Treatment Of Familial Hypercholesterolemia Research Articles

Canadian Cardiovascular Society Position Statement on Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is the most common genetic disorder causing premature cardiovascular disease and death. Heterozygous FH conservatively affects approximately 1:500 Canadians, and the more serious homozygous form affects approximately 1:1,000,000 Canadians, although these numbers might be underestimated. Of approximately 83,500 Canadians estimated to have FH, most are undiagnosed, which represents a simultaneous public health deficit and opportunity, because early treatment of heterozygous FH can normalize life expectancy. Diagnostic algorithms for FH incorporate increased plasma low-density lipoprotein cholesterol, pathognomonic clinical features, and family history of early cardiovascular disease and hyperlipidemia. DNA-based detection of causative mutations in FH-related genes can help with diagnosis. Maximizing diagnosis and treatment of FH in Canada will involve a multipronged approach, including: (1) increasing awareness of FH among health care providers and patients; (2) creating a national registry for FH individuals; (3) setting standards for screening, including cascade screening in affected families; (4) ensuring availability of standard-of-care therapies, in particular optimization of plasma low-density lipoprotein cholesterol levels and timely access to future validated therapies; (5) promoting patient-based support and advocacy groups; and (6) forming alliances with international colleagues, resources, and initiatives that focus on FH. This document aims to raise awareness of FH nationally, and to mobilize knowledge translation, patient support, and availability of treatment and health care resources for this underrecognized, but important medical condition.

Significant gaps in awareness of familial hypercholesterolemia among physicians in selected Asia-Pacific countries: a pilot study.

Familial hypercholesterolemia (FH) is a dominantly inherited disorder characterized by high plasma cholesterol levels and a very high risk of early heart disease. The prevalence of FH is estimated to be at least 1:500, with at least 3.6 million individuals in the Asia-Pacific region. To assess awareness, knowledge, and perception of FH among practicing physicians in Japan, South Korea, and Taiwan. Physicians from 3 economically developed Asian countries were requested to anonymously complete a structured Internet-based survey regarding FH. This survey sought responses on the clinical description, inheritance, prevalence, cardiovascular disease risk, practices, and opinions on screening. Of 230 physicians surveyed, 47% were aware of the heritability, 27% of the prevalence, and 13% of the risk of cardiovascular disease relating to FH. The majority (70%) perceived themselves to have an above-moderate familiarity with FH. Primary care physicians (59%) and lipid specialists (41%) were perceived as the best providers for caring for FH, including cascade screening services, with a lesser role perceived for cardiologists, endocrinologists, and no significant role for nursing staff. Only 35% of physicians were aware of specialist clinical services for lipid disorders in their geographic area. Extensive education and training programs are required to complement the implementation of region-specific models of care for FH in Asia. Further enhancement of existing lipid services and facilities are also warranted to optimise service models.

Diagnóstico y tratamiento de la hipercolesterolemia familiar en España: documento de consenso

Familial hypercholesterolemia (FH) is a common genetic disorder, clinically manifested since birth, and associated with very high levels of plasma LDL-cholesterol (LDL-c), xanthomas, and premature coronary heart disease. Its early detection and treatment reduces coronary morbidity and mortality. Despite effective treatment being available, FH is under-diagnosed and under-treated. Identification of index cases and cascade screening using LDL-c levels and genetic testing are the most cost-effective strategies for detecting new cases and starting early treatment. Long-term treatment with statins has decreased the vascular risk to the levels of the general population. LDL-c targets are <130mg/dL for children and young adults, <100mg/dL for adults, and <70mg/dL for adults with known coronary heart disease or diabetes. Most patients do not to reach these goals, and combined treatments with ezetimibe or other drugs may be necessary. When the goals are not achieved with the maximum tolerated drug treatment, a reduction ≥50% in LDL-c levels can be acceptable. Lipoprotein apheresis can be useful in homozygous, and in treatment-resistant severe heterozygous, cases. This Consensus Paper gives recommendations on the diagnosis, screening, and treatment of FH in children and adults, and specific advice to specialists and general practitioners with the objective of improving the clinical management of these patients, in order to reduce the high burden of coronary heart disease.

Diagnóstico y tratamiento de la hipercolesterolemia familiar en España: documento de consenso

Familial hypercholesterolemia (FH) is a common genetic disorder, clinically manifested since birth, and associated with very high levels of plasma LDL-cholesterol (LDL-c), xanthomas, and premature coronary heart disease. Its early detection and treatment reduces coronary morbidity and mortality. Despite effective treatment being available, FH is under-diagnosed and under-treated. Identification of index cases and cascade screening using LDL-c levels and genetic testing are the most cost-effective strategies for detecting new cases and starting early treatment. Long-term treatment with statins has decreased the vascular risk to the levels of the general population. LDL-c targets are <130mg/dL for children and young adults, <100mg/dL for adults, and <70mg/dL for adults with known coronary heart disease or diabetes. Most patients do not to reach these goals, and combined treatments with ezetimibe or other drugs may be necessary. When the goals are not achieved with the maximum tolerated drug treatment, a reduction ≥50% in LDL-c levels can be acceptable. Lipoprotein apheresis can be useful in homozygous, and in treatment-resistant severe heterozygous, cases. This Consensus Paper gives recommendations on the diagnosis, screening, and treatment of FH in children and adults, and specific advice to specialists and general practitioners with the objective of improving the clinical management of these patients, in order to reduce the high burden of coronary heart disease.

Management of familial hypercholesterolemia in children and adolescents. Position paper of the Polish Lipid Expert Forum

Familial hypercholesterolemia (FH) affects on average 1 in 500 individuals in European countries, and it is estimated that FH in Poland may affect more than 80,000 people. However, in Poland, only about 20% of the population is estimated to have been diagnosed with FH, of which only a small number receive adequate treatment. FH results in more rapid development of atherosclerosis and is associated with a high risk of cardiovascular events. Atherosclerosis develops beginning in childhood in patients with FH and reaches advanced stages before clinical manifestations develop. Inadequate diagnostics and treatment of FH in Polish children suggests a need for raising the level of awareness and understanding of the condition in both society and among health professionals. These recommendations present the current epidemiological status, guidelines for diagnosing FH in Polish children and adolescents, and effective treatment options.

Gene expression analysis of familial hypercholesterolemia

Familial hypercholesterolemia (FH) is a common cause of a variety of cardiovascular diseases. The aim of this study was to uncover the underlying mechanism of FH and provide a possible treatment project for FH. We tried to identify the differently expressed genes (DEGs) involved in FH by comparing the gene expression profiles between FH and normal cells. We performed GO and biological pathway analysis of differently expressed genes with DAVID. We searched for candidates for FH treatment by analyzing DEGs between normal cells and FH cells and compared the differences with the DEGs caused by the small interfering molecules in The Connectivity Map (CMap). Using a bioinformatics method, we identified the abnormal metabolic processes in the cells of FH patients, including cell adhesion, material transport, signal transduction and gene expression, and found that the small molecule trazodone could be a potential drug in restoring the dysregulated metabolic pathway. In conclusion, candidates for further evaluation as possible therapeutic agents for FH have been identified using bioinformatics analysis of differentially expressed genes. Phenotype targeting using genomic profiling is a rational approach to drug discovery, which provides a new guideline in treatment of FH and a potential new clinical drug for FH patients.

Usefulness of lipid apheresis in the treatment of familial hypercholesterolemia.

Lipid apheresis is used to treat patients with severe hyperlipidemia by reducing low-density lipoprotein cholesterol (LDL-C). This study examines the effect of apheresis on the lipid panel and cardiac event rates before and after apheresis. An electronic health record screen of ambulatory patients identified 11 active patients undergoing lipid apheresis with 10/11 carrying a diagnosis of FH. Baseline demographics, pre- and postapheresis lipid levels, highest recorded LDL-C, cardiac events, current medications, and first apheresis treatment were recorded. Patients completed a questionnaire and self-reported risk factors and interest in alternative treatment. There were significant reductions in mean total cholesterol (−58.4%), LDL-C (−71.9%), triglycerides (−51%), high-density lipoprotein (HDL) cholesterol (−9.3%), and non-HDL (−68.2%) values. Thirty-four cardiac events were documented in 8 patients before apheresis, compared with 9 events in 5 patients after apheresis. Our survey showed a high prevalence of statin intolerance (64%), with the majority (90%) of participants indicating an interest in alternative treatment options. Our results have shown that lipid apheresis primary effect is a marked reduction in LDL-C cholesterol levels and may reduce the recurrence of cardiac events. Apheresis should be compared to the newer alternative treatment modalities in a randomized fashion due to patient interest in alternative options.

Эффективность и безопасность Мертенила (розувастатина) 40 мг/сут у пациентов с семейной гиперхолестеринемией

Familial hypercholesterolemia (FH) is an inherited disease that results in high levels of total cholesterol, causing the risk of early ischemic heart disease (IHD). Rosuvastatin is the high-potency hypolipidemic agent of HMG-CoA reductase inhibitors which is approved for clinical use.The goal of our research is to study efficacy, safety Mertenil (rosuvastatin) acceptability of maximal course dose of 40 mg in patients with phenotypic FH. Materials and methods. The 16-week open study was prospective. The study included 40 men and women at the age of 18 years and older with phenotypic FH. 18 patients had the Arg3500Gln mutation in APOB100 gene. Men accounted for 40% of total number of patients. The average age of patients was 55,9 years and average LDL cholesterol (LDL-c) level was 7,2 (1,2) mmol/l. Patients did not accept statins before the inclusion in this study (for a period no less than 3 months).Results. Rosuvastatin40 mg monotherapy 16 weeks study contributed to decrease LDL-c by 50% (p<0,001) and ApoB-100 by 45,1% (p<0,001), TG by 20,1% (p<0,01). Aspartate aminotransferase, alanintransferase and creatinekinase activity were not statistically significant from the base values and were not exceed 1,5 superior normal limit after 16-weeks study. Through 16 weeks of therapy the identified reduction of hsCRP and uric acid were observed (p<0,05). Side-effects were not observed throughout the period of treatment.Conclusion. Therapy of Mertenil (rosuvastatin) 40 mgis available and effective in treatment of heterozygous FH.

Current Treatment of Familial Hypercholesterolaemia.

Familial hypercholesterolaemia is an autosomal-dominant disorder associated with mutations in the LDL receptor gene resulting in markedly elevated plasma low-density lipoprotein cholesterol levels. FH is significantly underrecognised with as many as 1 in 300 having the heterozygous form and 1 in 1 million having the homozygous form of the disease. Early diagnosis and treatment of FH is paramount to reduce the risk of premature atherosclerotic cardiovascular disease and death. The goal of treatment is to reduce LDL-C by 50 % from baseline levels with lifestyle modification, pharmacologic lipid-lowering therapy, LDL apheresis and in rare cases, liver transplantation. Pharmacologic treatment ranges from statin medications to newer agents such as lomitapide, mipomersin and PCSK9 inhibitors. Combination therapy is frequently required to achieve goal lipoprotein level reductions and prevent complications.

Probucol Suppresses Macrophage Infiltration and MMP Expression in Atherosclerotic Plaques of WHHL Rabbits

Probucol is a lipid-lowering drug that is often prescribed for the treatment of familial hypercholesterolemia. However, it is not known whether probucol can change the lesion quality of atherosclerosis. We examined this possibility using WHHL rabbits, a model of human familial hypercholesterolemia. Three-month-old male WHHL rabbits were treated with either probucol(85 mg/kg/day) or atorvastatin(6 mg/kg/day) for 16 weeks, and their plasma lipid levels and atherosclerotic lesions were compared with those of a control group. We found that probucol treatment reduced the plasma cholesterol levels, but less remarkably than atorvastatin treatment. In spite of this, probucol treatment led to a prominent reduction of aortic en face lesions by 39%(P＜0.01), whereas atorvastatin reduced these by 16%(P＞0.05), compared with those in the control. Histological examinations revealed that the aortic lesions of probucol-treated rabbits were characterized by reduced macrophages and increased smooth muscle cells compared with those from both the control and atorvastatin groups. Furthermore, probucol treatment reduced the coronary artery stenosis and increased the plaque stability. These results suggest that probucol treatment may have beneficial effects on the plaque stability of hypercholesterolemic patients.

Rationale and design of the familial hypercholesterolemia foundation CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia registry

Familial hypercholesterolemia (FH) is a hereditary condition caused by various genetic mutations that lead to significantly elevated low-density lipoprotein cholesterol levels and resulting in a 20-fold increased lifetime risk for premature cardiovascular disease. Although its prevalence in the United States is 1 in 300 to 500 individuals, <10% of FH patients are formally diagnosed, and many are not appropriately treated. Contemporary data are needed to more fully characterize FH disease prevalence, treatment strategies, and patient experiences in the United States. The Familial Hypercholesterolemia Foundation (a patient-led nonprofit organization) has established the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE FH) Registry as a national, multicenter initiative to identify US FH patients, track their treatment, and clinical and patient-reported outcomes over time. The CASCADE FH will use multiple enrollment strategies to maximize identification of FH patients. Electronic health record screening of health care systems will provide an efficient mechanism to identify undiagnosed patients. A group of specialized lipid clinics will enter baseline and annual follow-up data on demographics, laboratory values, treatment, and clinical events. Patients meeting prespecified low-density lipoprotein or total cholesterol criteria suspicious for FH will have the opportunity to self-enroll in an online patient portal with information collected directly from patients semiannually. Registry patients will be provided information on cascade screening and will complete an online pedigree to assist with notification of family members. The Familial Hypercholesterolemia Foundation CASCADE FH Registry represents a novel research paradigm to address gaps in knowledge and barriers to comprehensive FH screening, identification, and treatment.

Recent Developments in the Treatment of Familial Hypercholesterolemia: A Review of Several New Drug Classes

Familial hypercholesterolemia is a genetic disorder of the low-density lipoprotein cholesterol (LDL-c) receptor leading to severe elevations in plasma levels of LDL-c which results in premature atherosclerosis and cardiovascular events. Statins, ezetimibe, and bile acid sequestrants significantly lower LDL-c levels in these patients and subsequently markedly improve survival; however, even with these interventions LDL-c goals often are not met. Several new drug classes are in development and have the potential to make reaching these cholesterol goals easier. In this article we review the most recent trials of several classes of drugs with the potential to change the future of familial hypercholesterolemia management: microsomal triglyceride transfer protein (MTP) inhibitors, apolipoprotein B synthesis inhibitors (mipomersen), cholesterol ester transfer protein (CETP) inhibitors and inhibitors of pro-protein convertase subtilisin/kexin 9 (PCSK9). Each class has shown promise with regard to their effects on the lipid profile. However, the potential side-effects of each drug are also being determined and have limited the development of certain agents. Therefore, the long-term effects of these drug classes, both in terms of side-effects and their effect on clinical outcomes such as cardiovascular events and mortality, continue to be determined.

Diffuse giant tendon xanthomas in a patient with familial hypercholesterolaemia : case report

Familial hypercholesterolaemia is a genetic disease that provides the best evidence for the causal role of low-density lipoprotein cholesterol in human atherosclerosis. The disease was first described by Muller in 1939 and is characterised by high cholesterol levels from birth, and the subsequent development of tendon and cutaneous xanthomas and premature atherosclerosis. In this case report, we described an 18-yearold female patient who was admitted to the out-patient clinic with swellings on various parts of her body. Her family history, physical examination and laboratory evaluation revealed that these swellings were giant tendon xanthomas caused by familial hypercholesterolaemia. In this report we also discuss the pathogenesis, clinical manifestations, complications and treatment of familial hypercholesterolaemia.

Lipoprotein apheresis for the treatment of familial hypercholesterolemia

Lipoprotein apheresis involves the extracorporeal removal of LDL and lipoprotein(a) particles from whole blood or plasma by adsorption, precipitation or differential filtration. Used repetitively, this provides a safe and effective means of treating patients at high risk of premature cardiovascular mortality and morbidity from genetically determined increases in these atherogenic lipoproteins that are refractory to conventional therapy. Although evidence of benefit is based mainly on nonrandomized data, the procedure is widely accepted as first-line therapy for homozygous familial hypercholesterolemia and is increasingly used to treat patients with cardiovascular disease due to statin-refractory heterozygous familial hypercholesterolemia or raised levels of lipoprotein(a). However, randomized clinical trial data are required before the last of these indications can be regarded as evidence based.

Novel Drug Approaches in Development for the Treatment of Lipid Disorders

Lipid-lowering drug therapy with statins has become a cornerstone to reduce and prevent atherosclerosis and its detrimental complications like cardiovascular diseases and stroke. Due to the multifactorial pathogenesis of atherosclerosis the search for novel lipid-modifying drugs is still one of the most active areas in research and development in the pharmaceutical industry. Currently, the focus lies on novel LDL-cholesterol lowering drugs with a higher efficacy and improved safety profile as well as on approaches to increase plasma levels and functionality of high-density lipoproteins (HDL) based on the inverse relationship between high plasma HDL-levels and the risk for cardiovascular diseases. Whereas the today clinically used lipid-modifying drugs are predominantly small molecules for oral drug therapy a significant percentage of the drug candidates currently in development are biological drugs such as monoclonal antibodies and antisense oligonucleotides. Up-to-date around 70 novel drug molecules acting on about 20 different molecular targets are in clinical and preclinical development with antibodies inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) being the most intensively investigated and competitive approach. The clinical results reported so far with these antibodies are very promising whereas the clinical benefit for prevention of atherosclerosis and cardiovascular diseases by pharmacologically increasing of plasma high-density lipoproteins still remains to be demonstrated. However, with the recent approval of 2 innovative drugs for the treatment of familial hypercholesterolemia and the promising clinical results of several novel drug candidates for LDL cholesterol lowering and high-density lipoprotein modulation one can expect the appearance of new drug breakthroughs for the treatment of dyslipidemia in the near future.

Consenso de expertos sobre la detección y el manejo clínico de la hipercolesterolemia familiar

Familial hypercholesterolemia (FH) is one of the most common and severe genetic diseases, causing disabilities and premature death to those who suffer it. Lipid-lowering therapy substantially improves the prognosis of FH patients and, therefore, appropriate pharmacological treatment is of the utmost importance. The Spanish Society of Arteriosclerosis (SEA) has always been a pioneer in the diagnosis and treatment of FH. Since its inception, FH has been one of the main areas of clinical and scientific interest, mainly for Lipids Units of the SEA, where most patients with this pathology are referred in Spain. This document arises from the willingness of our society to update the scientific knowledge on this subject and to provide physicians with clear clinical guidelines regarding diagnosis and treatment of FH. These guidelines can be summarized in two main aspects: early diagnosis of the disease and a rapid normalization of LDLcholesterol. In the coming years, health providers should accomplish that the majority of patients with FH are aware of their diagnosis and that adequate treatment is provided.

Using microRNA as an Alternative Treatment for Hyperlipidemia and Cardiovascular Disease

It is now appreciated that over 90% of the human genome is comprised of noncoding RNAs that have the ability to affect other components of the genome and regulate gene expression. This has galvanized the development of RNA-based therapeutics for a myriad of diseases, including cancer, inflammatory conditions, and cardiovascular disease. Several classes of RNA therapeutics are currently under clinical development, including antisense oligonucleotides, small interfering RNA, and microRNA mimetics and inhibitors. The field of antisense technology saw a huge leap forward with the recent Food and Drug Administration approval of the first antisense therapy, directed against apolipoprotein B, for the treatment of familial hypercholesterolemia. In addition, recent progress in the development of approaches to inhibit microRNAs has helped to illuminate their roles in repressing gene networks and also revealed their potential as therapeutic targets. In this review, these exciting opportunities in the field of drug discovery, with a focus on emerging therapeutics in the field of cardiovascular disease, are summarized.

Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: Consensus Statement of the European Atherosclerosis Society

AimsThe first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD).Methods and resultsOf the theoretical estimated prevalence of 1/500 for heterozygous FH, <1% are diagnosed in most countries. Recently, direct screening in a Northern European general population diagnosed approximately 1/200 with heterozygous FH. All reported studies document failure to achieve recommended LDL cholesterol targets in a large proportion of individuals with FH, and up to 13-fold increased risk of CHD. Based on prevalences between 1/500 and 1/200, between 14 and 34 million individuals worldwide have FH. We recommend that children, adults, and families should be screened for FH if a person or family member presents with FH, a plasma cholesterol level in an adult ≥8 mmol/L(≥310 mg/dL) or a child ≥6 mmol/L(≥230 mg/dL), premature CHD, tendon xanthomas, or sudden premature cardiac death. In FH, low-density lipoprotein cholesterol targets are <3.5 mmol/L(<135 mg/dL) for children, <2.5 mmol/L(<100 mg/dL) for adults, and <1.8 mmol/L(<70 mg/dL) for adults with known CHD or diabetes. In addition to lifestyle and dietary counselling, treatment priorities are (i) in children, statins, ezetimibe, and bile acid binding resins, and (ii) in adults, maximal potent statin dose, ezetimibe, and bile acid binding resins. Lipoprotein apheresis can be offered in homozygotes and in treatment-resistant heterozygotes with CHD.ConclusionOwing to severe underdiagnosis and undertreatment of FH, there is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition.

Treatment of familial hypercholesterolaemia in children and adolescents in the last three decades

This study evaluated the effectiveness of long-term intensive lipid-lowering therapy in children and adolescents with familial hypercholesterolaemia. The charts of 89 children and adolescents with heterozygous familial hypercholesterolaemia among ∼1000 patients treated from 1974 to 2008 were reviewed. Familial hypercholesterolaemia was defined as low-density lipoprotein cholesterol level >90th percentile in individuals with a history of familial hypercholesterolaemia. Of the 89 patients, 51% were male; the mean age at diagnosis was 8 ± 4 years, and the mean follow-up was 13 ± 8 years. Baseline and most recent low-density lipoprotein cholesterol levels (mg/dl) under treatment were 250 ± 50 and 142 ± 49, respectively, reduced 43% from baseline (p < 0.0001). At the most recent visit, 39 patients received statin monotherapy, mainly atorvastatin or rosuvastatin, and 50 (56%) patients received combination therapy, mainly vytorin or rosuvastain/ezetimibe, 15 patients were >30 years of age, and none developed symptomatic cardiovascular disease or needed revascularisation. Long-term statin-based therapy can reduce low-density lipoprotein cholesterol levels in most children and adolescents with heterozygous familial hypercholesterolaemia and decrease cardiovascular risk significantly.

Current challenges in the management of patients with familial hypercholesterolemia

Familial hypercholesterolemia (FH) is a codominant monogenic disorder of lipoprotein metabolism, characterized by severely elevated levels of LDL cholesterol from birth onwards. Despite the availability of reliable diagnostic strategies, the vast majority of FH patients remain undiagnosed. Treatment of FH is mandatory to prevent premature cardiovascular disease and statins are the drug of choice. However, in some FH individuals, statins alone or in combination do not allow the attainment of therapeutic goals. LDL apheresis may be an option, mainly in homozygous FH. Nevertheless, the new lipid-lowering agents (blockers of apoB synthesis or PCSK9 inhibitors) hold promise for patients with resistant FH. There are still concerns when beginning pharmacological interventions in children with FH and also the management of FH in women of childbearing age or during pregnancy is a clinical dilemma. In the present article, these current challenges in the management of FH will be discussed.