Familiar Hypercholesterolemia Research Articles

Familiar Hypercholesterolemia, Overview: A Lethal Hereditary Disorder with Simple Diagnosis and Affordable Treatment.

Familial hypercholesterolemia (FH) is an underdiagnosed disorder characterized by high concentration of low- density lipoprotein (c-LDL) from birth, and if left untreated, causes premature cardiovascular morbidity and mortality. An effective and inexpensive method for detecting FH is to determine c-LDL, and genetic study reveals asymptomatic relatives. The most frequent mutations occur in the LDL receptor gene (RLDL) and the least frequent are in apolipoprotein B100 (ApoB 100), apoprotein convertase subtilisin/kexin 9 (PCSK9) and LDL receptor adaptor 1 (RLDLAP1). Patients with heterozygous FH (HFHe) have c-LDL levels above 190 mg/dL; homozygous patients (HFHo) have the most severe form, with c-LDL above 500 mg/dL. Treatment is a low-fat diet and lipid-lowering drugs, mainly statins in combination with cholesterol absorption inhibitors (ezetimibe). In HFHo or severe heterozygotes resistant to treatment, the use of anti-PCSK9 monoclonal antibodies and c-LDL apheresis is considered, however, this is not available in countries such as Mexico. Even the lack of governmental programs for the systematic detection of FH is frequent. Therefore, this panoramic review shows the generalities, genetic basis, diagnosis, clinical characteristics, and treatment of FH, with the purpose of informing and calling the attention of health professionals, legislators, and the population at large.

Refinement of the diagnostic approach for the identification of children and adolescents affected by familial hypercholesterolemia: Evidence from the LIPIGEN study

Background and aimsWe aimed to describe the limitations of familiar hypercholesterolemia (FH) diagnosis in childhood based on the presence of the typical features of FH, such as physical sings of cholesterol accumulation and personal or family history of premature cardiovascular disease or hypercholesterolemia, comparing their prevalence in the adult and paediatric FH population, and to illustrate how additional information can lead to a more effective diagnosis of FH at a younger age. MethodsFrom the Italian LIPIGEN cohort, we selected 1188 (≥18 years) and 708 (<18 years) genetically-confirmed heterozygous FH, with no missing personal FH features. The prevalence of personal and familial FH features was compared between the two groups. For a sub-group of the paediatric cohort (N = 374), data about premature coronary heart disease (CHD) in second-degree family members were also included in the evaluation. ResultsThe lower prevalence of typical FH features in children/adolescents vs adults was confirmed: the prevalence of tendon xanthoma was 2.1% vs 13.1%, and arcus cornealis was present in 1.6% vs 11.2% of the cohorts, respectively. No children presented clinical history of premature CHD or cerebral/peripheral vascular disease compared to 8.8% and 5.6% of adults, respectively. The prevalence of premature CHD in first-degree relatives was significantly higher in adults compared to children/adolescents (38.9% vs 19.7%). In the sub-cohort analysis, a premature CHD event in parents was reported in 63 out of 374 subjects (16.8%), but the percentage increased to 54.0% extending the evaluation also to second-degree relatives. ConclusionsIn children, the typical FH features are clearly less informative than in adults. A more thorough data collection, adding information about second-degree relatives, could improve the diagnosis of FH at younger age.

Atrial Fibrillation Outcome in Patients with Familiar Hypercholesterolemia

Atrial Fibrillation Outcome in Patients with Familiar Hypercholesterolemia

Abstract P596: Familiar Hypercholesterolemia is Associated With Lower All-Cause Mortality Despite Higher Complexity of Coronary Lesions and Interventions Among Patients Admitted With Acute Myocardial Infarction

Background: Familiar hypercholesterolemia is a genetic disorder affecting lipoprotein metabolism which is strongly associated with early atherosclerosis. Our resolve in this study is to evaluate the severity of coronary lesions ,complexity of acute interventions and clinical outcomes. Hypothesis: Patients with familiar hypercholesterolemia are relatively younger, have high coronary atheroma burden with less comorbidities, thus likely to have complex atherosclerosis but with paradoxical better prognosis. Method: A retrospective cohort study with data from the 2016 to 2018 combined National Inpatient Sample (NIS) database was employed. ICD-10 codes were used to sample all admissions for acute myocardial infarction who were then dichotomized based secondary diagnosis of familiar hypercholesterolemia. Procedure codes of ICD-10 were used to identify patients undergoing coronary revascularizations. We determined relative frequencies of various ischemic injury patterns and complexity of revascularization procedures among the two cohorts. Primary clinical outcome of mortality rate, and secondary outcomes including length of stay and total hospital charge were then assessed. Multivariate linear and logistic regressions were used to adjust for confounders. Results: We identified a total of 4,300,389 adult hospitalizations for acute myocardial infarction including 0.033% with familiar hypercholesterolemia. Patients with familiar hypercholesterolemia were younger (55.8 years vs 58.2 years, adjusted mean difference: -7.87 years, 95%CI: -9.49 years to -6.0 years). Table 1 below shows details of outcomes of our study. Conclusion: Among patients hospitalized with acute myocardial infarction, comorbid familiar hypercholesterolemia was associated with a 62% reduction in odds of in-hospital all-cause mortality despite a 2.25-fold increased odds of STEMI and higher odds for having multivessel percutaneous. revascularization.

APO E mutations as a cause of familiar hypercholesterolemia in North-East Moravia region

Background and Aims : Familiar hypercholesterolemia (FH) is a collective term for a set of genetically linked diseases that cause increased plasma LDL-C levels by various mechanisms, thereby increasing an individual's cardiovascular risk. FH is most frequently caused by one of the three following mechanisms: the absence or reduction of the number and thereby decreased function of LDL-receptors, the defect in apolipoprotein B or increased function of the PCSK9 enzyme.We recently encountered a remarkable occurrence of patients with mutations in Apo E lipoprotein.

Increased Lp(a) levels in a Caribbean family. Case report and literature review

Background and Aims : Lipoprotein (a) (Lp(a)) is a macromolecule synthesized by the liver, whose serum levels are determined genetically by the LPA gene (1-4). It’s associated with increased atherosclerotic risk (1, 2) when levels rise above 50 mg/dl independently of ethnicity (5). The cardiovascular risk (CVR) related to Lp(a) are associated with LDL-C. In patients with familiar hypercholesterolemia, the elevation of Lp(a) increase the risk of cardiovascular event at an early age (6,7). Levels above 180 mg/dl of Lp(a) are considered very high-risk patients (8).

Comparison of Evolocumab and Ezetimibe, Both Combined with Statin Therapy, for Patients with Recent Acute Coronary Syndrome: A Cost-Effectiveness Analysis from the Chinese Healthcare Perspective.

To assess the cost-effectiveness of evolocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, compared with ezetimibe, both added to background statin therapy in patients with recent acute coronary syndrome (ACS) events (in the past 12 months) and low-density lipoprotein cholesterol (LDL-C) levels ≥ 100 mg/dL in China. A health economic evaluation was performed from a Chinese healthcare perspective, using a Markov model over a lifetime horizon based on a baseline cardiovascular (CV) event rate from claims database data and efficacy from the FOURIER trial. The health benefit was reflected in the decrease of LDL-C level, which led to a decrease of cardiovascular events. The costs of cardiovascular events and the utility value of each health state were derived from the published literature. Sensitivity analyses were conducted to evaluate the effects of uncertainty in parameters and the robustness of the model. The cost-effectiveness of evolocumab was also explored in patients with recent myocardial infarction (MI), at very high risk (VHR) of atherosclerotic cardiovascular disease (ASCVD), and homozygous familiar hypercholesterolemia (HoFH). In patients with recent ACS, evolocumab was associated with incremental quality-adjusted life-years (QALYs) of 1.33 and incremental costs of 115,782 yuan versus ezetimibe, both with background statin therapy, resulting in an incremental cost-effectiveness ratio (ICER) of 87,050 yuan per QALY gained. The probability of evolocumab + statins being cost-effective at a threshold of 217,341 yuan (three times per capita GDP, 2020), compared with ezetimibe + statins, was 100% in patients with recent ACS, recent MI, VHR ASCVD, and HoFH. Compared with ezetimibe + statins, the combination of evolocumab + statins was found to be cost-effective at a threshold of 217,341 yuan (three times per capita GDP, 2020) in patients with recent ACS events in China.

Homozygous familiar hypercholesterolemia: still a long way to go

Homozygous familiar hypercholesterolemia (HoFH) is a rare condition characterised by very high levels of low-density lipoprotein cholesterol from birth and an extremely high risk of premature atherosclerotic cardiovascular disease (ACVD).1 Two pathogenic allelic variants at the LDLR, APOB, PCSK9, or LDLRAP1 gene loci are responsible for the disease.2 HoFH is a natural model showing the causal association between LDL cholesterol and ACVD, with cases of coronary disease described in childhood.3 Despite advances in the diagnosis and treatment of hypercholesterolemia in recent years, HoFH continues to be a disease with a low recognition rate in most countries, poor prognosis, low quality of life and life expectancy, and a high cost for health systems.

Variation in Child Serum Cholesterol and Prevalence of Familiar Hypercholesterolemia: The Health Oriented Pedagogical Project (HOPP).

Early stages of atherosclerosis may develop in childhood due to hyperlipidemia. The aims are to investigate the prevalence of familiar hypercholesterolemia in 6 to 12-year-old children and to study the deviation in cholesterol measures. Anthropometric data and venous blood were collected from children participating in the Health Oriented Pedagogical Project (HOPP). Out of 18 children with TC > 6.0 mmol/L, 15 were tested genetically and none diagnosed with FH. The prevalence of TC > 6.0 mmol/L declined from 1.3% in 2015 to 0.5% in 2016. The mean TC was 4.30 mmol/L both years, which is lower than in earlier studies. Usage of a single TC measurement and a threshold of TC > 6.0 mmol/L in screening children for FH, may not be a good screening strategy. While lipid values have a good reliability across 2 measurements, there are variations in individual TC levels across 1 year.

Proprotein Convertase Subtilisin/Kexin-Type 9 and Lipid Metabolism.

Plasma levels of cholesterol, especially low-density lipoprotein cholesterol (LDL-C), are positively correlated with the risk of cardiovascular disease. Buildup of LDL in the intima promotes the formation of foam cells and consequently initiates atherosclerosis, one of the main underlying causes of cardiovascular disease. Hepatic LDL receptor (LDLR) is mainly responsible for the clearance of plasma LDL. Mutations in LDLR cause familiar hypercholesterolemia and increase the risk of premature coronary heart disease. Proprotein convertase subtilisin/kexin-type 9 (PCSK9) promotes LDLR degradation and thereby plays a critical role in the regulation of plasma cholesterol metabolism. PCSK9 can bind to LDLR and reroute the receptor to lysosomes for degradation, increasing both circulating LDL-C levels and the risk of cardiovascular disease. PCSK9 is mainly regulated by sterol response element binding protein 2 (SREBP2) at the transcriptional level. Furthermore, many proteins have been identified as interacting with PCSK9, regulating plasma cholesterol levels. Pharmacotherapeutic inhibition of PCSK9 dramatically reduces plasma levels of LDL cholesterol and significantly reduces cardiovascular events. In this article, we summarize the latest advances in PCSK9, mainly focusing on the structure, function, and regulation of the protein, the underlying molecular mechanisms, and its pharmacotherapeutic applications.

P818Incidence of coronary heart disease in patients with familiar hypercholesterolemia compared to age- and sex- matched controls

Abstract Background Familial hypercholesterolemia (FH) is caused by mutations leading to high levels of low-density lipoprotein cholesterol (LDL-C) in the blood. The primary aim was to describe mutations in a large sample of individuals with FH, and compare risk of first-time hospitalization for coronary heart disease (CHD) and acute myocardial infarction (AMI) between FH mutation carriers and healthy controls. The secondary aim was to compare risk of death and re-hospitalization among FH mutation carriers and controls with a first event of CHD and AMI. Methods This study is a prospective matched cohort study comprising a sample of 5691 persons with FH and 119 511 age- and sex- matched controls randomly selected from the general Norwegian population. Information on CHD and AMI were obtained from Norwegian Patient Registry, the Cardiovascular Disease in Norway project and the Norwegian Cause of Death Registry. Endpoints are defined according to the International Classification of Diseases, version 9 (ICD9) or version 10 (ICD10). Risk among persons with FH will be compared to healthy controls in terms of hazard ratios (HR) from Cox regression with follow-up time calculated from time of FH-diagnosis for the person with FH in each matched set. Results In total 51.8% (n=61866) of the combined sample were women with mean age 49.0±20.3 years, whereas 48.2% (n=57645) were men with mean age 46.8±19.6 years. There were 236 different FH mutations registered among the FH mutation carriers. The most frequent mutation was 313+1g&gt;A, that accounted for 20.7% (n=1178) of the total, followed by C210G with 12.1% (n=690). Results for incidence of CHD, AMI, and mortality after CHD and AMI and readmission rates are not yet available but will be presented at the conference. Acknowledgement/Funding The study is funded by South-Eastern Norway Regional Health Authority

Prognostic value of exercise tolerance test for predicting cardiovascular disease in asymptomatic individuals with heterozygous familiar hypercholesterolemia.

Heterozygous familiar hypercholesterolemia (hFH) is an autosomal dominant inherited dyslipidemia, associated with premature cardiovascular disease (CVD). Aim of the study was to define prognostic factors for cardiovascular events (CVE) in asymptomatic individuals with hFH. All participants with recent diagnosis of hFH were recruited from the outpatient lipid clinic from 1987 to 2016, without any previous clinical evidence of CVD. A detailed clinical evaluation and laboratory investigation was obtained. Exercise tolerance test (ETT) was performed until maximum exercise capacity was achieved, without evidence of ischemia. Primary endpoint of the study was the first CVE. Four hundred fifty one participants were followed up for 10 ± 8years, with 68 recorded cases of CVD (15%). Cumulative incidence of CVD was 15%, 24% and 32% for the 3 decades, respectively. In univariate analysis, male gender (p = 0.016), progression of age (p < 0.001), menopause (p = 0.030), waist-hip ratio (p = 0.043) and increased levels of Lp(α) (p = 0.014) were significantly associated with increased CVD incidence; whereas, exercise capacity (p = 0.025), low variation of heart rate (HR) during all stages of ETT compared to resting state (p = 0.020), maximum systolic (p = 0.014) and diastolic (p < 0.001) blood pressure were inversely associated with CVD. In multi-adjusted analysis, male gender (p < 0.001), duration of ETT (p = 0.023), estimated HR (p = 0.029), variation of HR during ETT compared to resting state (p < 0.05) and maximum diastolic pressure (p = 0.044) were significantly associated with CVD. Parameters of ETT in asymptomatic individuals with hFH, without any evidence of ischemia, may predict CVD in these high-risk patients after decades of observation.

PCSK9 Inhibition: New Treatment Options and Perspectives to Lower Atherogenic Lipoprotein Particles and Cardiovascular Risk.

To summarize latest clinical studies and to put them into perspectives for clinical relevant subgroups and new therapeutic options. Have investigated PCSK9 inhibitors in patients with very high cardiovascular risk and insufficient LDL cholesterol lowering under current maximal tolerated lipid-lowering therapy, patients with statin intolerance, or genetic forms of familiar hypercholesterolemia, and patients on LDL apheresis. Purpose of recent cardiovascular endpoint trials has proven cardiovascular benefit of this new approach. PCSK9 inhibition with fully humanized antibodies has proven to be effective, safe, and well-tolerated in reducing cardiovascular risk by LDL cholesterol lowering. Therefore, research interests are to elucidate additional roles and effects of PCSK9 modulation on inflammation and cellular processes of the atherosclerotic plaque and to develop alternative therapeutic strategies addressing PCSK9 as a proven and therefore promising drug target.

The Study of rs693 and rs515135 in APOB in People with Familial Hypercholestrolemia.

Objective APOB-related familial hypercholesterolemia (FH) is the most common hereditary hyperchlosterolemia with an autosomal dominant pattern. A number of APOB variants are the most important risk factors for hyperchlosterolemia. APOB is a large glycoprotein that plays an important role in the metabolism of lipoproteins in the human body. Small changes in the structure and function of APOB can cause major problems in lipid metabolism. Two forms of APOB are produced by an editing process of gene replication. APOB48 is required for the production of chylomicrons in the small intestine and APOB100 is essential in liver for the production of very low density lipoprotein (VLDL) and is also a ligand for LDL receptor (LDLR) that mediates LDL endocytosis. Materials and Methods In this case-control study, rs693 (in exon 26 of APOB) and rs515135 (5 'end of APOB) single nucleotide polymorphisms (SNPs) were analyzed in 120 cases of familial hypercholesterolemia and 120 controls. Both SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) where PCR products were digested with specific restriction enzymes recognising each single nucleotide polymorphism. Results This study was analyzed by odds-ratio (OR) and its 95% confidence interval (CI) to examine the association of the two SNPs with familial hypercholostermia susceptibility. Statistical analysis showed that both SNPs were in Hardy- Weinberg equilibrium. ConclusionWe found no significant relationship between rs515135 and familiar hypercholesterolemia. However, there was a significant association between the C allele of rs693 and high familial cholesterol levels. Furthermore, it seems the dominant model of T allele occurrence has a protective role in emergence of disease.

The prevalence of familiar hypercholesterolemia in patients of Lodz hospital and their treatment analysis

The prevalence of familiar hypercholesterolemia in patients of Lodz hospital and their treatment analysis

A novel gene, cilia flagella associated protein 44, encoding an enzyme cleaving FtsZ and tubulin contributes to the regulation of secretory pathway

We identified a novel gene, encoding the central region of the cilia and flagella associated protein 44 (Cfap44), that regulates trafficking of cellular components and morphology via the cleavage of cellular proteins (particularly β-tubulin). Although Cfap44 is registered in GenBank, the functions of both the central part and full-length protein are unknown except for a polymorphism associated with proprotein convertase 9 activity, the third gene of familiar hyper-cholesterolemia. In mice and humans, both unspliced and spliced RNAs were transcribed, and the spliced form was predominantly transcribed in the brain and embryonic tissues. In transfectants carrying this gene, various cellular processes such as cell division, transport of cellular components, and proteolytic processing of several proteins were found to be affected. The cleavage of β-tubulin was observed. A bacterial tubulin homolog, cell division protein FtsZ, was also cleaved in vivo and in vitro by the spliced form of Cfap44 product. Furthermore, the unspliced form showed proteolytic activity with low substrate specificity. Various biological activities of Cfap44 may be due to a direct effect of cleavage of β-tubulin inhibiting microtubule formation, or an indirect effect with the cross-recognition of the cleavage site between β-tubulin and other molecules.

LDL cholesterol and familial hypercholesterolemia in children. Significance of familial history in detecting familial hypercholesterolemia

Aim: Determine the percentage of children with LDL cholesterol values (LDL-C) (>4mmol/l) where familiar hypercholesterolemia ( FH) is suspected, and (>5mmol/l) where diagnosis is recommended to be confirmed, in relation to family history, with previously excluded secondary causes of high LDL-C.

P3439Erectile dysfunction and risk of adverse cardiovascular events in males with familiar hypercholesterolemia and familiar combined hyperlipidemia

P3439Erectile dysfunction and risk of adverse cardiovascular events in males with familiar hypercholesterolemia and familiar combined hyperlipidemia

The incidence of familiar hypercholesterolemia in patients of the cardiology and internal diseases department in a Lodz hospital and their treatment analysis

Aim: To establish a database of patients with FH to provide the adequate prevention and treatment of cardiovascular disease.

P5315Statin therapy and risk of diabetes mellitus in elderly patients with heterozygous familiar hypercholesterolemia or familiar combined hyperlipidemia: A 10-year follow-up

P5315Statin therapy and risk of diabetes mellitus in elderly patients with heterozygous familiar hypercholesterolemia or familiar combined hyperlipidemia: A 10-year follow-up