercholesterolaemia to perturbed lipid homeostasis in HSPCs, characterized by lipid droplet formation and transcriptomic changes compatible with increased intracellular cholesterol availability.ConclusionsCollectively, these data highlight that LDL-C impacts haematopoiesis, promoting both the number and the proinflammatory activation of circulating monocytes. Furthermore, this study reveals a potential contributory role of HSPC transcriptomic reprogramming to residual inflammatory risk in FH patients despite cholesterol-lowering therapy.

Evinacumab for treatment of familial hypercholesterolemia

Introduction Familial hypercholesterolemia (FH) is characterized by lifelong elevation of low-density lipoprotein cholesterol (LDL-C), early onset coronary atherosclerosis and premature death. FH is underdiagnosed and undertreated, but requires aggressive LDL-C-lowering to prevent complications. Current treatment strategies, lifestyle modification and numerous LDL-C-lowering medications, are often insufficient to achieve lipid goals in FH. Areas covered Angiopoietin-like 3 protein (ANGPTL3) is intricately involved in lipid metabolism. Loss-of-function mutations in ANGPTL3 are associated with panhypolipidemia and reduced coronary atherosclerosis. Evinacumab, a fully human monoclonal antibody, inhibits ANGPTL3 and reduces multiple lipoprotein fractions ~50%, including LDL-C. The use of evinacumab within the FH population is described, as well as its regulatory journey to an approved therapeutic. Expert opinion Evinacumab, with its capacity to lower multiple lipoprotein fractions, particularly LDL-C, independently of LDLR function has potential to revolutionize treatment for FH patients. Current FDA-approval is only for homozygous FH (HoFH), arguably the most impactful indication, but use in other lipid disorders is under investigation. Short-term tolerability of evinacumab is very good, with infrequent, mild, and transient adverse events, however, long-term safety data are needed. The high cost and requirement for intravenous administration may limit adoption of evinacumab, but dramatic LDL-C-lowering and need for new therapeutic options for HoFH will drive interest.

Genetic spectrum of familial hypercholesterolemia and correlations with clinical expression: Implications for diagnosis improvement.

Familial hypercholesterolemia (FH) is the most common genetic disease caused by variants in LDLR, APOB, PCSK9 genes; it is characterized by high levels of LDL‐cholesterol and premature cardiovascular disease. We aim to perform a retrospective analysis of a genetically screened population (528 unrelated patients—342 adults and 186 children) to evaluate the biochemical and clinical correlations with the different genetic statuses. Genetic screening was performed by traditional sequencing and some patients were re‐analyzed by next‐generation‐sequencing. Pathogenic variants, mainly missense in the LDLR gene, were identified in 402/528 patients (76.1%), including 4 homozygotes, 17 compound heterozygotes and 1 double heterozygotes. A gradual increase of LDL‐cholesterol was observed from patients without pathogenic variants to patients with a defective variant, to patients with a null variant and to patients with two variants. Six variants accounted for 51% of patients; a large variability of LDL‐cholesterol was observed among patients carrying the same variant. The frequency of pathogenic variants gradually increased from unlikely FH to definite FH, according to the Dutch Lipid Clinic Network criteria. Genetic diagnosis can help prognostic evaluation of FH patients, discriminating between the different genetic statuses or variant types. Clinical suspicion of FH should be considered even if few symptoms are present or if LDL‐cholesterol is only mildly increased.

Screening and treatment of familial hypercholesterolemia in a French sample of ambulatory care patients: A retrospective longitudinal cohort study.

Untreated Familial Hypercholesterolemia (FH) leads to premature morbidity and mortality. In France, its epidemiology and management are understudied in ambulatory care. We described the clinical profile, pharmacological management, and clinical outcomes in a French sample of FH patients. This was a retrospective longitudinal study on patients from The Health Improvement Network (THIN®) database in France, between October 2016-June 2019. Patients ≥18 years, with probable/definite FH based on the Dutch Lipid Clinic Network (DLCN) criteria were included. Baseline characteristics, lipid profile, lipid-lowering therapy (LLT), low-density lipoprotein-cholesterol (LDL-C) goal achievement; and disease management at 6-month of follow-up were analyzed. 116 patients with probable (n = 70)/definite (n = 46) FH were included (mean age:57.8±14.0 years; 56.0% women; 9.5% with personal history of cardiovascular events); 90 patients had data available at follow-up. At baseline, 77.6% of patients had LDL-C>190 mg/dL, 27.6% were not receiving LLTs, 37.9% received statins alone, 20.7% statins with other LLTs, and 7.7% other LLTs. High-intensity statins were prescribed to 11.2% of patients, 30.2% received moderate-intensity statins, and 8.6% low-intensity statins. Only 6.0% of patients achieved LDL-C goal. At 6-month of follow-up, statins discontinuation and switching were 22.7% and 2.3%, respectively. None of the patients received proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors at baseline nor follow-up. Despite the existence of effective LLTs, FH patients are suboptimally-treated, do not achieve LDL-C goal, and exhibit worsened pharmacological management over time. Future studies with longer follow-up periods and assessment of factors affecting LDL-C management, including lifestyle and diet, are needed.

MiRNA target-binding sites as regulators of genes involved in the lipid metabolism might explain the hypercholesterolaemia in FH patients

Background and Aims: Familial hypercholesterolemia (FH) is due to mutations in LDLR, APOB and PCSK9, however, about 50% of clinical FH patients do not have an identifiable genetic cause. MicroRNAs (small non-coding RNAs) are negative regulators of gene expression and creation of new biding sites can be the cause of hypercholesterolaemia in mutation-negative families. The present work aims to analyse miRNAs targets as regulators of genes involved in lipid metabolism in FH patients.

Detection of Familial Hypercholesterolemia through centralized analytical data. HF HUELVA DETECTA Program

BackgroundFamilial Hypercholesterolemia is the most frequent genetic cause of premature coronary heart disease. The delay in the diagnosis prevents the correct early treatment. There are no effective screening strategies at the national level that ensure a correct diagnosis. ObjectiveTo determine the capacity of a centralized laboratory for the diagnosis of Familial Hypercholesterolemia through the creation of a health program for population screening in the province of Huelva. MethodActive search of patients with primary hypercholesterolemia through the blood tests carried out in the reference laboratories with results of low-density lipoprotein cholesterol greater than 200 mg/dl and assessment in the Lipid Unit of Huelva to identify index cases, with subsequent family cascade screening. Results37,440 laboratory tests with lipid profile were examined. After screening, 846 individuals were seen in the Lipid Unit, of which they were diagnosed according to criteria of the Dutch Lipid Clinic Network as possible 654 and probable/definitive 192 individuals, representing 1.74% and 0.51% of the general population examined respectively. ConclusionsThe point prevalence of Familial Hypercholesterolemia in patients submitted to laboratory lipid profile tests was 1:195, higher compared to the prevalence of Familial Hypercholesterolemia in the general population (based on 1 in 200–300). The opportunistic search strategy of the index case through a laboratory alert and centralized screening is an efficient strategy to implement a national screening for the diagnosis of Familial Hypercholesterolemia.

Implication of ESC/EAS 2019 dyslipidemia guidelines for PCSK9 inhibition in patients with familial hypercholesterolemia: An analysis from the Hellas-FH registry

Background and Aims: The ESC/EAS 2019 guidelines for the management of dyslipidemia recommend aggressive LDL-C targets in patients with familial hypercholesterolemia (FH). Intensive hypolipidemic treatment with statin and ezetimibe is often insufficient to achieve these targets. For very-high-risk FH patients (that is, with atherosclerotic cardiovascular disease or with another major risk factor) who do not achieve their goal on a maximum tolerated dose of a statin and ezetimibe, the addition of a PCSK9 inhibitor (PCSK9i) is recommended.

Effect of omega-3 fatty acid supplementation on postprandial arterial elasticity in familial hypercholesterolaemia on statin therapy

Background and Aims: Impaired arterial elasticity may contribute to increased risk of atherosclerotic cardiovascular disease (ASCVD) in patients with familial hypercholesterolaemia (FH) despite statin therapy. This abnormality may be further exacerbated in the postprandial state. Omega-3 fatty acid (ω-3FA) supplementation has been shown to improve arterial elasticity in FH patients in the post-absorptive state. However, its effect on postprandial arterial elasticity has not been investigated.

Event-free FH patients >65 years of age are characterized by higher concentration of large HDL particles

Background and Aims: Familial hypercholesterolemia (FH) is a genetic disorder characterized by lifelong elevated low-density lipoprotein cholesterol (LDL-C) and premature coronary heart disease (CHD). Cholesterol-lowering therapy (statins) reduces CHD risk, but have only been available for the last 25 years, thus, elderly (>65 years) FH patients have been untreated several decades of their life. Surprisingly, some of these have never experienced any CHD event, raising the question whether they present CHD-resistant characteristics. To our knowledge, there are no reports of comprehensive metabolite profiling in these individuals. Therefore, we aimed to characterize metabolic differences between elderly FH subjects with and without CHD.

Functional analysis of LDLR genetic variants identified in hypercholesterolemic patients in BRAZIL, using CRISPR/CAS9

Background and Aims: Introduction: The familial hypercholesterolemia (FH) is one of the main causes of cardiovascular diseases, and it is mainly caused by genetic variants at the low-density lipoprotein receptor (LDLR). Although ultrasequencing technology has allowed the identification of several genetic variants, few of them was functional analyzed. The CRISPR/Cas9 tool promotes precise genetic editing and allows the creation of experimental models, therefore contributing to the functional validation process. Aim: To use the CRISPR/Cas9 tool to perform in vitro functional analysis of LDLR variants identified in FH patients.

In vitro characterization revealed five new potential pathogenic variants in the APOB gene

Background and Aims: Familial hypercholesterolemia (FH) is a disease inherited with a dominant trait, caused by pathogenic variants in the LDLR, APOB, PCSK9 genes. The identification of a pathogenic variant allows to confirm clinical diagnosis and extend genetic screening to the patient’s relatives. According to the guidelines for the interpretation of sequence variants, most of APOB variants remain of uncertain significance. To improve the interpretation of genetic screening, we aim to perform an in vitro characterization of 5 APOB rare variants identified at heterozygous status in FH patients.

Efficacy of hyperlipoproteinemia(a) cascade screening in FH patients

Background and Aims: Familial hypercholesterolemia (FH) is the second most common monogenic cause of inherited lipid metabolism disorders after elevated lipoprotein(a) level [hyperLp(a)]. FH cascade screening is an effective method of diagnosing this disease and is recommended for each index case. The effectiveness of hyperLp(a) cascade screening was still under-researched. The aim of this study was to evaluate the effectiveness of cascade hyperLp(a) screening in patients with FH.

Coronary heart disease probability in familial hypercholesterolemia patients

Background and Aims: Cardiovascular risk assessment in patients with familial hypercholesterolemia (FH) is complicated. Aim: to create the formula for estimating the probability of cardiovascular heart disease (CHD) in FH patients.

Functional characterization of variants in the 5’ UTR and promoter of LDLR gene

Background and Aims: Familial hypercholesterolemia (FH) is the most common genetic disorder conferring an increased cardiovascular risk due to cholesterol accumulation since birth. FH patients have usually mutations in LDLR, APOB or PCSK9 genes, but in about 50% a variant causing disease is not identified. The 5' and 3’ untranslated regions (UTRs) and promoter of these genes is poorly studied. The aim of this project is to perform an in vitro characterization of variants in 5’ UTR and promoter of LDLR gene.

Use of Longitudinal Strain Bull’s-Eye Plot by Speckle Tracking Echocardiography for Evaluation of Homozygous Familial Hypercholesterolemia with Myocardial Ischemia

Background: In recent years, two-dimensional speckle tracking echocardiography (2D-STE) has been increasingly used to detect left ventricular myocardial ischemia with high accuracy for a reliable and comprehensive assessment of myocardial function by myocardial strain analysis. The present study aimed to assess whether the longitudinal strain (LS) bull’s eye plot could accurately detect left ventricular myocardial ischemia in homozygous familial hypercholesterolemia (HoFH) patients. Methods: A total of 28 HoHF patients, who underwent 2D-STE and myocardial perfusion imaging (MPI), were classified into two groups as diagnosed by MPI for myocardial ischemia. The myocardial ischemia score by MPI, LS bull’s-eye plot, and strain parameters were analyzed and compared. Results: Among the 28 HoFH patients, MPI detected 30.77% and 2D-STE showed 30.19% ischemic segments in 13 and 15 HoFH patients with myocardial ischemia, respectively. All segmental LSs in the left anterior descending artery (LAD) perfusion territory were significantly decreased in patients with myocardial ischemia. The diagnostic capability of 2D-STE for myocardial ischemia was 85.29%, 95.34%, and 93.91% for sensitivity, specificity and accuracy, respectively. Conclusion: Left ventricular LS bull’s-eye plot can assist rapid and accurate evaluation of myocardial ischemia in HoFH patients. The myocardial ischemia is mainly distributed in the LAD perfusion territory in these patients.

The relationship between elevated lipoprotein(a) levels and antiatherogenic toll-like receptor genes polymorphism in familial hypercholesterolemia

Background and Aims: It was recently demonstrated that G allele of the rs4986790 polymorphism (Asp299Gly) of TLR4 Gene (AG genotype) has been associated with decreased development of atherosclerosis. The aim of the study was to analyze the relationships between polymorphism of TLR4 Gene and lipid disorders in patients with familial hypercholesterolemia (FH) since it is known that a part of FH patients do not manifest cardiovascular event regardless elevated low density lipoprotein cholesterol (LDL-C) levels.

Variants of candidate genes in familial hypercholestrolaemia patients with premature coronary artery disease

Background and Aims: Familial hypercholesterolaemia (FH) is a genetic disorder that leads to elevation of low-density lipoprotein cholesterol (LDL-C), causing premature coronary artery disease (PCAD). This study aims to investigate FH-causative gene mutations in clinically diagnosed FH patients with PCAD.

Detection of familial hypercholesterolemia in the South of Spain in collaboration wiht the Spanish foundation of familial hypercholesterolemia

Background and Aims: Familial hypercholesterolemia (FH) is a genetic disorder with an autosomal dominant Mendelian inheritance pattern. In its heterozygous form (HeFH) it has a prevalence of 1:250. FH accelerates atherosclerotic disease constituting the genetic disorder most frequently associated with premature coronary artery disease (CPD). The prevalence and high risk of developing DBS make FH a public health problem, although the majority of FH patients are underdiagnosed and undertreated.

MLB-LDLR: A machine learning model for predicting the pathogenicity of LDL receptor missense variants

Background and Aims: Cardiovascular disease (CVD) is the leading cause of death worldwide and is often related to high plasma concentrations of low-density lipoprotein cholesterol (LDL-c). One of the most frequent dyslipidaemias is familial hypercholesterolemia (FH), which is mostly caused by mutations in the LDL receptor (LDLr). Although an early identification is essential to reduce premature mortality, only the 10 % of FH patients are properly diagnosed. In vitro characterization of variants is time consuming and expensive, so computational predictors of pathogenicity of mutations are under constant development.

Treatment with lipoprotein apheresis is associated with significant decrease of biomarkers related to endothelial dysfunction and inflammation not only after each procedure but in the long-term follow-up of up to 15 years, in both HeFH and HoFH patients

Background and Aims: Lipoprotein apheresis (LA) is an add-on therapy for patients with familial hypercholesterolemia (FH). We aimed to analyze the data collected in the last 15 years from FH patients treated with LA, to elucidate the benefit of this procedure with respect to plasma lipids, biomarkers of inflammation, and endothelial dysfunction and soluble endoglin.