About all

Is cholesterol genetic: Genetic Conditions, Family History, and Unhealthy Habits

Содержание

Familial hypercholesterolemia: MedlinePlus Genetics

Mutations in the APOB, LDLR, LDLRAP1, or PCSK9 gene cause familial hypercholesterolemia. Changes in the LDLR gene are the most common cause of this condition. The LDLR gene provides instructions for making a protein called a low-density lipoprotein receptor. This type of receptor binds to particles called low-density lipoproteins (LDLs), which are the primary carriers of cholesterol in the blood. By removing LDLs from the bloodstream, these receptors play a critical role in regulating cholesterol levels. Some LDLR gene mutations reduce the number of low-density lipoprotein receptors produced within cells. Other mutations disrupt the receptors’ ability to remove low-density lipoproteins from the bloodstream. As a result, people with mutations in the LDLR gene have very high levels of blood cholesterol. As the excess cholesterol circulates through the bloodstream, it is deposited abnormally in tissues such as the skin, tendons, and coronary arteries.

Less commonly, familial hypercholesterolemia is caused by mutations in the APOB, LDLRAP1, or PCSK9 gene. Proteins produced from these genes are essential for the normal function of low-density lipoprotein receptors. Mutations in any of these genes prevent cells from making functional receptors or alter the receptors’ function. Hypercholesterolemia results when low-density lipoprotein receptors are unable to remove cholesterol from the blood effectively. Some people with familial hypercholesterolemia do not have a mutation in one of these genes. In these cases, the cause of the condition is unknown.

Both genetic and environmental risk factors play roles in familial hypercholesterolemia. Lifestyle choices including diet, exercise, and tobacco smoking strongly influence the amount of cholesterol in the blood and the risk of coronary artery disease. Additional factors that impact the outcome of the condition include a person’s sex, age, and health problems such as diabetes and obesity.

Familial hypercholesterolemia accounts for only a small percentage of all cases of high cholesterol. Researchers are working to identify and characterize additional genes that may influence cholesterol levels and the risk of heart disease in people with other forms of hypercholesterolemia.

High cholesterol runs in my family. Should I be concerned?

Knowing your family’s cardiovascular health history is crucial for maintaining your own best health. Has anyone in your family experienced a heart attack, needed a stent or undergone bypass surgery before 55 years of age? Chances are, high cholesterol was to blame.

For most people, high cholesterol is caused by eating too many cholesterol-rich foods and not getting enough exercise. But some people are born with a genetic condition that can cause cholesterol levels to rise. Familial hypercholesterolemia, also called FH, is inherited and affects the way your body processes LDL cholesterol — the “bad” cholesterol that can put you at a higher risk for coronary heart disease leading to a heart attack or stroke.  

“If your LDL cholesterol level is higher than 190 mg/dL and doesn’t change with diet and exercise, and if you have a family history of premature cardiovascular disease, there’s a strong chance you have inherited FH,” explains Caroline deRichemond, CRNP, cardiology advanced practice provider at Geisinger Wyoming Valley Medical Center. “I have a patient who started seeing me when he was 24. His grandfather died of a heart attack at age 42, and his father had six bypass surgeries before the age of 35. He’d been taking statins since his teenage years. I gave him a clinical diagnosis of FH, and he had genetic testing to confirm it. It took his statin therapy, a healthy lifestyle and an injectable medication to bring his LDL to goal. Now seven of his family members are being treated for FH with statins and injections and won’t live the legacy of early cardiovascular disease that their ancestors faced.”

Advances in medicine mean there are treatment options to lower your risk of developing cardiovascular disease that were not available to past generations as well as new, more precise ways of diagnosing FH through genetic testing.

Diagnosing FH: genetic testing gives you answers

If your healthcare provider suspects FH, you may be referred to a genetic counselor for testing. The test itself is simple — a blood sample or cheek swab is all that’s needed. 

“FH is most commonly caused by a mutation in one of three genes: PCSK9, APOB and LDLR,” says Amy Sturm, a certified and licensed genetic counselor and director of Cardiovascular Genomic Counseling at Geisinger. “If the mutation for FH is found, siblings and children will have a 50 percent chance of having the same genetic mutation, and we know to work with other family members to control their risk.”

Geisinger is one of the few healthcare systems in the region with a dedicated team of genetic counselors to educate patients about inherited conditions. Patients and family members are then treated by a multidisciplinary team, which includes their primary care doctor, cardiology doctors, pharmacists and nutritionists to keep symptoms under control and — in the best cases — keep them from occurring.

Men who aren’t treated for FH are at a 50 percent risk for serious heart problems by age 50, and untreated women are at a 30 percent risk by age 60. According to Ms. Sturm, an estimated 1 in 250 adults has the FH genetic mutation. “But thanks to advances in genomics and the advent of personalized precision medicine, it’s easy to determine if you’re at risk and take the necessary steps to manage this and other inherited conditions,” she says.

In addition to being a leader in genetic counseling, Geisinger has been collecting and analyzing DNA samples through the MyCode® Community Health Initiative for over a decade. This innovative program looks for gene mutations that indicate increased risks for various types of cancer, autism spectrum disorders and other inherited conditions such as FH. 

Treating FH for you and your loved ones

“You don’t think of children as having high cholesterol, but since FH is an inherited condition, adults and kids are equally affected,” says Ms. deRichemond. “Eating right and exercising are especially important for families with FH. Healthy lifestyle choices combined with the right medical treatments can make all the difference.”

If you have FH, the plan to reduce your chance of a future heart attack or stroke might involve:

  • Checking for high cholesterol, which should start as early as age 8 for anyone at risk 
  • Using medications to lower your cholesterol levels
  • Controlling other risk factors for diseases like high blood pressure and diabetes
  • Adopting healthy habits such as a heart-healthy diet, regular exercise and not smoking
  • Undergoing medical tests to look for existing heart or blood vessel disease

Next steps:

Get care for high cholesterol
Find a heart care specialist
Sign up for MyCode

Common and Rare Gene Variants Affecting Plasma LDL Cholesterol

Clin Biochem Rev. 2008 Feb; 29(1): 11–26.

John R Burnett

1 Department of Core Clinical Pathology & Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital

2 School of Medicine and Pharmacology, University of Western Australia, Royal Perth Hospital, Perth, Australia

Amanda J Hooper

1 Department of Core Clinical Pathology & Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital

1 Department of Core Clinical Pathology & Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital

2 School of Medicine and Pharmacology, University of Western Australia, Royal Perth Hospital, Perth, Australia

*John Burnett was the AACB Roman Lecturer for 2007.

The contents of articles or advertisements in The Clinical Biochemist – Reviews are not to be construed as official statements, evaluations or endorsements by the AACB, its official bodies or its agents. Statements of opinion in AACB publications are those of the contributors. Print Post Approved – PP255003/01665. Copyright © 2005 The Australasian Association of Clinical Biochemists Inc. No literary matter in The Clinical Biochemist – Reviews is to be reproduced, stored in a retrieval system or transmitted in any form by electronic or mechanical means, photocopying or recording, without permission. Requests to do so should be addressed to the Editor. ISSN 0159 – 8090This article has been cited by other articles in PMC.

Abstract

The plasma level of LDL cholesterol is clinically important and genetically complex. LDL cholesterol levels are in large part determined by the activity of LDL receptors (LDLR) in the liver. Autosomal dominant familial hypercholesterolaemia (FH) – with its high LDL cholesterol levels, xanthomas, and premature atherosclerosis – is caused by mutations in either the LDLR or in APOB – the protein in LDL recognised by the LDLR. A third, rare form – autosomal recessive hypercholesterolaemia – arises from mutations in the gene encoding an adaptor protein involved in the internalisation of the LDLR. A fourth variant of inherited hypercholesterolaemia was recently found to be associated with missense mutations in PCSK9, which encodes a serine protease that degrades LDLR. Whereas the gain-of-function mutations in PCSK9 are rare, a spectrum of more frequent loss-of-function mutations in PCSK9 associated with low LDL cholesterol levels has been identified in selected populations and could protect against coronary heart disease. Heterozygous familial hypobetalipoproteinaemia (FHBL) – with its low LDL cholesterol levels and resistance to atherosclerosis – is caused by mutations in APOB. In contrast to other inherited forms of severe hypocholesterolaemia such as abetalipoproteinaemia – caused by mutations in MTP – and homozygous FHBL, a deficiency of PCSK9 appears to be benign. Rare variants of NPC1L1, the gene encoding the putative intestinal cholesterol receptor, have shown more modest effects on plasma LDL cholesterol than PCSK9 variants, similar in magnitude to the effect of common APOE variants. Taken together, these findings indicate that heritable variation in plasma LDL cholesterol is conferred by sequence variation in various loci, with a small number of common and multiple rare gene variants contributing to the phenotype.

Introduction

Genetic, pathological and epidemiological studies have clearly shown that plasma levels of LDL cholesterol are directly related to the incidence of coronary events and cardiovascular deaths. Elevated concentrations of apoB-containing lipoproteins, particularly LDL, are associated with an increased risk of developing atherosclerotic coronary heart disease (CHD).1 Clinical trials using lipid-lowering drugs have unequivocally shown that lowering plasma LDL cholesterol results in significant reductions in both morbidity and mortality from CHD in patients with or without established CHD. 2,3 Furthermore, plasma LDL cholesterol reduction as secondary prevention increases survival rates.

Plasma LDL cholesterol concentrations vary over a three-fold range in the population. It is estimated that up to 50% of the interindividual variation in plasma LDL cholesterol levels is due to genetic variation,4 and that the major portion of this variation is polygenic attributable to sequence variation in various loci. A small percentage of patients with very high or low plasma LDL cholesterol concentrations have monogenic forms of hypercholesterolaemia or hypocholesterolaemia. This review gives an overview of LDL metabolism, the genes affecting plasma concentrations of LDL cholesterol, and the mechanism by which mutations in these genes affect LDL cholesterol levels.

LDL Metabolism

Lipids are water-insoluble organic molecules, and include triglycerides, cholesterol and its esters, and phospholipids. As they are hydrophobic molecules they do not circulate freely in blood, but instead are transported in plasma in particles called lipoproteins from their sites of absorption or synthesis to the peripheral tissues. Lipoproteins are spherical complexes of lipids, and apoproteins that stabilise the lipid emulsions and act as ligands for receptor-mediated processes.

LDL, a cholesterol-rich lipoprotein, is the metabolic product of VLDL, a triglyceride-rich lipoprotein secreted by the liver. ApoB-100, the structural backbone of LDL, is essential for the assembly and secretion of triglyceride-rich lipoproteins. In a normal individual, LDL contains ~70% of the total plasma cholesterol. Each LDL particle contains a single molecule of apoB which cannot be exchanged or lost to other lipoproteins, and as such, fasting plasma apoB-100 concentrations directly reflect the number of circulating LDL particles. Like LDL cholesterol, plasma levels of apoB are directly related to the incidence of coronary events and cardiovascular deaths.

In the liver, a two-step model for lipoprotein assembly has been accepted as the mechanism for VLDL production ().5 Initially, a lipid-poor apoB is synthesised, followed by the bulk addition of neutral lipids to its core. The chaperone microsomal triglyceride transfer protein (MTP) stabilises the nascent apoB within the cell endoplasmic reticulum, and facilitates the transfer of lipids from the endoplasmic reticulum membrane to apoB.6 A similar process occurs in the intestine to form triglyceride-rich chylomicrons, containing apoB-48.7 ApoB-48 is produced from the same gene as apoB-100, but in the intestine, an mRNA editing process occurs which results in only the amino-terminal 48% of apoB-100 being produced.8,9

ApoB-containing lipoprotein production and metabolism. As its synthesis occurs, apoB is directed to the endoplasmic reticulum (ER) via its signal peptide sequence, and formation of a nascent lipoprotein facilitated by the chaperone MTP. This is followed by bulk triglyceride (TG) addition to form the lipoprotein (Inset). The intestine secretes apoB-48-containing chylomicrons (CM), which are metabolised to remnant particles that are subsequently cleared, mediated by apoE, by receptors in the liver. The liver secretes apoB-100-containing VLDL, and its core triglycerides are hydrolysed by lipoprotein lipase (LPL) to form IDL, which is further metabolised by hepatic lipase (HL) to form LDL. LDL is cleared mostly by the LDLR, into the liver or peripheral tissues. HDL facilitates reverse cholesterol transport, the transport of lipids from peripheral tissues to the liver.

In the circulation, VLDL triglyceride is hydrolysed by lipoprotein lipase on the endothelial surface and the released free fatty acids are taken up by peripheral tissues. This process converts VLDL to smaller, denser particles. Some of these VLDL remnants are cleared from the circulation, while the remaining particles enter the VLDL→LDL lipolytic cascade.

In this pathway, intermediate density lipoprotein (IDL) is formed by the hydrolysis of core triglyceride by lipases. IDL is either cleared by the liver (mediated by apoE) or further metabolised to LDL. Most of the LDL particles are cleared by the liver via the LDL receptor (LDLR). 10 The LDLR pathway was elucidated by Brown and Goldstein, for which they were awarded the Nobel Prize in Physiology or Medicine in 1985. Both apoB-100 and apoE are ligands for LDLR-mediated uptake, but as LDL contains no apoE, apoB-100 is the sole ligand for LDL clearance.11

LDL in the circulation can become modified by oxidation in the arterial wall, and taken up by macrophages. These macrophages become cholesterol-loaded ‘foam cells’, and their accumulation within the vessel wall is an early sign of atherosclerosis.12 Fatty streaks can develop into a fibrous cap. This fibrous cap can become unstable, and rupture results in formation of a thrombus, which can cause further occlusion at the site of formation or at a distant site, which can result in myocardial infarction or stroke.

Inherited disorders of lipoprotein metabolism help us to understand these pathways. Mutations of genes affecting apoB production and secretion tend to result in reduced circulating LDL and hypobetalipoproteinaemia, whereas mutations in genes involved in clearance of LDL by the LDLR tend to result in increased circulating LDL and hypercholesterolaemia.

Gene Variants Affecting LDL Cholesterol Levels

summarises the major genes affecting circulating LDL cholesterol levels. These range from common variants having small effects (e.g. apoE), to rare mutations causing hypo- and hypercholesterolaemia.

Table 1

Summary of major genes affecting plasma LDL cholesterol concentrations.

Gene Protein Gene locus Mutation frequency Effect of mutation on LDL Mechanism
APOB Apolipoprotein B 2p24 1:500 200–300% increase (familial ligand- defective apoB-100) Decreased clearance of LDL due to defective binding with LDLR
1:3000 >50% decrease (heterozygous familial hypobetalipoproteinaemia) Decreased production of apoB-containing lipoproteins
1:1 million Absent or very low (homozygous familial hypobetalipoproteinaemia) Ability to assemble and secrete apoB-containing lipoproteins either absent or markedly reduced
APOE Apolipoprotein E 19q13. 2 E2 0.06 5% decrease in E2 vs E3 E2-containing lipoproteins have delayed clearance, leading to up-regulation of LDLR
E3 0.81
E4 0.13 5% increase in E4 vs E3 E4 lipoproteins catabolised rapidly leading to increased hepatic cholesterol and down-regulation of LDLR
ARH Adaptor protein 1p36-p35 1:10 million 300–1000% increase (autosomal recessive hypercholesterolaemia) ARH adaptor protein absent or unable to interact with the LDLR and promote LDLR clustering in clathrin-coated pits
LDLR LDL receptor 19p13. 2 1:500 200–300% increase (heterozygous) Defective LDLR production, function, or recycling leads to reduced clearance of LDL
1:1 million 500–1000% increase (homozygous)
MTP Microsomal triglyceride transfer protein 4q22-q24 1:1 million Absent or very low (abetalipoproteinaemia; recessive) ApoB-containing lipoproteins unable to be assembled, due to the absence, or defective activity, of the chaperone MTP
NPC1L1 Niemann-Pick C 1-like 1 protein 7p13 Unknown Multiple variants with small effects Unknown
PCSK9 Proprotein convertase subtilisin/kexin-type 9 1p34. 1-p32 Unknown 2% African Americans 200–300% increase (gain-of-function mutations) 30% decrease (nonsense mutations) PCSK9 degrades the LDLR; gain-of-function mutations reduce LDLRs on the cell surface and lead to accumulation of LDL in plasma Fewer LDLRs are degraded, due to reduced PCSK9 activity, allowing more LDL particles to be cleared from plasma

APOE

ApoE has an important role in the metabolism of remnant lipoproteins (chylomicron remnants and IDL) by binding to the LDLR and LDLR-related protein and mediating clearance of lipoproteins from the circulation. However, the mechanism for the association between apoE and atherosclerosis is not clear. This 299 amino acid protein also plays a role in neuronal growth and repair, inflammation, and in the immune system mediating the presentation of serum-borne lipid antigens. 13,14 ApoE and its isoforms have also been implicated in the pathogenesis of neurological disorders, including multiple sclerosis and Alzheimer’s disease.15

There are three common APOE isoforms, named epsilon 2, 3 and 4, differing at two amino acid positions. ApoE2 has two cysteine residues at positions 112 and 158, whereas E4 has two arginines and E3 Cys112 and Arg158. E3 is the most common isoform, with a frequency in Australia of 0.81, followed by E4 (0.13) and E2 (0.06).16 Approximately 10% of inter-individual variation in total cholesterol concentrations is due to the apoE polymorphism.17 Historically, apoE phenotyping was determined by isoelectric focusing, but this has been replaced by modern genotyping techniques.

E4 carriers have 5% higher plasma LDL cholesterol levels, and have slightly increased risk for CHD compared to E3 carriers.18 ApoE4 has a high affinity for LDLR compared to E2 and E3. Particles containing E4 are therefore catabolised more rapidly than E3, leading to increased hepatic cholesterol and down-regulation of the LDLR, resulting in increased plasma LDL cholesterol levels.19 E2 carriers have ~5% lower plasma LDL cholesterol concentrations and a 20% lower risk of CHD.18 E2 binds LDLR about 1% that of E3, resulting in delayed clearance of apoE2-carrying lipoproteins, which leads to up-regulation of the LDLR.19 Homozygosity for apoE2 is also associated with familial dysbetalipoproteinaemia (type III hyperlipidaemia), a remnant hyperlipidaemia characterised by elevated plasma triglyceride and cholesterol concentrations.

NPC1L1

The function of NPC1L1 remains to be determined. It plays a role in intestinal cholesterol transport and, until very recently, was thought to be the molecular target of the cholesterol absorption inhibitor ezetimibe.20,21 However, NPC1L1 is also expressed in the liver, and a recent study has shown that NPC1L1 allows the retention of biliary cholesterol by hepatocytes and that ezetimibe disrupts hepatic NPC1L1 function. 22

Variants in NPC1L1 are associated with reduced sterol absorption and plasma LDL levels.23 Multiple rare variants of NPC1L1 were found in low cholesterol absorbers. These variants were found in 6% of African Americans, and were associated with lower plasma levels of LDL cholesterol (2.5 vs 2.7 mmol/L).23 A possible relationship between NPC1L1 variation and ezetimibe response has also been reported.24,25

Polygenic, Sporadic and Multifactorial Hypercholesterolaemia

These terms have been used to describe hypercholesterolaemia of uncertain aetiology. They may occur in the absence of a positive family history (sporadic), may be associated with a familial component of unclear mode of inheritance or may be interpreted as being the result of the interaction of multiple genes with a small effect (polygenic). They may also result from one or more environmental factors (e.g. high saturated fat/cholesterol diet, obesity, caloric excess, stress, subclinical hypothyroidism, pregnancy, menopause) interacting (or otherwise) with a genetic predisposing factor or susceptibility gene (multifactorial). Polygenic hypercholesterolaemia is more common than FH, and importantly, tendon xanthomas are absent with this disorder.

Monogenic Hypercholesterolaemia

Monogenic hypercholesterolaemia is characterised by high levels of circulating LDL and reduced clearance of LDL from plasma by the LDLR pathway, leading to premature CHD. Inheritance is usually autosomal codominant and commonly results from defective apoB binding to LDLR (familial ligand-defective apoB, FDB) or mutations in LDLR FH. In rare cases mutations in PCSK9 have been identified. Autosomal recessive hypercholesterolaemia (ARH) is even rarer and is caused by mutations in the adaptor protein named ARH.

LDLR

The familial clustering of patients showing xanthomas, premature coronary artery disease (CAD), and hypercholesterolaemia was first recognised in the 1930s and led to the suggestion of a genetic basis for the disorder.26 Khachadurian in the early 1960s studied Lebanese families with hypercholesterolaemia and deduced the differences between heterozygotes and homozygotes, providing the evidence for a single-gene disorder.27 In 1974, Brown and Goldstein reported the discovery of the LDLR and demonstrated that LDLR defects cause FH.28 Since the characterisation of the LDLR gene in 198529 there have been ~800 known LDLR mutations identified causing FH.30 The frequency of FH among Caucasians has been estimated at 1:500, and is therefore thought to be one of the two most common human diseases caused by mutations in a single gene, the other being haemochromatosis.26 FH is more prevalent in certain populations: 1:100 Afrikaners, 1:170 Christian Lebanese, and 1:270 French Canadians.26

In heterozygous FH, plasma LDL cholesterol concentrations are typically two to three times normal at 5–11 mmol/L. Cholesterol deposits around the body, manifesting in the eyes as corneal arcus and xanthelasma, and tendons, particularly the Achilles, as xanthomas (). These manifestations are common after age 20 years, followed by the development of CAD. Estimates suggest that 75% of male heterozygotes and 45% of female heterozygotes have symptoms of CHD by the age of 60 years.26 There is little impact on LDL cholesterol levels in FH heterozygotes by optimising other cardiovascular risk factors. Instead, lifelong cholesterol-lowering therapy with agents such as statins and ezetimibe, is recommended, commencing in children aged over 10 years.31

Discrete clinical manifestations of FH. A, Corneal arcus and xanthelasma; B, extensor tendon xanthomas; C and D, Achilles tendon xanthomas.

Homozygous FH is rare, found in one in a million individuals, and characterised by large elevations in plasma LDL (in the order of 15 24 mmol/L) and severe cutaneous and tendinous xanthomas, with coronary atherosclerosis occurring in childhood.26 Untreated, FH homozygotes will often die before reaching age 20 years, and there have been reports of children as young as 18 months experiencing acute myocardial infarction. Drug treatments are not as effective in FH homozygotes compared to heterozygotes. LDL apheresis, the direct removal of LDL from plasma, performed every 1–2 weeks on a long-term basis, can reduce plasma LDL cholesterol by ~70%.26 Despite LDL apheresis, patients remain at increased risk for the development and progression of atherosclerotic CHD. Although liver transplantation offers the most definitive therapy for homozygous FH, it requires major surgery and lifelong immunosuppression. FH is a good candidate disease for liver-targeted gene therapy.

The LDLR protein consists of five domains: ligand-binding, epidermal growth factor (EGF) precursor homology, O-linked sugars, membrane-spanning and cytoplasmic domains ().26,32 Mutations causing FH span the entire LDLR gene, but are most commonly found in the ligand-binding and the EGF-precursor homology domain. Mutations are classed into five categories according to their phenotypic effects on the LDLR protein: defects in synthesis, transport, binding, internalisation and recycling (). Mutations include nucleotide substitutions (missense and nonsense), splice site mutations, and small deletions and insertions, and ~10% are large structural rearrangements. These major gene rearrangements can be readily detected by multiplex ligation-dependent probe amplification analysis.

Structure of LDLR protein, related to gene structure. Exon 1 encodes a signal sequence which is cleaved during LDLR synthesis. Exons 2–18 encode the mature 839 amino acid protein, which consists of five domains. Reprinted, with permission, from the Annual Review of Genetics, Volume 24 c1990 by Annual Reviews www.annualreviews.org.32

Classification of LDLR mutations based on function. These mutations disrupt the synthesis of mature LDLR, transport to the Golgi complex, binding of apoprotein ligands, clustering in clathrin-coated pits, and recycling. Reprinted, with permission, from the Annual Review of Genetics, Volume 24 c1990 by Annual Reviews www.annualreviews.org.32

Of the estimated 40,000 cases of FH in Australia, only 20% are diagnosed and less than 10% are being adequately treated.33 An international initiative, Make Early Diagnosis – Prevent Early Death (MED-PED), has been established in many countries, with the goal of identifying individuals with FH and providing treatment. Other criteria for FH diagnosis, such as the Dutch Lipid Network criteria34 () and UK-based Simon Broome Register Group criteria,35 have been established. The Dutch have been particularly successful, by 2005 identifying ~3000 index cases and over 7000 relatives since the inception of a national screening program in 1994.36

Table 2

Dutch Lipid Network clinical criteria for diagnosis of heterozygous familial hypercholesterolaemia.

Criteria Points
1. Family history
A first degree relative with known:
 a) Premature* coronary and vascular disease 1
 b) Plasma LDL-C concentration >95th percentile for age and sex
  i) In an adult relative 1
  ii) In a relative <18 years of age 2
 c) Tendon xanthomata or arcus cornealis 2
2. Clinical history
Patient has premature*:
 a) Coronary artery disease 2
 b) Cerebral or peripheral vascular disease 1
3. Physical examination of the patient
 a) Tendon xanthomata 6
 b) Arcus cornealis in a patient <45 years of age 4
4. LDL-C levels in patient’s blood (mmol/L)
 a)≥8.5 8
 b) 6.5–8.4 5
 c) 5.0–6.4 3
 d) 4.0–4.9 1
5. DNA analysis showing functional mutation in the LDLR or other FH-related gene 8
Interpretation Diagnosis Total points
Definite FH >8
Probable FH 6–8
Possible FH 3–5

Due to phenotypic heterogeneity, there is a need for accurate clinical diagnostic criteria for the early diagnosis of FH, if a genetic diagnosis has not been made. Genetic testing plays a key role in screening programs for FH which are under development in many Western countries.37 In addition to the absence or presence of a functional mutation in the LDLR gene, differences in prognosis due to the type of mutation could influence commencement of lipid-lowering therapies in FH.38

APOB

Like FH, FDB is characterised by elevated plasma concentrations of LDL cholesterol and apoB, normal triglyceride and high density lipoprotein (HDL) cholesterol levels, the presence of tendon xanthomas, and premature CAD.3941 FDB is caused by mutations in the LDLR-binding region of apoB, causing defective binding and an accumulation of LDL in plasma (). FDB cannot be clinically distinguished from heterozygous LDLR-FH, although the phenotype of FDB can be milder. In general, the hypercholesterolaemia is less severe and there appears to be a lower incidence of CAD in FDB compared to LDLR-FH.

Model for the mechanism of FDB. Normally, the LDLR-binding region of apoB (site B) is available to interact with the LDLR; the interaction between arginine R3500 and tryptophan W4369 being particularly important (left). In FDB, mutations such as R3500Q alter the conformation of the C-terminal region of apoB, leading to occlusion of site B (centre). This model is supported by the finding that mutation of W4369 also disrupts LDLR binding (right). Excerpt reprinted with permission, from the Journal of Biological Chemistry, 276 c 2001 by The American Society for Biochemistry and Molecular Biology, Inc.44

Several mutations in the LDLR-binding domain of apoB have been described that are associated with hypercholesterolaemia with an autosomal codominant inheritance pattern. The most common involves the substitution of a glutamine for arginine at position 3500 and affects about 1 in 500 individuals of European descent.42,43 By haplotype analysis, R3500Q is thought to originate from a single founder living in Europe 7000 years ago.44 Another missense mutation at the same position, where a tryptophan is substituted for arginine (R3500W), has been found in hyperlipidaemic patients of Chinese or Malay descent.45,46 Additional rarer mutations in exon 26 affecting surrounding residues (R3480W, R3480P, R3500L, R3531C and h4543Y) have been reported.36,45,4749

Determining FDB mutation status is important, as FDB cannot be clinically distinguished from heterozygous FH without genetic testing. Genotyping for the R3500Q mutation is available at many specialist biochemical genetics laboratories. High resolution melting analysis has recently emerged as a sensitive method, capable of detecting all known APOB variants associated with FDB.50

PCSK9

Proprotein convertase subtilisin kexin type 9 (PCSK9), originally named neural apoptosis regulated convertase 1 (NARC-1), is a serine protease expressed in the body’s two main sites for lipoprotein metabolism: the liver and small intestine.51 Proprotein convertases are enzymes that cleave precursor proteins into their active forms. Linkage to chromosome 1p32, a locus containing the PCSK9 gene, was demonstrated in FH families not carrying LDLR or APOB mutations, and the subsequent discovery of PCSK9 missense mutations in two such families confirmed its importance in cholesterol metabolism, as the third gene responsible for dominant FH.52

FH-causing mutations result in ‘gain-of-function’ and reduce the number of LDLRs on the cell surface and the amount of LDL they internalise.53 The frequency of PCSK9 mutations causing FH is unknown. Several PCSK9 mutations causing FH have been reported, including S127R, D129G, F216L and D374Y.54,55 Other mutations, N425S and R496W, have so far only been identified in families who also carry LDLR mutations.56 Individuals who are heterozygous for LDLR and PCSK9 mutations have ~50% higher plasma LDL cholesterol concentrations. Other mutations are associated with hypocholesterolaemia ().

PCSK9 and mutations associated with increased and decreased concentrations of LDL cholesterol. PCSK9 has a 30 amino acid signal sequence (SS), followed by a prodomain (Pro), catalytic domain and C-terminal domain. Reprinted from Trends in Biochemical Sciences, 32, Horton JD, Cohen, JC, Hobbs HH, Molecular biology of PCSK9: its role in LDL metabolism, 71–7, Copyright 2007, with permission from Elsevier.54

Recent studies have elucidated the function of PCSK9. It is secreted into plasma and binds directly to cell-surface LDLR, leading to endocytosis and intracellular degradation of the LDLR.57,58 PCSK9 has also been shown to induce degradation of the VLDL receptor (VLDLR) and apoE receptor 2 (APOER2), the closest family members of the LDLR.59 Serum concentrations of PCSK9 directly correlate with plasma cholesterol and LDL cholesterol levels.60 However, PCSK9 does not need to be secreted to have its effect on LDLR degradation. Cellular studies of two nonsecreted PCSK9 mutants causing FH, S127R and D129G, were shown to reduce LDLR expression.61

ARH

In very rare cases (<1:10 million) hypercholesterolaemia is inherited as an autosomal recessive trait.62 Although ARH was first described over 30 years ago,63 it was not until 2001 that mutations in adaptor protein ARH on chromosome 15 were identified as the cause.64 In affected subjects the LDLR is normal but accumulates at the cell surface, unable to be internalised. ARH interacts with the cytoplasmic tail of the LDLR and promotes LDLR clustering into clathrin coated pits.65

ARH presents with a clinical phenotype similar to homozygous FH, but is generally less severe and more responsive to lipid-lowering therapy.66 It is also more variable in presentation; ARH individuals have been diagnosed between ages 1 to 46 years and have total cholesterol from 9.6 to 27.1 mmol/L.67 In addition, most patients manifest large, bulky xanthomas from early childhood. ARH is more responsive to statins compared to homozygous FH, and this could be related to the observation that the LDLR pathway functions normally in cultured skin fibroblasts from ARH patients. This would allow increased removal of plasma LDL from extrahepatic tissues, and may also be related to the accelerated presence of xanthomas. Another adaptor protein Disabled-2 (Dab2) has recently been shown to mediate LDLR synthesis in skin broblasts from ARH patients.68

Monogenic Hypocholesterolaemia

Hypobetalipoproteinaemia is characterised by <5th percentile levels of plasma LDL cholesterol and apoB for age and sex, usually LDL cholesterol <1.8 mmol/L and apoB <0.5 g/L. Secondary causes of hypobetalipoproteinaemia include vegan diet, malnutrition, malabsorption, cachexia, hyperthyroidism, severe liver disease. Primary causes of hypobetalipoproteinaemia include FHBL, abetalipoproteinaemia (ABL), and chylomicron retention disease. Chylomicron retention disease, as the name suggests, relates to an inability of the gut to secrete chylomicrons, and as it is not a disorder of LDL metabolism, will not be discussed further in this review. More recently, nonsense variants in PCSK9 have been associated with hypocholesterolaemia.

APOB

FHBL is an autosomal codominant disorder of LDL deficiency, and is one of few monogenic disorders associated with protection against atherosclerosis. Characterised by plasma LDL and apoB concentrations <5th percentile for age and sex, it has a prevalence of ~1:3000.69

FHBL is caused by mutations in the APOB gene. FHBL heterozygotes are usually asymptomatic, and their low circulating plasma LDL concentrations, by reducing their cardiovascular disease risk, are thought to increase their lifespan by 10 years on average.70 FHBL heterozygotes were shown to have decreased arterial wall stiffness, indicative of cardiovascular protection.71 Emerging evidence suggests that FHBL subjects that are heterozygous for APOB mutations are at increased risk of developing fatty liver, and/or insulin resistance.72,73 Increased concentrations of serum liver enzymes ALT, AST and GGT are also observed in FHBL subjects compared to their unaffected relatives. Clinical manifestations in FHBL homozygotes vary, from no symptoms to severe gastrointestinal and neurological dysfunction, similar to that seen in ABL. This variation could relate to the severity of the APOB mutation(s) present, as well as other genetic or environmental factors. Acanthocytes are also observed in homozygous and occasionally in heterozygous FHBL ().

Acanthocytosis in hypocholesterolaemia. A, Blood film from a normal subject; B, apoB-40.3 FHBL heterozygote; C, apoB-6.9 FHBL heterozygote; and D, subject with ABL.

About 60 mutations have been reported to date in APOB causing FHBL, most of which result in a truncated apoB molecule. ApoB truncations larger than apoB-29 (i.e. 29% of full-length apoB-100) can be detected in plasma by Western blotting, giving an indication of the target region of the APOB gene that needs to be sequenced in order to identify the mutation. However, truncations shorter than apoB-29 are not detectable in plasma and can only be identified by DNA sequencing. These very short apoBs appear to be unable to acquire sufficient lipid, which leads to their intracellular degradation rather than secretion.74

Stable isotope tracer methodology has been used in FHBL subjects to study the in vivo kinetics of apoB.75 The secretion rate of apoB species was found to be linked to the degree of truncation, equating to a 1.4% reduction in secretion for each 1% of apoB truncated.76 In addition, clearance of the truncated species apoB-75 and apoB-89, which contain the LDLR-binding domain, is faster than clearance of normal apoB-100.77,78 Based on the ‘ribbon and bow’ model of apoB structure on LDL particles (), the absence of the carboxyl terminus of apoB-100 would result in enhanced receptor binding.47

We have used oral fat tolerance tests to study postprandial lipoprotein metabolism in FHBL heterozygotes with apoB truncations shorter than apoB-48.79 After baseline blood samples are taken following a 12 hour fast, subjects are given a fat load in the form of a milkshake, along with some vitamin A (retinol), and blood samples are taken 2-hourly over 10 hours. The retinol is used as a marker for chylomicron lipids, and we measured apoB-48 as an indicator of chylomicron and remnant particle number. By using a multicompartmental modelling approach, our results suggest that these FHBL subjects have reduced production of chylomicrons rather than increased clearance.

Our studies have discovered the first two missense mutations, L343V and R463W, in apoB causing FHBL.80,81 The N-terminal βα1 domain of apoB contains sequence elements that are important for interaction with its chaperone MTP and therefore triglyceride-rich lipoprotein assembly. This domain was sequenced in FHBL subjects in whom a truncated apoB was not detected by Western blotting. R463W and L343V were identified in large families with n=14 and n=10 heterozygous FHBL subjects respectively.80,81 The R463W kindred is of Christian Lebanese background and also includes two homozygous individuals who were the result of consanguineous unions. Both L343V and R463W occur within the putative MTP-binding region of apoB and track with the low-cholesterol phenotype within each family. L343 and R463 are also conserved among other mammalian species, further indicating the importance of these residues.

In vitro studies showed that the L343V and R463W mutations impaired secretion of apoB-100 and VLDL.81 Decreased secretion of mutant apoB-100 was also associated with increased endoplasmic reticulum retention and increased binding to MTP and BiP, a general molecular chaperone. Biochemical and biophysical analyses of apoB domain constructs showed that L343V and R463W altered folding of the alpha-helical domain within the N-terminus of apoB.

MTP

ABL, also known as Bassen-Kornzweig syndrome, is an extremely rare autosomal recessive disorder characterised by the absence of apoB containing lipoproteins in plasma.82,83

Patients with ABL show a range of clinical symptoms similar to homozygous FHBL, and often present in childhood with failure to thrive, fat malabsorption (steatorrhoea), and low plasma cholesterol and vitamin E levels. Symptoms can progress to include atypical retinitis pigmentosa and progressive spinocerebellar degeneration. Liver biopsies in ABL patients have shown steatosis, which may or may not be reflected in raised serum transaminases.82 ABL is caused by mutations in the MTP gene, and is distinguished from homozygous FHBL by the inheritance pattern; in ABL the parents will have normal lipids.

The human MTP gene is located on chromosome 4q22–24 and encodes the 894 amino acid MTP. MTP forms a heterodimer with the ubiquitous endoplasmic reticulum enzyme protein disulfide isomerase (PDI), and acts as a chaperone to facilitate apoB assembly into lipoproteins. MTP’s involvement in ABL was first reported in 1992, when MTP activity was not detected in intestinal biopsies of ABL subjects,84 and in the following year mutations in MTP causing ABL were described.85,86 About 30 ABL mutations occurring throughout the MTP gene have been described, including missense mutations R540H, G746E, and N780Y.8789MTP missense mutations affect either the PDI- or apoB-binding ability of MTP, or defective lipid transfer activity onto apoB, resulting in reduced secretion of apoB-containing lipoproteins.

Vitamin E, transported in plasma in association with the apoB-containing lipoproteins, is essential for neurological function. In ABL and homozygous FHBL, concentrations of the other fat-soluble vitamins (A, D and K) are reduced but, as they have alternate transport mechanisms, not to the same extent as vitamin E. High-dose vitamin E in ABL is recommended to inhibit progression of neurologic symptoms.40,82 In the absence of the apoB-containing lipoproteins vitamin E can be packaged into HDL. Supplementation with a combination of vitamins E and A has been shown to be effective in reducing, but not preventing, retinal degeneration.90 Recently, it was found that the human retina expresses MTP and apoB, suggesting that apoB-containing lipoprotein assembly is an important retinal function.91 Therefore, retinopathy in ABL could be due to defective MTP rather than vitamin E deficiency.

PCSK9

As described above, ‘gain-of-function’ missense mutations in PCSK9 cause hypercholesterolaemia. Other missense mutations are associated with lower cholesterol levels and possibly increased response to statin therapy.92 Two ‘loss-of-function’ nonsense variations, Y142X and C679X, were described in 2005, which occurred at a combined frequency of 2% in African Americans and reduced plasma LDL cholesterol by 40%.93 A reduction in PCSK9 activity would mean fewer LDLRs degraded, allowing more LDL particles to be cleared and a reduction in plasma LDL.

We genotyped for PCSK9 nonsense variants in a southern African population consisting of 653 young black females attending antenatal clinics in Zimbabwe.94 We did not find Y142X, suggesting a founder effect in the African American population. C679X occurred in 3.7% of subjects and was associated with a 27% reduction in plasma LDL cholesterol (1.6 ± 0.3 mmol/L vs 2.2 ± 0.7 mmol/L in non-carriers) (). We also described the first homozygote for C679X, with the lowest LDL cholesterol of the studied population, at 0.4 mmol/L. This plasma LDL cholesterol concentration is comparable to that found in heterozygous FHBL, which suggests that homozygosity for PCSK9 nonsense mutations should be considered as a cause for severe hypocholesterolaemia.

Plasma LDL cholesterol distributions in control subjects and subjects carrying the nonsense mutation of PCSK9, C679X. C679X was present in 24 out of 653 screened subjects, and associated with a 27% reduction in LDL. Reprinted from Atherosclerosis, 193, Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR, The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population, 445–8, Copyright 2007, with permission from Elsevier.94

PCSK9 mutations are interesting in that they illustrate the concept that time and not just LDL lowering plays an important role in the development of CHD.95 A 2 mmol/L decrease in LDL by statin treatment for five years only decreases the incidence of CHD by 40%. In contrast, PCSK9 nonsense mutation carriers have a 1 mmol/L reduction in plasma LDL cholesterol compared to non-carriers, but this is over a lifetime. A large study including 3363 African American subjects showed an 88% reduction in CHD risk in PCSK9 mutation carriers.96 Moreover, the only PCSK9 nonsense mutation carrier who developed CHD was obese, smoked, had hypertension with a family history of CHD, and died at age 68 years.

Conclusions

Heritable variation in plasma LDL cholesterol is conferred by sequence variation in various loci, with a small number of common and multiple rare gene variants contributing to the phenotype. Analysis of naturally occurring rare gene variants has been useful in identifying important domains governing the assembly and secretion of lipoproteins into plasma, and their metabolism and clearance.

Acknowledgements

This work was supported by grants from the Royal Perth Hospital Medical Research Foundation, the Raine Medical Research Foundation, the National Health & Medical Research Council (403908), and the National Heart Foundation of Australia (G 139 115).

Footnotes

Competing Interests: None declared.

References

1. Babiak J, Rudel LL. Lipoproteins and atherosclerosis. Baillieres Clin Endocrinol Metab. 1987;1:515–50. [PubMed] [Google Scholar]2. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) Lancet. 1994;344:1383–9. [PubMed] [Google Scholar]3. Shepherd J. Preventing coronary artery disease in the West of Scotland: implications for primary prevention. Am J Cardiol. 1998;82:57T–59T. [PubMed] [Google Scholar]4. Heller DA, de Faire U, Pedersen NL, Dahlen G, Mc Clearn GE. Genetic and environmental influences on serum lipid levels in twins. N Engl J Med. 1993;328:1150–6. [PubMed] [Google Scholar]5. Olofsson SO, Asp L, Boren J. The assembly and secretion of apolipoprotein B-containing lipoproteins. Curr Opin Lipidol. 1999;10:341–6. [PubMed] [Google Scholar]6. Hussain MM, Iqbal J, Anwar K, Rava P, Dai K. Microsomal triglyceride transfer protein: a multifunctional protein. Front Biosci. 2003;8:500–6. [PubMed] [Google Scholar]7. Kane JP, Hardman DA, Paulus HE. Heterogeneity of apolipoprotein B: isolation of a new species from human chylomicrons. Proc Natl Acad Sci U S A. 1980;77:2465–9. [PMC free article] [PubMed] [Google Scholar]8. Chen SH, Habib G, Yang CY, Gu ZW, Lee BR, Weng SA, et al. Apolipoprotein B-48 is the product of a messenger RNA with an organ-specific in-frame stop codon. Science. 1987;238:363–6. [PubMed] [Google Scholar]9. Powell LM, Wallis SC, Pease RJ, Edwards YH, Knott TJ, Scott J. A novel form of tissue-specific RNA processing produces apolipoprotein-B48 in intestine. Cell. 1987;50:831–40. [PubMed] [Google Scholar]10. Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986;232:34–47. [PubMed] [Google Scholar]11. Havel RJ, Kane JP. Structure and metabolism of plasma lipoproteins. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler K, Vogelstein B, editors. The Metabolic and Molecular Bases of Inherited Disease. 8. New York: McGraw-Hill; 2001. pp. 2705–16. [Google Scholar]12. Libby P. Atherosclerosis: disease biology affecting the coronary vasculature. Am J Cardiol. 2006;98:3Q–9Q. [PubMed] [Google Scholar]13. Nathan BP, Bellosta S, Sanan DA, Weisgraber KH, Mahley RW, Pitas RE. Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science. 1994;264:850–2. [PubMed] [Google Scholar]14. van den Elzen P, Garg S, Leon L, Brigl M, Leadbetter EA, Gumperz JE, et al. Apolipoprotein-mediated pathways of lipid antigen presentation. Nature. 2005;437:906–10. [PubMed] [Google Scholar]15. Fazekas F, Enzinger C, Ropele S, Schmidt H, Schmidt R, Strasser-Fuchs S. The impact of our genes: consequences of the apolipoprotein E polymorphism in Alzheimer disease and multiple sclerosis. J Neurol Sci. 2006;245:35–9. [PubMed] [Google Scholar]16. van Bockxmeer FM, Mamotte CD. Apolipoprotein epsilon 4 homozygosity in young men with coronary heart disease. Lancet. 1992;340:879–80. [PubMed] [Google Scholar]17. Sing CF, Davignon J. Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation. Am J Hum Genet. 1985;37:268–85. [PMC free article] [PubMed] [Google Scholar]18. Bennet AM, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, Ahlbom A, et al. Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA. 2007;298:1300–11. [PubMed] [Google Scholar]19. Reardon CA. Differential metabolism of apolipoprotein E isoproteins. J Lab Clin Med. 2002;140:301–2. [PubMed] [Google Scholar]20. Garcia-Calvo M, Lisnock J, Bull HG, Hawes BE, Burnett DA, Braun MP, et al. The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1) Proc Natl Acad Sci U S A. 2005;102:8132–7. [PMC free article] [PubMed] [Google Scholar]21. Knopfel M, Davies JP, Duong PT, Kvaerno L, Carreira EM, Phillips MC, et al. Multiple plasma membrane receptors but not NPC1L1 mediate high-affinity, ezetimibe-sensitive cholesterol uptake into the intestinal brush border membrane. Biochim Biophys Acta. 2007;1771:1140–7. [PubMed] [Google Scholar]22. Temel RE, Tang W, Ma Y, Rudel LL, Willingham MC, Ioannou YA, et al. Hepatic Niemann-Pick C1-like 1 regulates biliary cholesterol concentration and is a target of ezetimibe. J Clin Invest. 2007;117:1968–78. [PMC free article] [PubMed] [Google Scholar]23. Cohen JC, Pertsemlidis A, Fahmi S, Esmail S, Vega GL, Grundy SM, et al. Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels. Proc Natl Acad Sci U S A. 2006;103:1810–5. [PMC free article] [PubMed] [Google Scholar]24. Hegele RA, Guy J, Ban MR, Wang J. NPC1L1 haplotype is associated with inter-individual variation in plasma low-density lipoprotein response to ezetimibe. Lipids Health Dis. 2005;4:16. [PMC free article] [PubMed] [Google Scholar]25. Wang J, Williams CM, Hegele RA. Compound heterozygosity for two non-synonymous polymorphisms in NPC1L1 in a non-responder to ezetimibe. Clin Genet. 2005;67:175–7. [PubMed] [Google Scholar]26. Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler K, Vogelstein B, editors. The Metabolic and Molecular Bases of Inherited Disease. 8. New York: McGraw-Hill; 2001. pp. 2863–913. [Google Scholar]27. Khachadurian AK. The Inheritance of Essential Familial Hypercholesterolemia. Am J Med. 1964;37:402–7. [PubMed] [Google Scholar]28. Brown MS, Goldstein JL. Expression of the familial hypercholesterolemia gene in heterozygotes: mechanism for a dominant disorder in man. Science. 1974;185:61–3. [PubMed] [Google Scholar]29. Sudhof TC, Goldstein JL, Brown MS, Russell DW. The LDL receptor gene: a mosaic of exons shared with different proteins. Science. 1985;228:815–22. [PMC free article] [PubMed] [Google Scholar]31. Iughetti L, Predieri B, Balli F, Calandra S. Rational approach to the treatment for heterozygous familial hypercholesterolemia in childhood and adolescence: a review. J Endocrinol Invest. 2007;30:700–19. [PubMed] [Google Scholar]32. Hobbs HH, Russell DW, Brown MS, Goldstein JL. The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. Annu Rev Genet. 1990;24:133–70. [PubMed] [Google Scholar]33. Burnett JR, Ravine D, van Bockxmeer FM, Watts GF. Familial hypercholesterolaemia: a look back, a look ahead. Med J Aust. 2005;182:552–3. [PubMed] [Google Scholar]34. WHO/HGN/FH/CONS/992. Familial hypercholesterolemia. Report of a second WHO Consultation. Geneva, Switzerland: World Health Organization; 1999. [Google Scholar]35. Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. BMJ. 1991;303:893–6. [PMC free article] [PubMed] [Google Scholar]36. Fouchier SW, Kastelein JJ, Defesche JC. Update of the molecular basis of familial hypercholesterolemia in The Netherlands. Hum Mutat. 2005;26:550–6. [PubMed] [Google Scholar]37. Leren TP. Cascade genetic screening for familial hypercholesterolemia. Clin Genet. 2004;66:483–7. [PubMed] [Google Scholar]38. van Aalst-Cohen ES, Jansen AC, Tanck MW, Defesche JC, Trip MD, Lansberg PJ, et al. Diagnosing familial hypercholesterolaemia: the relevance of genetic testing. Eur Heart J. 2006;27:2240–6. [PubMed] [Google Scholar]39. Innerarity TL, Weisgraber KH, Arnold KS, Mahley RW, Krauss RM, Vega GL, et al. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci U S A. 1987;84:6919–23. [PMC free article] [PubMed] [Google Scholar]40. Kane JP, Havel RJ. Disorders of the biogenesis and secretion of lipoproteins containing the B apolipoproteins. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler K, Vogelstein B, editors. The Metabolic and Molecular Bases of Inherited Disease. 8. New York: McGraw-Hill; 2001. pp. 2717–52. [Google Scholar]41. Whitfield AJ, Barrett PHR, van Bockxmeer FM, Burnett JR. Lipid disorders and mutations in the APOB gene. Clin Chem. 2004;50:1725–32. [PubMed] [Google Scholar]42. Innerarity TL, Mahley RW, Weisgraber KH, Bersot TP, Krauss RM, Vega GL, et al. Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolemia. J Lipid Res. 1990;31:1337–49. [PubMed] [Google Scholar]43. Soria LF, Ludwig EH, Clarke HR, Vega GL, Grundy SM, McCarthy BJ. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci U S A. 1989;86:587–91. [PMC free article] [PubMed] [Google Scholar]44. Myant NB, Forbes SA, Day IN, Gallagher J. Estimation of the age of the ancestral arginine3500–>glutamine mutation in human apoB-100. Genomics. 1997;45:78–87. [PubMed] [Google Scholar]45. Gaffney D, Reid JM, Cameron IM, Vass K, Caslake MJ, Shepherd J, et al. Independent mutations at codon 3500 of the apolipoprotein B gene are associated with hyperlipidemia. Arterioscler Thromb Vasc Biol. 1995;15:1025–9. [PubMed] [Google Scholar]46. Tai DY, Pan JP, Lee-Chen GJ. Identification and haplotype analysis of apolipoprotein B-100 Arg3500–>Trp mutation in hyperlipidemic Chinese. Clin Chem. 1998;44:1659–65. [PubMed] [Google Scholar]47. Boren J, Ekstrom U, Agren B, Nilsson-Ehle P, Innerarity TL. The molecular mechanism for the genetic disorder familial defective apolipoprotein B100. J Biol Chem. 2001;276:9214–8. [PubMed] [Google Scholar]48. Soufi M, Sattler AM, Maerz W, Starke A, Herzum M, Maisch B, et al. A new but frequent mutation of apoB-100-apoB His3543Tyr. Atherosclerosis. 2004;174:11–6. [PubMed] [Google Scholar]49. Wenham PR, Henderson BG, Penney MD, Ashby JP, Rae PW, Walker SW. Familial ligand-defective apolipoprotein B-100: detection, biochemical features and haplotype analysis of the R3531C mutation in the UK. Atherosclerosis. 1997;129:185–92. [PubMed] [Google Scholar]50. Liyanage KE, Hooper AJ, Defesche JC, Burnett JR, van Bockxmeer FM. High-resolution melting analysis for detection of familial ligand-defective apolipoprotein B-100 mutations. Ann Clin Biochem. doi: 10.1258/acb.2007.007077. in press. [PubMed] [CrossRef] [Google Scholar]51. Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A. 2003;100:928–33. [PMC free article] [PubMed] [Google Scholar]52. Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154–6. [PubMed] [Google Scholar]53. Maxwell KN, Fisher EA, Breslow JL. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci U S A. 2005;102:2069–74. [PMC free article] [PubMed] [Google Scholar]55. Lambert G. Unravelling the functional significance of PCSK9. Curr Opin Lipidol. 2007;18:304–9. [PubMed] [Google Scholar]56. Pisciotta L, Priore Oliva C, Cefalu AB, Noto D, Bellocchio A, Fresa R, et al. Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia. Atherosclerosis. 2006;186:433–40. [PubMed] [Google Scholar]57. Qian YW, Schmidt RJ, Zhang Y, Chu S, Lin A, Wang H, et al. Secreted proprotein convertase subtilisin/kexin-type 9 downregulates low-density lipoprotein receptor through receptor-mediated endocytosis. J Lipid Res. 2007;48:1488–98. [PubMed] [Google Scholar]58. Zhang DW, Lagace TA, Garuti R, Zhao Z, McDonald M, Horton JD, et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem. 2007;282:18602–12. [PubMed] [Google Scholar]59. Poirier S, Mayer G, Benjannet S, Bergeron E, Marcinkiewicz J, Nassoury N, et al. The proprotein convertase PCSK9 induces the degradation of LDLR and its closest family members VLDLR and APOER2. J Biol Chem. 2008;283:2363–72. [PubMed] [Google Scholar]60. Alborn WE, Cao G, Careskey HE, Qian YW, Subramaniam DR, Davies J, et al. Serum proprotein convertase subtilisin kexin type 9 is correlated directly with serum LDL cholesterol. Clin Chem. 2007;53:1814–9. [PubMed] [Google Scholar]61. Homer VM, Marais AD, Charlton F, Laurie AD, Hurndell N, Scott R, et al. Identification and characterization of two non-secreted PCSK9 mutants associated with familial hypercholesterolemia in cohorts from New Zealand and South Africa. Atherosclerosis. doi: 10.1016/j.atherosclerosis.2007.07.022. in press. [PubMed] [CrossRef] [Google Scholar]62. Soutar AK, Naoumova RP. Autosomal recessive hypercholesterolemia. Semin Vasc Med. 2004;4:241–8. [PubMed] [Google Scholar]63. Khachadurian AK, Uthman SM. Experiences with the homozygous cases of familial hypercholesterolemia. A report of 52 patients. Nutr Metab. 1973;15:132–40. [PubMed] [Google Scholar]64. Garcia CK, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M, et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science. 2001;292:1394–8. [PubMed] [Google Scholar]65. Garuti R, Jones C, Li WP, Michaely P, Herz J, Gerard RD, et al. The modular adaptor protein autosomal recessive hypercholesterolemia (ARH) promotes low density lipoprotein receptor clustering into clathrin-coated pits. J Biol Chem. 2005;280:40996–1004. [PubMed] [Google Scholar]66. Naoumova RP, Neuwirth C, Lee P, Miller JP, Taylor KG, Soutar AK. Autosomal recessive hypercholesterolaemia: long-term follow up and response to treatment. Atherosclerosis. 2004;174:165–72. [PubMed] [Google Scholar]67. Soutar AK, Naoumova RP, Traub LM. Genetics, clinical phenotype, and molecular cell biology of autosomal recessive hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2003;23:1963–70. [PubMed] [Google Scholar]68. Eden ER, Sun XM, Patel DD, Soutar AK. Adaptor protein disabled-2 modulates low density lipoprotein receptor synthesis in fibroblasts from patients with autosomal recessive hypercholesterolaemia. Hum Mol Genet. 2007;16:2751–9. [PubMed] [Google Scholar]69. Welty FK, Lahoz C, Tucker KL, Ordovas JM, Wilson PW, Schaefer EJ. Frequency of apoB and apoE gene mutations as causes of hypobetalipoproteinemia in the Framingham offspring population. Arterioscler Thromb Vasc Biol. 1998;18:1745–51. [PubMed] [Google Scholar]70. Glueck CJ, Gartside P, Fallat RW, Sielski J, Steiner PM. Longevity syndromes: familial hypobeta and familial hyperalpha lipoproteinemia. J Lab Clin Med. 1976;88:941–57. [PubMed] [Google Scholar]71. Sankatsing RR, Fouchier SW, de Haan S, Hutten BA, de Groot E, Kastelein JJ, et al. Hepatic and cardiovascular consequences of familial hypobetalipoproteinemia. Arterioscler Thromb Vasc Biol. 2005;25:1979–84. [PubMed] [Google Scholar]72. Schonfeld G, Patterson BW, Yablonskiy DA, Tanoli TS, Averna M, Elias N, et al. Fatty liver in familial hypobetalipoproteinemia: triglyceride assembly into VLDL particles is affected by the extent of hepatic steatosis. J Lipid Res. 2003;44:470–8. [PubMed] [Google Scholar]73. Tanoli T, Yue P, Yablonskiy D, Schonfeld G. Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity. J Lipid Res. 2004;45:941–7. [PubMed] [Google Scholar]74. Yao ZM, Blackhart BD, Linton MF, Taylor SM, Young SG, McCarthy BJ. Expression of carboxyl-terminally truncated forms of human apolipoprotein B in rat hepatoma cells. Evidence that the length of apolipoprotein B has a major effect on the buoyant density of the secreted lipoproteins. J Biol Chem. 1991;266:3300–8. [PubMed] [Google Scholar]75. Burnett JR, Barrett PHR. Apolipoprotein B metabolism: tracer kinetics, models, and metabolic studies. Crit Rev Clin Lab Sci. 2002;39:89–137. [PubMed] [Google Scholar]76. Parhofer KG, Barrett PHR, Aguilar-Salinas CA, Schonfeld G. Positive linear correlation between the length of truncated apolipoprotein B and its secretion rate: in vivo studies in human apoB-89, apoB-75, apoB-54.8, and apoB-31 heterozygotes. J Lipid Res. 1996;37:844–52. [PubMed] [Google Scholar]77. Krul ES, Parhofer KG, Barrett PHR, Wagner RD, Schonfeld G. ApoB-75, a truncation of apolipoprotein B associated with familial hypobetalipoproteinemia: genetic and kinetic studies. J Lipid Res. 1992;33:1037–50. [PubMed] [Google Scholar]78. Parhofer KG, Barrett PHR, Bier DM, Schonfeld G. Lipoproteins containing the truncated apolipoprotein, Apo B-89, are cleared from human plasma more rapidly than Apo B-100-containing lipoproteins in vivo. J Clin Invest. 1992;89:1931–7. [PMC free article] [PubMed] [Google Scholar]79. Hooper AJ, Robertson K, Barrett PH, Parhofer KG, van Bockxmeer FM, Burnett JR. Postprandial lipoprotein metabolism in familial hypobetalipoproteinemia. J Clin Endocrinol Metab. 2007;92:1474–8. [PubMed] [Google Scholar]80. Burnett JR, Shan J, Miskie BA, Whitfield AJ, Yuan J, Tran K, et al. A novel nontruncating APOB gene mutation, R463W, causes familial hypobetalipoproteinemia. J Biol Chem. 2003;278:13442–52. [PubMed] [Google Scholar]81. Burnett JR, Zhong S, Jiang ZG, Hooper AJ, Fisher EA, McLeod RS, et al. Missense mutations in APOB within the βα1 domain of human APOB-100 result in impaired secretion of ApoB and ApoB-containing lipoproteins in familial hypobetalipoproteinemia. J Biol Chem. 2007;282:24270–83. [PubMed] [Google Scholar]82. Berriot-Varoqueaux N, Aggerbeck LP, Samson-Bouma M, Wetterau JR. The role of the microsomal triglygeride transfer protein in abetalipoproteinemia. Annu Rev Nutr. 2000;20:663–97. [PubMed] [Google Scholar]83. Hooper AJ, van Bockxmeer FM, Burnett JR. Monogenic hypocholesterolaemic lipid disorders and apolipoprotein B metabolism. Crit Rev Clin Lab Sci. 2005;42:515–45. [PubMed] [Google Scholar]84. Wetterau JR, Aggerbeck LP, Bouma ME, Eisenberg C, Munck A, Hermier M, et al. Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science. 1992;258:999–1001. [PubMed] [Google Scholar]85. Sharp D, Blinderman L, Combs KA, Kienzle B, Ricci B, Wager-Smith K, et al. Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia. Nature. 1993;365:65–9. [PubMed] [Google Scholar]86. Shoulders CC, Brett DJ, Bayliss JD, Narcisi TM, Jarmuz A, Grantham TT, et al. Abetalipoproteinemia is caused by defects of the gene encoding the 97 kDa subunit of a microsomal triglyceride transfer protein. Hum Mol Genet. 1993;2:2109–16. [PubMed] [Google Scholar]87. Ohashi K, Ishibashi S, Osuga J, Tozawa R, Harada K, Yahagi N, et al. Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia. J Lipid Res. 2000;41:1199–204. [PubMed] [Google Scholar]88. Rehberg EF, Samson-Bouma ME, Kienzle B, Blinderman L, Jamil H, Wetterau JR, et al. A novel abetalipoproteinemia genotype. Identification of a missense mutation in the 97-kDa subunit of the microsomal triglyceride transfer protein that prevents complex formation with protein disulfide isomerase. J Biol Chem. 1996;271:29945–52. [PubMed] [Google Scholar]89. Wang J, Hegele RA. Microsomal triglyceride transfer protein (MTP) gene mutations in Canadian subjects with abetalipoproteinemia. Hum Mutat. 2000;15:294–5. [PubMed] [Google Scholar]90. Chowers I, Banin E, Merin S, Cooper M, Granot E. Long-term assessment of combined vitamin A and E treatment for the prevention of retinal degeneration in abetalipoproteinaemia and hypobetalipoproteinaemia patients. Eye. 2001;15:525–30. [PubMed] [Google Scholar]91. Li CM, Presley JB, Zhang X, Dashti N, Chung BH, Medeiros NE, et al. Retina expresses microsomal triglyceride transfer protein: implications for age-related maculopathy. J Lipid Res. 2005;46:628–40. [PubMed] [Google Scholar]92. Berge KE, Ose L, Leren TP. Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy. Arterioscler Thromb Vasc Biol. 2006;26:1094–100. [PubMed] [Google Scholar]93. Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37:161–5. [PubMed] [Google Scholar]94. Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis. 2007;193:445–8. [PubMed] [Google Scholar]95. Brown MS, Goldstein JL. Biomedicine. Lowering LDL–not only how low, but how long? Science. 2006;311:1721–3. [PubMed] [Google Scholar]96. Cohen JC, Boerwinkle E, Mosley TH, Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264–72. [PubMed] [Google Scholar]

Both Genetics And Diet Influence Cholesterol Levels — ScienceDaily

New research on twins shows that genetics plays a predominate role in differences in cholesterol levels between people. However, a person’s diet also is significantly associated with cholesterol level independent of inherited factors.

Identical twins who differed the most in their dietary intake had corresponding differences in blood cholesterol measures, showing that the association between diet and cholesterol levels was independent of genetic factors, say Jeanne M. McCaffery and Michael F. Pogue-Geile, who conducted the research in the Department of Psychology at the University of Pittsburgh.

This is the first research in twins to demonstrate an environmental association between diet and cholesterol, according to the study published in the September issue of Health Psychology.

“Because [identical] twins share all their genes, differences between [identical] co-twins, and the correlations of these differences seen here must be attributable to environmental effects of some nature,” they say.

The researchers recruited 204 pairs of same-sex twins from the Pittsburgh area to participate in the study. Blood samples were drawn and subjects were instructed to keep a food diary over a three-day period. Subjects ranged in age from 18 to 30.

The researchers also found that identical twins displayed more similarities in cholesterol levels than were seen in fraternal twins, who do not have all of the same genes. This shows that there are important genetic factors that account for variation in cholesterol levels. In fact, genetic factors accounted for the majority of differences in cholesterol levels among these young adults.

Controlling for this variation due to genetic factors allowed the researchers to show that factors such as fat and calorie intake also have an environmental association with total cholesterol, high-density lipoprotein and low-density lipoprotein levels, although this accounts for a smaller proportion of the differences among individuals.

While the results of this study are consistent with recommendations for changes in caloric and fat intake, it was based on existing associations in the community and did not attempt to alter dietary habits. Therefore, the nature of this study does not directly address the effects of dietary changes on cholesterol lowering, says Pogue-Geile.

Jeanne M. McCaffery currently works at Centers for Behavioral and Preventive Medicine at Brown Medical School.

The study was supported with funding from the National Heart, Lung and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institutes of Mental Health.

Story Source:

Materials provided by Center For The Advancement Of Health. Note: Content may be edited for style and length.

High cholesterol can be genetic killer. It’s more common than you think.

High cholesterol can be genetic

Fern Taylor at her home on Wednesday, September 4, 2019. Taylor has familial hypercholesterolemia (FH), which is genetic high cholesterol.

Michael Karas, NorthJersey

Fern Taylor wears a yellow dress in the faded photo, standing with her mother at a wedding in 1978. It’s the only picture of them together — her mother, a photographer, was usually behind the camera.

The photo is even more special because Taylor’s mother died suddenly a year later, at age 56.

Taylor’s mother hadn’t shown any cardiac abnormalities when she had her first heart attack. But a blood test revealed she had genetic high cholesterol, causing her level to soar to 600 miligrams per deciliter, nearly six times normal.

And Taylor inherited the condition.

But unlike her mother, Taylor, now 61 and a Wayne resident, won’t suffer premature cardiovascular disease, thanks to an early diagnosis — and medical advancements in the form of a $14,000 drug. Her medications, she said, are saving her life.

Familial hypercholesterolemia, or FH, affects one in 250 people in the U.S. But 90% of people who have it aren’t aware they’re affected.

In New Jersey, that’s approximately 35,600 people with FH, including 32,040 who don’t know about it.

“It is remarkably underdiagnosed,” said Daniel Rader, a professor of molecular medicine at the University of Pennsylvania’s Perelman School of Medicine who specializes in lipid disorders, including FH.

The condition elevates the risk of cardiovascular events, such as heart attacks and strokes, and the threat increases for people who have already experienced a cardiac event, are overweight or smoke. Untreated people with FH experience heart attacks 20 times more than normal.

FH can be identified by two factors: family history and cholesterol levels determined by a blood test. Rader said he suspects FH when a patient has a family history of high cholesterol and LDL or low-density lipoprotein levels higher than 190, despite maintaining a healthy lifestyle. LDL is considered bad cholesterol.

That diagnosis “tells someone they have an inherited cause to their high cholesterol,” Rader said. After one person is diagnosed, their family members should be tested.

More: 6 battled back from bad injuries, illnesses. Now they’re honored for inspiring others

Family tree

From a stack of papers on her kitchen table, Taylor retrieved a hand-drawn family tree. She circled the relatives with FH. There are at least 15, and five have died from FH complications.

Taylor has heterozygous FH, the more common form, which results when a child inherits one mutated gene from a parent. Siblings and children of someone with heterozygous FH have a 50% chance of inheriting the mutation, according to the Centers for Disease Control and Prevention.

The outlook for homozygous FH is worse.  The rare form of the condition occurs when both parents pass down the gene mutation.

“Things progress much faster,” said Cat Davis Ahmed, an FH patient and spokeswoman for the FH Foundation. “Their LDL cholesterol is much higher.”

Taylor knows the mutation runs on her mother’s side of the family. But her brother, she said, “lucked out”: He’s part of the 50% without the mutation.

Taylor’s two sons have a similar situation. Alex, now 31, was tested and diagnosed with FH when he was 2. Hisbrother doesn’t have it. 

“I was upset, at first,” Taylor said of her son’s diagnosis. She withheld the family history from Alex for years, even as treatment became routine for him.

But because he was diagnosed and began treatment young, Alex Taylor said he is not concerned.

“It’s not debilitating,” he said. “It doesn’t really affect my day-to-day much.

“It’s people who don’t know about it,” he added, “is really where it affects this population.”

First line of treatment

Fern Taylor became involved in the FH community a few years ago, hoping to raise awareness about the condition. She’s improved her social media skills just in time for a tweet-a-thon on FH Awareness Day, which is Sept. 24.

One of her main goals, she said, is to help people understand that FH isn’t a typical high-cholesterol situation. While lifestyle choices can help manage FH, diet and exercise alone aren’t enough.

Taylor knows this firsthand. At one point, she ate only frozen vegetables for two months, then had her cholesterol levels tested.

They hadn’t changed.

“It was really discouraging,” Taylor said. “I had a terrible fear the same thing would happen to me that happened to my mother.”

But Taylor’s mother lived before FH treatments were invented. The first statin, a lipid-lowering medication prescribed to people with FH, went on the market in 1987, nearly a decade after her death.

“Statins are absolutely the first line of treatment for patients with FH,” Rader said. “There’s no reason to consider any medication class other than statins, initially. They’re underutilized.”

Children as young as 8 can take statins, Rader added. The earlier the condition is managed, the better the outlook.

When Fern Taylor started taking statins in her late 20s, the medications brought her total cholesterol down to 285 from 400 — an improvement, but well above the ideal safe level, which is no more than 200.

Enter PCSK9 inhibitors, injections that minimize  proliferation of bad cholesterol in the bloodstream.

The injections, which became available in 2015, can lower cholesterol by as much as 60% within a week, Rader said.

Patients using the inhibitors continue taking statins, Ahmed said. In Taylor’s case, the combination brought her cholesterol level down to “miraculous” numbers. .

For Alex Taylor, insurance covers a chunk of the PCSK9 inhibitor treatment cost. A co-pay plan from the drug’s manufacturer covers nearly all the rest. He pays $10 a month.

But in other instances, getting coverage is a thorny task. Insurance companies reject PCSK9 inhibitor coverage frequently, according to a 2018 report from the FH Foundation.

Without insurance, the drug’s price tag is more than $14,000 annually, according to the American Journal of Managed Care.

In the FH Foundation study, people diagnosed with FH who had commercial insurance had a 35% PCSK9 inhibitor prescription rejection rate. Medicare patients had a 20% rejection rate.

Rejection likelihood varies by provider.

Staff at Rader’s specialized practice are used to making calls to insurance companies on patients’ behalf and having physicians make appeals, he said.

That also means it’s harder for patients at smaller practices to receive coverage for treatment, making lack of access to specialists a major barrier to care, he said.

The study also found that women, minorities and low-income individuals were disproportionately affected by insurance company denials.

Many prescriptions approved go unfilled, likely because of high-out-of-pocket costs, Rader said. Two-thirds of the unfilled prescriptions were among Medicare patients.

“We can speculate,” Rader said, “but the fact is that this is a health care disparities issue.”

More: Disabled athletes to participate in first ‘Hope and Possibility’ race in Englewood

Hurdles

The treatments aren’t one-size-fits-all.

Some patients can’t tolerate statins or PCSK9 inhibitors. For people with the rare form of FH, the two treatments simply don’t do enough. Pregnant women can’t take the medications because their effect on child development are unknown.

“Sometimes it’s a shuffle of medications until you find your ideal treatment,” Fern Taylor said. “You might start out with a smaller statin, a weaker one, and then increase it.”

The number of medical advancements she’s seen in her lifetime have made Taylor confident the treatment options will continue to grow, she said.

“Before my mother died, she said to me, ‘don’t worry,’” Taylor said. “She said, ‘there will be breakthroughs and you will be helped.’”

She paused.

“I don’t know if she really knew,” Taylor added. “It’s very sad. And I’m just so thankful.”

High cholesterol can be genetic, and a DNA test may help

Familial Hypercholesterolemia—often known by its acronym, FH, is a condition where a person’s body processes cholesterol differently, leading to chronically elevated cholesterol levels. It is genetic, which is why you may have heard it described as “inherited high cholesterol.” So, why is it so important to know whether you or members of your family have FH?

Your body packages cholesterol into fat pods (doctors know these as lipids) that circulate through the body. When there is more cholesterol and less fat in those pods, they are called low-density lipoproteins (LDL-C)—also known as “bad cholesterol.” These LDL-C fat pods are normally pulled out of the bloodstream by your liver. But in individuals with FH, gene variants affect one or more of the proteins involved in collecting LDL-C from the blood. These variants limit the liver’s ability to remove LDL-C and can lead to heart conditions in both children and adults, including coronary heart disease and stroke.

 

Unfortunately, FH is underdiagnosed

FH is a genetic disorder, and there are various forms of it depending on which gene variant a person carries. (A gene variant is what we call a gene when there is a slight difference in its DNA sequence relative to other people, so there can be multiple variations, or variants, of a given gene.) The most common form of FH is when a person has one copy of an FH related gene variant that’s inherited from one of their parents, which is what we commonly refer to when talking about FH. (In this article we focus on this type, but great resources are available to learn about other types.)

Unfortunately, FH is underdiagnosed. In fact, in the US population, rates of FH may be as high as 1 in every 200-250 individuals. For those who have FH, the risk of heart attack is more than 20 times greater than someone without FH and with normal cholesterol.

How can you know if you have FH?

FH can be identified through genetic testing. Genetic testing reads your DNA in search of gene variants among four different genes that are known to be associated with FH. For individuals who have been diagnosed with FH, it is recommended that family members also get tested, because the condition can be inherited. For three of the four genes associated with FH, at least 50% of direct relatives (parents, children, and siblings) will have the disease-causing gene variant as well.

What can be done after an FH diagnosis?

It’s important to talk to your doctor, because both lifestyle changes and medication can be essential parts of FH management. Individuals with FH are often put on statin therapy, which helps to prevent dangerous cholesterol buildup in the blood. Because people with FH are exposed to high cholesterol levels from birth, early diagnosis and active treatment is important in reducing risk. Amazingly, a 2008 study showed that statin therapy could reduce the risk of heart disease by some 76% in those with FH.

Genetic testing pushed for hereditary high cholesterol disease

For the past four years cardiologist Josh Knowles, MD, PhD, has been treating patients at Stanford who have a little-known but common genetic heart disease called familial hypercholesterolemia, or FH, an often undiagnosed condition that causes lifelong high cholesterol. FH is thought to be the cause for 12,500 heart attacks each year among people under the age of 60 in the U.S., he told me.

Catching the disease early on can save lives, he emphasizes.

“Two individuals may have the exact same high cholesterol level, but if one has FH, they’re at much higher risk,” Knowles explained. “They need to be treated more aggressively and their relatives need to be aware of the risks for themselves.”

Now a panel of international experts recommends that genetic testing for FH become the standard of care in the United States for patients thought to have the condition and their relatives — as it has been since the early 1990s for many other countries. Knowles, a member of the panel which published its recommendations this month in the Journal of the American College of Cardiology, has seen firsthand the benefits of genetic testing which he offers routinely to his patients.

“Genetic testing should be offered as part of standard of care for FH,” says Knowles, who also researches the genetic causes of FH. “Part of the reason it has not been offered is that providers have not fully understood the potential benefits.”

Prohibitive costs in the past have limited the use of genetic testing in general for patients, but as availability has increased and costs have declined its use has become increasingly more routine for a variety of disorders. Four or five years ago, costs ran between $2,000 to $2,500 for FH testing, but have since dropped to just a few hundred dollars, Knowles said, although its use is currently far from routine.

The paper, which was based on a review of the literature, found that genetic testing for FH not only improved diagnosis but led to better treatment plans, and encouraged patients to be more vigilant in taking their prescribed lipid-lowering medications such as statins.

“Despite FH being a genetic disorder, genetic testing is rarely used,” the authors write. By making genetic testing routine, not only would it improve diagnosis, it would also lead to better identification of relatives with the disease. FH is a condition that affects families, they write.

An estimated 1 million people in the United States have FH yet only 10 percent have been diagnosed, the paper says. Many of these people might realize they have high cholesterol, but have no clue they also have FH. Since they are born with high levels of LDL — the so-called bad cholesterol — that build up in the arteries and can ultimately choke off blood flow to the heart, if not treated, they’re at much higher risk of heart attacks and stroke.

The panel was convened by the FH Foundation to assess the use of genetic testing for the condition. Knowles is a volunteer advisor for the foundation.

Photo by Robina Weermeijer

90,000 High cholesterol? Bring your relatives for examination!

Familial hypercholesterolemia is a hereditary monogenic disease. It occurs due to a genetic defect that causes high blood cholesterol levels and is passed down from generation to generation. The type of cholesterol that is specifically elevated in familial hypercholesterolemia is low-density lipoprotein cholesterol (LDL-C) so-called. “Bad cholesterol”. The higher it is, the higher the risk of early development of cardiovascular diseases (coronary heart disease, myocardial infarction or stroke).In patients with this disease, the level of LDL-C is increased from birth by 2 times, compared with the norm.

Familial hypercholesterolemia is one of the most common hereditary diseases. Approximately 1 in 200 people worldwide have genetic damage that causes the disease. If one of the parents has familial hypercholesterolemia, then with a 50% probability, children will also be sick with it. It is important to identify and correctly treat familial hypercholesterolemia as early as possible (ideally in childhood), as this significantly reduces the risk of developing cardiovascular diseases and prolongs life.

Doctors sound the alarm and urge everyone to donate blood for cholesterol without fail!
This is especially true for those who have a dysfunctional heredity – cardiovascular diseases or high cholesterol levels in close relatives. Familial hypercholesterolemia is diagnosed by a doctor using specially developed diagnostic criteria that take into account a whole range of clinical criteria:
– cholesterol level,
– the presence of tendon xanthomas,
– diseases caused by atherosclerosis in the patient and his family members, etc.
– genetic factors.

DNA isolated from blood cells is used for genetic testing. Close relatives, such as parents, siblings and children of a patient with familial hypercholesterolemia, have a 50% risk of also having this disease. Evaluation of family members is key to early diagnosis of familial hypercholesterolemia.
Patients with familial hypercholesterolemia should be treated under the supervision of a lipidologist – a specialist in blood lipid disorders.For treatment, a lipid-lowering diet, regular physical activity, drug correction with lipid-lowering drugs, and, in some cases, apheresis of atherogenic lipoproteins are used.

A lipid clinic operates on the basis of the FSBI NMITs TPM, which is fully ready to provide assistance to such patients. The clinic employs experienced lipidologists who, over the past few years, have been actively studying various lipid metabolism disorders and are introducing the accumulated experience and knowledge into everyday practice.Any laboratory and instrumental diagnostics is available, including a genetic blood test.
You can make an appointment with a lipidologist by phone +7 (495) 790-71-72

High cholesterol

Patient Education Program

Basic Information:

Millions of people around the world have high blood cholesterol levels.This condition is described by the medical term hyperlipidemia. Elevated cholesterol levels increase the risk of myocardial infarction and stroke. This course explains what cholesterol is, how elevated levels lead to heart disease, and what can be done (with and without medication) to lower cholesterol.

1. What are lipids and cholesterol?

Cholesterol, fatty acids and triglycerides are types of fats (lipids).This lesson explains what lipids are and shows why they are important to life.

Description

There are three types of lipids: cholesterol, fatty acids and triglycerides. Fatty acids are of two types: saturated and unsaturated. Unsaturated fatty acids can be monounsaturated or polyunsaturated.

Cholesterol

Cholesterol is normally present in all tissues of the body. The human body is made up of millions of cells. Their walls include lipids, including cholesterol.Without cholesterol, our cells would not be able to function properly. Cholesterol is also one of the basic building blocks of bile salts (which aid in the digestion of fats), vitamin D and hormones. Cholesterol comes from two sources. Approximately 70% is synthesized by the body itself, mainly in the liver. Another 30% comes from food. We all consume foods that contain cholesterol.

Fatty acids

Other important types of lipids are fatty acids and triglycerides.Like cholesterol, they are essential components of cell walls.

Fatty acids are formed in the body, but some of them must be ingested with food. Fatty acids are of two types: saturated and unsaturated. Unsaturated fatty acids can be monounsaturated or polyunsaturated.

Lipoproteins

Lipids are needed by all body tissues, so they are transported by the blood using chemicals called lipoproteins.These lipoproteins can bind to various cell structures in the body and release lipids as needed. The two main categories of lipoproteins that carry cholesterol in the body are called High Density Lipoproteins (HDL) and Low Density Lipoproteins (LDL). These are described in more detail in the next section

2. What is the difference between HDL and LDL cholesterol?

HDL and LDL are the main lipoproteins used for the transport of cholesterol in the body.HDL cholesterol is often referred to as “good” and LDL cholesterol is often referred to as “bad.” This section explains why.

Description

Lipoproteins – such as high density lipoproteins (HDL) and low density lipoproteins (LDL) – are the main carriers of cholesterol. They bind to cholesterol, transfer it to another part of the body, and then release it if necessary.

LPNP

LDL can carry 60 – 70% of blood cholesterol. One of the unpleasant features of LDL is their tendency to “stick” to the walls of blood vessels.Therefore, LDL is the main class of lipoproteins found in atherosclerosis (a disease that builds up deposits on the walls of arteries), and high LDL cholesterol levels are an important risk factor for cardiovascular disease.

This will be described in more detail in the next section. Because of this, LDL cholesterol is often referred to as “bad” cholesterol.

HDL

HDL is the smallest class of lipoproteins, which carries 20-30% of blood cholesterol.HDL binds excess cholesterol and returns it to the liver for processing and / or removal from the body. Thus, unlike LDL, HDL removes cholesterol from the circulating blood. High HDL is believed to lower the risk of heart disease, which is why HDL cholesterol is often referred to as “good.”

Ratio

The ratio of LDL to HDL is often used to assess the risk of cardiovascular disease in a patient. High values ​​reflect the predominance of LDL cholesterol (bad) and indicate a high risk.Low values ​​reflect the predominance of HDL (good) cholesterol and indicate low risk.

3. What is dyslipidemia?

Dyslipidemia is a condition in which the levels of lipids in the blood are altered, for example, high cholesterol levels. This section explains what dyslipidemia is and points out two of its causes.

Description

Besides cholesterol, there are other important classes of lipids, including fatty acids and triglycerides.The set of lipids and their levels in each patient is usually referred to as his lipid profile. The body regulates the levels of these lipids, which depend on each other. Most people have normal levels of these lipids. However, in some people, the amounts of certain types of lipids may fall outside the normal range. This condition is called dyslipidemia. So what can cause dyslipidemia? Dyslipidemia can be either primary or secondary. Primary dyslipidemia is caused by genetic or hereditary disorders, and these conditions are quite rare.Secondary dyslipidemias are much more common. They are caused by another medical condition, certain drugs, hormones, or lifestyle factors (such as fatty foods, obesity, and insufficient physical activity). Undoubtedly, it is much easier to treat secondary dyslipidemia.

4. Elevated cholesterol is the cause of the disease

An increase in cholesterol levels can lead to the formation of plaque on the walls of the arteries – atherosclerosis. As a result, the movement of blood through the vessels may be impaired, and in some cases rupture of the affected vessel may occur.Depending on the organ in which this happens, such a process can cause a serious complication, such as a stroke or heart attack. This tutorial explains how this happens.

Description

Atherosclerosis is a process of formation of fatty or fibrous deposits in the form of plaques on the walls of blood vessels. In this case, the lumen of the blood vessel narrows over time, and its wall becomes denser.

So what is the role of high cholesterol in the formation of these plaques?

Plaque

Plaque formation begins with damage to the inner lining of a blood vessel.This damage can result from smoking, high blood pressure, or too high blood glucose levels (such as in diabetes). This damage allows LDL to penetrate into the walls of blood vessels. Immune cells also enter the vessel wall and, absorbing LDL, turn into foam cells. Clusters

foam cells under the microscope look like fat strips. The foam cells produce chemicals that form a fibrous layer on the surface of the fatty strip, resulting in an atheromatous plaque.What disorders do these plaques lead to? There are three main events caused by the presence of atherosclerotic plaques.

Ischemia

Growing plaque can narrow the lumen of a blood vessel, restricting tissue blood flow and oxygen supply. This condition is called ischemia.

Embolism

Small pieces of plaque can break off and circulate in the blood, blocking other vessels. This is called an embolism. The rupture of the plaque can also lead to the release of stored cholesterol into the bloodstream.The contents of the plaque can also cause a blood clot to form at the rupture site.

Aneurysm

Plaque formation on the walls of blood vessels can weaken the walls of blood vessels, resulting in spherical expansions called aneurysms. As the aneurysm grows, the walls of the vessel become thinner and weaker; the likelihood of rupture and life-threatening hemorrhage increases. These three processes can have serious consequences, depending on where in the body they occur.Move the cursor over the three areas of the body shown.

5. What does your lipid profile mean

Your doctor may order a lipid profile test if you suspect you have dyslipidemia. In this case, the blood test will determine the levels of basic lipids and lipoproteins. Before taking blood for this test, you should not eat for 12 hours, as many of these lipids rise after meals.

Description

In the study of the lipid profile, the content of triglycerides, total cholesterol, HDL (sometimes written “HDL cholesterol”) and LDL (sometimes written “LDL cholesterol”) are determined.The LDL / HDL ratio is often reported in the study report. In the United States, the unit for measuring lipid levels is milligrams per deciliter (mg / dl), and in Europe and Russia, millimoles per liter (mmol / L). Recommended levels vary from country to country and change frequently. In Russia, the European guidelines for the prevention of CVD are used. According to these recommendations, the optimal lipid values ​​are: total cholesterol <5 mmol / L (<200 mg / dL), LDL cholesterol <3.0 mmol / L (<115 mg / dL), HDL cholesterol> 1.0 mmol / L in men (> 40 mg / dL) and> 1.2 mmol / L in women (> 46 mg / dL), triglycerides <1.7 mmol / L (<155 mg / dL).

In patients with ischemic heart disease and / or atherosclerosis of peripheral arteries, carotid arteries, as well as in the presence of diabetes mellitus, the recommended level of total cholesterol is <4.5 mmol / l, and "bad" cholesterol <2.6 mmol / l.

Rollover Text:

Triglycerides (TG): Triglycerides are not as closely related to disease as cholesterol. However, normal levels should not exceed 1.7 mmol / L (150 mg / dL), and your doctor may prescribe medication if they find you have more than 200 mg / dL (2.3 mmol / L).

Total Cholesterol: Ideally, your total cholesterol should be below 5.2 mmol / L (200 mg / dL).

HDL cholesterol: “Good cholesterol” should ideally be above 1.1 mmol / L (45 mg / dL) in men and 1.4 mmol / L (55 mg / dL) in women before menopause. Levels above 60 mg / dL (1.55 mmol / L) are particularly beneficial and reduce the risk of cardiovascular disease.

LDL Cholesterol: This “bad cholesterol” should ideally be below 2.6 mmol / L (100 mg / dL).

The ratio of LDL cholesterol to HDL cholesterol: A ratio below 3.5 is considered normal. A ratio of 5.0 or higher should be alarming. This attitude is often considered to be an indicator of a high risk of cardiovascular disease.

6. What is your risk of heart attack?

High cholesterol is only one of many risk factors associated with atherosclerosis and cardiovascular events such as myocardial infarction. This section describes these risk factors.

Description

A risk factor is a symptom (such as obesity or smoking) that increases the likelihood of developing a disease. Risk factors that indicate the possibility of developing heart disease are subdivided into manageable and unmanageable. Unmanageable factors are factors that a person cannot influence, for example, age (the risk of cardiovascular disease increases with age), heredity, gender and ethnicity. Controllable risk factors are those that can be changed.Among them – smoking, obesity, diet, lack of physical activity, dyslipidemia, high

blood pressure and diabetes. Answer the following questions and press enter to see a numerical estimate of your risk factors. If you are not sure about the answer, leave it blank. Click “continue” when you’re done with this section. The risk of coronary heart disease increases significantly when multiple risk factors are present, as the influence of the individual factors is multiplied rather than cumulative.This diagram shows how the relative risks are combined. For example, if a person smokes, his relative risk is 1.6, i.e. the likelihood of developing cardiovascular disease, which can lead to a heart attack, is 1.6 times higher than that of a nonsmoker. If the same person also has high blood pressure, the relative risk rises to 4.5. If the same person has high cholesterol levels, the relative risk rises sharply to 16. Therefore, the more risk factors you eliminate, the lower your risk of cardiovascular disease.

7. How can you lower your cholesterol level?

There are many ways to reduce cholesterol levels. Most of these are associated with lifestyle changes such as dietary changes and increased physical activity. Such changes are described in this section.

Description

A list of foods and dishes is shown here. Check the ones that you regularly eat or drink. Click “continue” when you’re done with this section.Shown here is a diagram describing the different types of lipids.

Rollover Text:

Fats / Lipids: Eat less fatty foods. Fat should be less than 30% of your calories. (For a person consuming 2,000 calories per day, this means a daily intake of no more than 65 grams of fat.)

Cholesterol: Cholesterol is found only in food of animal origin, i.e. in meat, dairy products, but not in fruits, vegetables, or nuts.Limit your cholesterol intake to no more than 300 milligrams (mg) per day.

Fatty acids / triglycerides (TG): Unlike cholesterol, they are

are found in food of animal and plant origin. Saturated Fat: These are the worst fats. Saturated fats are dense at room temperature. They are found in animal fats and some oils of tropical plants (including palm and coconut).These fats raise LDL cholesterol levels. Saturated fat should make up less than 10% of your calories.

Unsaturated fat: Unsaturated fat is better than saturated fat.

Unsaturated fats are found in plants. They have a liquid consistency at room temperature.

Polyunsaturated fat: Sunflower, corn and soybean oils contain polyunsaturated fats.

Monounsaturated Fat: These are the best fats.Examples: rapeseed and rice oils. This type of fat helps raise HDL cholesterol levels.

8. What medications can be used?

There are currently 5 main classes of drugs that can lower lipid levels. Statins are the most commonly used drugs. In addition, resins (also known as bile acid sequestrants), cholesterol absorption inhibitors, fibrates, and niacin are available. This section describes these drugs.

Description

Statins

Statins are the most commonly used lipid-lowering drugs.Cholesterol is produced in all cells of the body, but most of it is formed in the liver. Therefore, reducing the production of cholesterol by the liver has become the main goal of drug therapy. To understand the mechanism of action of statins, you need to know the pathways for the synthesis of cholesterol. Cholesterol is formed as a result of a multi-stage process, and statins inhibit one of its stages. The main enzyme that controls this process is HMG CoA reductase. Statins affect the activity of this enzyme and block the pathway of cholesterol synthesis in the body.Therefore, the body produces less cholesterol, and its level in the patient’s blood decreases. Several statins are currently available. Talk to your doctor about the various statins and their benefits. There are also other drugs that lower cholesterol and triglyceride levels. They can be used alone or in combination with statins.

Resins

Resins bind salts of bile acids, after which they are excreted in the feces. The liver responds to the loss of bile salts by using more cholesterol to synthesize new bile salts, and thus lowering cholesterol levels in the body.

Cholesterol absorption inhibitors

Likewise, cholesterol absorption inhibitors limit cholesterol absorption in the intestine and thereby lower lipid levels.

Fibrates

Fibrates are another example of nonstatin drugs for the treatment of dyslipidemia. These drugs lower LDL levels somewhat, but are mainly used to correct high triglycerides and low HDL levels.

Nicotinic acid

Finally, nicotinic acid, which belongs to the group of PP vitamins, lowers LDL cholesterol and triglycerides, while increasing HDL cholesterol.It is an effective remedy for raising HDL cholesterol levels.

Thank you!

We hope you enjoyed this course. If you think that you or someone close to you have this disease, consult your doctor.

Atherosclerosis / Diseases / Clinic EXPERT

What is atherosclerosis and what is its danger to human health?

At the beginning of the 21st century, cardiovascular diseases are the leading cause of death in the world.In Russia, more than 50% of deaths are due to diseases of the heart and blood vessels.

Of course, most cardiovascular diseases, both in men and women, occur over the age of 65. However, in recent years, heart disease has been steadily getting younger. And it is no longer uncommon for a thirty-year-old “hypertensive” person or a patient who had a heart attack at the age of 40-45.

What is the reason?

The answer is quite simple: atherosclerosis.

Atherosclerosis is a chronic, systemic, long-term disease that affects the arteries of the elastic (aorta) and muscular-elastic (arteries of the heart, brain) type.It has an undulating course with phases of progression, stabilization and even reverse development of the disease.

But over the past 50 years, people have faced a significant acceleration in the development of atherosclerosis. If in the first half of the twentieth century such complications of atherosclerosis as heart attack and angina pectoris were not socially significant, today atherosclerosis is considered an epidemic.

The main element that determines the danger of atherosclerosis is an atherosclerotic plaque, which, protruding into the lumen of the vessel, causes its narrowing and impedes blood flow.Atherosclerotic plaque is a complex structure of formation, consisting of an accumulation of lipids (fats), smooth muscle cells, connective tissue. Atherosclerotic plaques can grow in size, rupture, ulcers and blood clots can form on their surface. The result of the development of an atherosclerotic plaque will be a violation of the free flow of blood through the vessel, up to its complete cessation.

Grades of atherosclerosis

I degree – preclinical period of the disease

II degree – mild atherosclerosis

III degree – significantly pronounced atherosclerosis

IV degree – pronounced atherosclerosis

The clinical picture varies depending on the prevalence of the process and the prevalence of the process is determined by the consequences of tissue or organ ischemia.

In the twentieth century, several dozen theories were proposed to explain the origin and progression of atherosclerosis. But to date, none of them has been conclusively proven.

Let’s try to figure out what leads to the formation of atherosclerotic plaques in the vessels, and what causes them to grow, rupture and lead a person to death.

One of the first theories of the development of atherosclerosis was the theory of excessive consumption of cholesterol, which was put forward by the famous Russian scientist N.N. Anichkov. “There is no atherosclerosis without cholesterol.” For many years this postulate determined the tactics of treating patients, and today it has not lost its relevance. However, now we know perfectly well: atherosclerosis is a complex disease, which is based on various disorders in the biochemical, genetic and immune processes of the body. And now it became clear why a person with normal cholesterol levels can develop serious atherosclerosis.

Information for those who consider themselves perfectly healthy

Atherosclerosis itself, especially in the initial stages, may not manifest itself in any way.

This period is called the preclinical stage. It is very important to identify the disease at this stage, since the appearance of symptoms usually indicates the irreversibility of the process. Atherosclerosis is the main cause of the development of coronary heart disease, which is characterized by the appearance of chest pain during physical exertion, the development of a heart attack and heart failure, serious heart rhythm disturbances. Sometimes the first clinical manifestation of atherosclerosis is stroke or sudden death.Even this information is enough to think: “Do I have atherosclerosis or the risk of its development?”

Currently, there are more than 200 risk factors for the development of atherosclerosis, but the main ones are arterial hypertension, smoking and lipid (cholesterol) metabolism disorders. At the same time, smoking increases the risk of developing a heart attack or stroke by 1.6 times, high blood pressure (BP) by 3 times, lipid metabolism disorders by 4 times, and the combination of these three factors increases the risk of vascular catastrophes by 16 times.Other significant risk factors for the development of atherosclerosis include: male sex, obesity, disorders of carbohydrate metabolism (diabetes mellitus), age (over 60 years), the onset of menopause in women, unfavorable heredity for early cardiovascular pathology (relatives got sick before 50-55 years ), chronic stress. In addition, in recent years, in the light of the changed ideas about the causes of atherosclerosis, much attention is paid to the presence of a chronic inflammatory process in the body, diseases of the liver and stomach (especially in the presence of Helicobacter pylori), and excessive levels of homocysteine ​​in the blood.

It has been proven that almost all risk factors for atherosclerosis have an adverse effect on the endothelial cells that form the inner surface of the vascular wall. Damage to these cells and impairment of their function is a key factor in the development of atherosclerosis.

So, the risk of getting atherosclerosis increases if:

  • you smoke
  • there is arterial hypertension
  • there is an increase in cholesterol level
  • there is overweight
  • you have been diagnosed with diabetes mellitus
  • vascular diseases under the age of 50)
  • there is a pathology of the gastrointestinal tract (fatty hepatosis, chronic gastritis or peptic ulcer disease)
  • menopause has begun.

Atherosclerosis is dangerous for its complications. It is necessary to identify it as early as possible in order to prevent the development of complications and begin timely treatment.

Diagnostics

The main studies for the diagnosis of atherosclerosis are:

  • lipidogram
  • angiography
  • Doppler sonography (ultrasound screening for atherosclerosis).

The very first step towards detecting atherosclerosis is to take a simple blood lipid test.In this case, it is precisely a detailed lipidogram that is needed, and not just a blood test for cholesterol. After all, it is known that atherosclerosis can develop with a normal level of total cholesterol, and the low level of the so-called “good cholesterol” is to blame for this.

A blood test for lipid spectrum is taken from a vein, on an empty stomach (after 12-14 hours of fasting).

What indicators of lipid metabolism are currently accepted as the norm?

The lipidogram will indicate the following indicators:

  • total cholesterol level – must be less than 5.2 mmol / L
  • low density lipoprotein level (LDL, beta-lipoproteins, “bad cholesterol”) – must be less than 3, 0 mmol / L
  • High-density lipoprotein level (HDL, alpha-lipoproteins, “good cholesterol”) – must be more than 1.2 mmol / L
  • Triglyceride (TG) level – less than 1.7 mmol / L
  • coefficient atherogenicity (CA) – should not exceed 4.0e.
  • in some cases, chylomicrons (HM) and very low density lipoproteins (VLDL) will be indicated

If these lipid profiles differ from the given standards, even in one of the parameters, this is a reason to consult a cardiologist.

What methods can be used to confirm the presence of atherosclerosis or to reveal the impaired function of the vascular wall, which is the initial stage in the development of atherosclerosis?

The EXPERT Clinic performs ultrasound screening for atherosclerosis.An ultrasound machine examines the carotid (sometimes femoral) arteries to detect changes in the vascular wall or to identify asymptomatic atherosclerotic plaques. Since atherosclerosis is a disease that affects all vessels, the condition of the carotid arteries can be used to indirectly judge the condition of all vascular pools of the body.

To identify impaired endothelial function, a special test is carried out under the control of ultrasound, the so-called “Test with Reactive Hyperemia”. This is a highly sensitive method that allows detecting violations at very early stages and predicting the risks of developing cardiovascular pathology in people without any complaints, as well as monitoring the treatment process in patients with proven pathology.The EXPERT Clinic is one of the few institutions in the city where this study is performed.

What will happen if you do not pay attention to your health, ignore the “first bells”? Atherosclerosis will develop, progress and will inevitably lead to serious complications associated with impaired blood flow in vital organs.

Atherosclerosis is a serious disease that is easier to prevent than cure.

An atherosclerotic plaque is a kind of patch on the vascular wall.It is already impossible to “fight” it, you can only hinder its further growth.

There is now a lot of popular science literature on atherosclerosis, and many patients say we know that cholesterol has nothing to do with it. At the very beginning of the article, we also mentioned this: not only cholesterol is to blame for the development of atherosclerosis. There are about 200 other factors!

Let’s dwell on one of them in more detail: homocysteine.

Homocysteine ​​is an amino acid that is not found in food, but is formed in the body from another amino acid, methionine.Animal products (meat, dairy products, eggs) are rich in methionine. Excessive accumulation of homocysteine ​​inside cells can cause irreparable harm to them, up to cell death. Homocysteine ​​has a direct toxic effect on endothelial cells, damages them (“patches” – plaques are formed at the sites of damage), increases blood cholesterol levels, increases blood clotting and accelerates the growth of already existing atherosclerotic plaques.

Metabolism (destruction) of homocysteine ​​in the body occurs with the participation of vitamins B6, B12 and folic acid.Homocysteine ​​is excreted from the body by the kidneys.

Reasons for the development of an increased level of homocysteine:

  • age and sex (over 55 years old, men, menopause in women)
  • food and lifestyle (smoking, lack of folic acid and vitamins B6, B12, excessive consumption of meat foods and foods rich in methionine, drinking more than 6 cups of coffee a day, drinking too much alcohol, cholesterol-rich diet)
  • diseases (diabetes mellitus, renal failure, hypothyroidism, various tumors)
  • drugs (anticonvulsants, long-term use of hormonal contraceptives, etc. …

Today it has become clear that without control of homocysteine ​​levels it is impossible to effectively prevent and treat diseases of the cardiovascular system.

How can the negative effects of homocystenia be reduced?

There is only one way – to replenish the deficiency in the body, first of all, of folic acid, as well as vitamins B6 and B12. Taking vitamins in the necessary dosages (which can only be determined by a doctor) helps to reduce the level of homocysteine ​​in the blood.

Which homocysteine ​​level is dangerous?

A homocystenin level of 10 µmol / L or less is considered normal.

An increase of more than 20 μmol / L leads to a 4-fold increase in mortality from cardiovascular complications.

At the EXPERT Clinic you can check the level of homocystenin, along with the lipid spectrum of the blood, especially if you are in a risk group.

What to do if atherosclerosis is detected late, there are already its complications?

Don’t panic!

In any case, treatment is necessary to prevent further progression of the disease. But more aggressive therapy with the use of various groups of drugs is already required.

What are the complications of atherosclerosis?

With damage to the heart vessels, a malnutrition of the heart muscle develops, this, as a rule, leads to the appearance of pain behind the sternum during physical exertion, but sometimes it can be asymptomatic and manifest itself only in the development of myocardial infarction, which, unfortunately, can result in the death of the patient …

If the vessels supplying the brain are damaged, the risk of ischemic stroke is very high. The disease, which, as a rule, leads to deep disability of the patient and forever changes his life and the life of his loved ones.

In men, especially smokers, one of the first manifestations of atherosclerosis is damage to the vessels of the legs, which appears first as slight fatigue in the legs when walking fast, then pains in the legs appear and now it is impossible to walk more than 100 meters without stopping. It can end with gangrene and amputation! But tell me, how many of today’s men walk at least 2 kilometers a day every day? Many of them are driving, and therefore they simply cannot detect the first symptoms of the disease.But it has already been mentioned that the male gender is a separate risk factor for the development of cardiovascular diseases.

At this stage of development of atherosclerosis, an extended instrumental examination is required, the volume of which must be determined by a cardiologist.

Summarizing all of the above, we suggest thinking about your future and the future of your loved ones. Contact the experts of the EXPERT Clinic, undergo a minimal or detailed examination and live happily ever after.

If abnormalities in the lipid spectrum of the blood are found, or any risk factors for atherosclerosis, it is necessary to make an appointment with a cardiologist.

As a result, you will receive:

  • individual consultation on whether you have a disease or a predisposition to it
  • the doctor will make a plan for the necessary instrumental or laboratory examination to clarify the diagnosis
  • will give recommendations on changing diet and lifestyle, as well as assess the need drug therapy
  • will teach the correct control of parameters such as blood pressure, blood sugar, weight fluctuations
  • will recommend the necessary physical activity, taking into account your condition

Joint work of a doctor and a patient is the key to the success of the treatment of any disease, especially such an insidious one as atherosclerosis.With the established diagnosis of atherosclerosis, the patient should be under the supervision of a cardiologist at least once every 6 months, and when correcting violations, identified complications of the disease, the frequency of meetings, the volume of additional examinations are set individually.

Treatment stories

Case No. 1

Alexey, 27 years old. Young specialist, graduate of the medical university. He has no health complaints. Overweight (grade 1 obesity). Blood pressure was not controlled, the level of blood lipids is unknown.Has been smoking for about 10 years. At the request of colleagues, he took part in one of the medical studies and conducted the “Test with Reactive Hyperemia”. As a result of the test, pronounced dysfunctions of the endothelium were revealed. Taking into account the data obtained, he began to control the blood pressure (BP) figures and was surprised to find borderline values: blood pressure averaged 130/90 mm Hg. Art. In the lipid spectrum, all indicators were normal except for a slightly reduced level of “good cholesterol”, it was 1.0 mmol / L.Upon questioning, it turned out that the family has a tendency to develop hypertension, diabetes mellitus, and the father suffered a heart attack at the age of 57. All this made the young man take a very responsible approach to his future. He quit smoking, began to control his weight, and increased physical activity. After 6 months, control tests showed normalization of endothelial function. The BP figures assessed using 24-hour Holter monitoring were also within the normal range. Re-examination of the lipid spectrum revealed the level of “good cholesterol”, which remained moderately reduced, which indicated its hereditary nature.However, given the absence of other risk factors for the development of atherosclerosis, this deviation is insignificant.

Case No. 2

Margarita, 62 years old. 10 years ago, a significantly increased cholesterol level (more than 8.0 mmol / l) was revealed. After menopause at age 52, blood pressure began to rise. At the same time, the patient was not overweight, and she never smoked. The patient did not let everything go by itself, but in a timely manner turned to the cardiologist of the EXPERT Clinic 4 years ago.The examination was carried out: ultrasound screening for atherosclerosis, which revealed a diffuse thickening of the vascular wall of the carotid arteries (complex “intima-media”), and a single atherosclerotic plaque with a height of 2.5 mm. Taking into account the latest international recommendations, the thickening of the “intima-media” complex of the vascular wall is an indication for the appointment of drug therapy to lower cholesterol. The patient began to follow a strict diet, restricting animal fats. Blood pressure medications were prescribed and cholesterol-lowering medication was started.The patient has been observed in the clinic for 4 years. Repeated ultrasound screening for atherosclerosis does not reveal violations of the vascular wall, and the atherosclerotic plaque decreased in height to 1.8 mm, its structure became dense (such plaques are not dangerous in terms of complications). Blood pressure figures are within normal limits, lipid metabolism indicators are normal.

Case No. 3

Constantine, 60 years old. I went to the EXPERT Clinic. At the reception he claimed that he was absolutely healthy and came only because “my wife had eaten all the bald head”.Thorough questioning really did not reveal serious complaints, but the patient said that he loved to eat, smoked for more than 20 years, but quit a year ago, does not engage in physical activity and generally walks little, but at work he is always “in good shape” and “fun.” The pressure during the examination was increased, which surprised him very much, since at home, with rare measurements (“for the sake of company”), the figures, according to him, were normal. He didn’t check his cholesterol levels. Taking into account all the data, the patient was assigned an extended laboratory and instrumental examination, which included a study of the lipid spectrum and carbohydrate metabolism, 24-hour ECG and blood pressure monitoring, echocardiography and ultrasound screening for atherosclerosis.Comprehensive examination data revealed the presence of persistent arterial hypertension complicated by the development of left ventricular hypertrophy, episodes of painless ischemia of the heart muscle during physical exertion, pronounced changes in the lipid spectrum in the form of high cholesterol and triglycerides, as well as low levels of “good cholesterol”. There were borderline figures for blood glucose. The most dramatic was the identification of atheroscleoric plaques in the carotid arteries, and one of them clogged the vessel by more than 80%, which increases the risk of stroke at times.The patient was prescribed a serious multicomponent drug therapy, and recommendations were given for changing his lifestyle. The patient was also consulted by a vascular surgeon, who insisted on coronary angiography. During this study, the patient was diagnosed with critical stenosis of one of the coronary arteries, which required stenting, since the risk of developing myocardial infarction was very high. The patient continues to be monitored at the EXPERT Clinic and very responsibly fulfills all the recommendations of the specialists.

Take blood test for total cholesterol in Samara LDL

Cholesterol (cholesterol) is a water-insoluble polycyclic lipophilic alcohol that is synthesized in the liver. It is a part of the cell wall, is a source of synthesis of sex hormones, bile acids. The transport form of cholesterol is lipoproteins of various densities.
The level of cholesterol in the blood depends on its synthesis in the liver and, to a lesser extent, on the intake of fats from food. It is one of the most important indicators of lipid metabolism, it is used as a screening test to assess the risk of atherosclerotic changes and vascular disorders in the future.
For a more complete assessment of the state of lipid metabolism, a comprehensive assessment is recommended along with high and low density cholesterol, triglycerides.

Increased cholesterol: consequences for the body

With an excess amount of LDL, they are deposited on the walls of blood vessels. This leads to a narrowing of the lumen of the vessel, its complete blockage is possible. Vessels lose their elasticity and, as a result, their ability to expand. This leads to increased stress on the heart.Complete overlap of the lumen is fraught with a violation of the blood supply to the organ to which the affected vessel supplies blood. If the coronary vessels are affected, ischemic disease develops, a heart attack is possible. Most often high LDL level leads to damage to the vessels of the lungs, brain and heart. If treatment is not started in a timely manner, in most cases, the result is the development of life-threatening conditions.

Symptoms and causes of high cholesterol In the early stages, hypercholesterolemia is asymptomatic.The problem can only be identified by the results of laboratory tests, which are carried out during a preventive examination. The first clinical manifestations that allow one to suspect an increase in cholesterol are shortness of breath, excess weight, high blood pressure. In the future, as the vessels are damaged, symptoms characteristic of pathologies of various organs are added to the clinical picture.
An increase in cholesterol can be caused by genetic abnormalities, a number of non-congenital diseases, and other reasons.Most often, an increase in the concentration of this substance is caused by the abuse of foods high in cholesterol, trans fats and saturated fats, fried foods. Overweight people with a sedentary standard of living are more likely to have high cholesterol levels. The likelihood increases with a genetic predisposition. Also, the risk increases with age.


Diagnostics and treatment

An accurate diagnosis is made on the basis of laboratory tests aimed at determining total cholesterol, high and low density lipoproteins (HDL, LDL), triglycerides.Both medication and lifestyle changes are recommended to lower cholesterol. In many cases, changes in your daily lifestyle are enough to correct your cholesterol levels. These include adjusting the diet, increasing physical activity and giving up bad habits.

It is important for people with high cholesterol to pay enough attention to exercise. Regular physical activity and a balanced diet can help maintain weight within the normal range.Quitting alcohol and smoking also helps lower cholesterol levels and improves overall health. If the change in the standard of living is not enough to normalize the indicators, drug treatment is prescribed.

90,000 Scientists Understand How Foods High in Cholesterol Trigger Cancer – Social Responsibility

Researchers at the University of California, Los Angeles have found that foods high in cholesterol accelerate the development of cancer cells a hundred times.Scientists have seen for the first time the mechanism by which “bad” cholesterol (a low-molecular-weight complex compound, low-density lipoproteins) causes colon cancer, which makes it possible to look for new drugs that can prevent the disease. The study was reported by The Independent.

“Cholesterol affects the growth of stem cells in the gut, which in turn speeds up the rate of tumor formation by more than 100 times,” said Peter Tontonoz of UCLA School of Medicine.“While the link between dietary cholesterol and colon cancer is well established, no one has previously understood how this mechanism works.”

Cholesterol is an essential component of the membrane of all cells of most living organisms. In the human body, it is produced in the liver as a necessary building block for the production of other essential substances. High cholesterol, especially “bad” cholesterol, can increase the chances of a heart attack or stroke, although this fact is currently being questioned by scientists.

Researchers studied two groups of mice, the first fed a diet high in cholesterol, and the second with genetically modified foods so that their bodies naturally produce more cholesterol. In both cases, the extra cholesterol triggered the replication (a self-replicating process that accurately copies genetic information and transfers it from generation to generation) of the intestinal stem cells, which are responsible for gut growth.

As cholesterol increased, these stem cells dividing faster, the inner intestinal tissue increased, and the intestines of the mice became longer and longer.But such a rapid growth also meant a significant acceleration in the growth of tumor cells.

Scientists have concluded that high cholesterol levels in food increase cholesterol levels in intestinal cells, and cellular cholesterol regulates increased tissue growth. Therefore, it is this previously unnoticed mechanism that affects the growth of tumors in people with high cholesterol.

In the future, scientists plan to explore how this data can be used as a strategy for therapeutic intervention in gastrointestinal diseases.

Scientists disagree whether lipid-lowering drugs (which inhibit the enzyme that promotes cholesterol production), such as statins, which are widely prescribed for people at risk of heart attacks or strokes, can also reduce the risk of bowel cancer.

Colorectal cancer accounts for 11.5% of the 303,000 new cases of all cancers reported in England in 2016, according to the UK National Statistical Office.

Material provided by the “+1” project.

90,000 25 facts you need to know about cholesterol.

25 facts you need to know about cholesterol.

Details
Category: Uncategorized

Views: 32736

25 facts you need to know about cholesterol.

If you think that cholesterol is a harmful substance found in fatty foods and causes various diseases, then this article is for you.

An organic molecule is much more complex than we think. From a chemical point of view, cholesterol is a modified steroid – a lipid molecule that is formed as a result of biosynthesis in all animal cells. It is an essential structural component in all animal cell membranes and is required to maintain the structural integrity and fluidity of the membranes.In other words, in a certain amount of cholesterol is absolutely necessary for survival

25 facts about cholesterol

  1. 1. Cholesterol does not dissolve in the blood; it is transported through the blood by carriers called lipoproteins. There are two types of lipoproteins: low density lipoprotein (LDL), known as “ bad cholesterol ” and high density lipoprotein (HDL), known as “ good cholesterol “.
  1. 2. Low-density lipoproteins are considered “bad cholesterol” because they contribute to the formation of cholesterol plaques, which clog the arteries and make them less flexible. High-density lipoproteins are considered “good” because they help move low-density lipoproteins from the arteries to the liver, where they are broken down and excreted from the body.
  2. 3. Cholesterol itself is important for us, performing important functions in our body. It helps in the formation of tissues and hormones, protects the nerves and aids in digestion.Moreover, cholesterol helps to form the structure of every cell in our body .
  3. 4. Contrary to popular belief, not all of the cholesterol in our body comes from the food we consume. In fact 90,030 most of it (about 75 percent) is naturally produced by the liver . The remaining 25 percent comes from food.
  4. 5. In some families, high cholesterol levels are inevitable due to such a hereditary disease as familial hypercholesterolemia .The disease affects 1 in 500 people and can cause a heart attack at a young age.
  5. 6. Every year high cholesterol levels in the world lead to 2.6 million deaths.

Cholesterol level

  1. 7. Children also suffer from unhealthy cholesterol levels. According to a study 90,030, the accumulation of cholesterol in the arteries begins in childhood .
  1. 8. Experts advise 90,030 people over 20 to check their cholesterol levels every 5 years. It is best to take a test called the Lipoprotein Profile , before which you need to abstain from food and drinks for 9-12 hours to obtain information on total cholesterol, LDL, HDL, and triglycerides.
  1. 9. Sometimes you can find out about high cholesterol levels without tests. If you have a white rim around your cornea, your cholesterol levels are likely high. A white rim around the cornea and visible fat bumps under the skin of the eyelids are some of the sure signs of cholesterol accumulation.
  1. 10. Eggs contain about 180 mg of cholesterol. is a fairly high figure. However, cholesterol in eggs has little effect on blood LDL cholesterol levels.
  1. 11. Low cholesterol can be as bad for your health as high . Cholesterol levels below 160 mg / dL can lead to serious health problems, including cancer. Pregnant women with low cholesterol levels are more likely to give birth prematurely.
  1. 12. In the case of high cholesterol, there are even more health problems. In addition to heart attack, high blood cholesterol levels can cause kidney failure to liver cirrhosis, Alzheimer’s disease and erectile dysfunction.
  1. 13. Paradoxically, cholesterol is (normally) responsible for your libido. It is 90,030 the main substance involved in the production of the hormones testosterone, estrogen and progesterone .
  1. 14.The highest cholesterol levels in the world are found in western and northern European countries such as Norway, Iceland, the United Kingdom and Germany, with an average of 215 mg / dL.

Cholesterol in men and women

  1. 15. Although men have higher total cholesterol levels than women before menopause, 90,030 women tend to have higher cholesterol levels after age 55 and become higher than men 90,031.
  1. 16. In addition to the aforementioned functions, cholesterol also helps protect the skin by being one of the ingredients in most moisturizers and other skin care products.It protects the skin from UV damage and is essential for the production of vitamin D.
  1. 17. Although usually about a quarter of all cholesterol in our body comes from food, it has been found that even if a person does not consume cholesterol at all, the liver is still able to produce cholesterol necessary for body functions.

Cholesterol in food

  1. 18. Most commercial foods, such as fried foods and baked goods, chips, cakes and biscuits that claim to be cholesterol free on packaging, actually contain trans fats in the form of hydrogenated vegetable oils, which cholesterol “, and lower the level of” good cholesterol “.
  1. 19. Once cholesterol begins to accumulate in the arteries, they gradually become thicker, harder and even turn a yellowish appearance of cholesterol. If you saw what cholesterol-clogged arteries look like, you will notice that they seem to be covered with a thick layer of butter.

Diet with high cholesterol

  1. 20. To prevent the risks associated with high cholesterol levels, it is most often recommended to make changes in your diet.It is worth increasing your intake of cholesterol-lowering foods such as vegetables, fish, oatmeal, walnuts, almonds, olive oil, and even dark chocolate .
  1. 21. However, to lower the level of “bad cholesterol” and increase the level of “good cholesterol”, you can not only eat well. Experts also recommend to engage in physical activity for at least 30 minutes a day .
  1. 22. Pregnant women naturally have higher cholesterol levels than most women.During pregnancy, total cholesterol and LDL cholesterol levels reach their maximum levels. High cholesterol levels are essential not only for conception, but also for childbirth.
  1. 23. On the other hand, in a couple, where both the man and the woman have high cholesterol levels, it is more often difficult to conceive. For example, a couple may take longer to conceive if one of the partners has too high a cholesterol level.
  1. 24. In addition to unhealthy diet, genetic predisposition, physical inactivity, smoking, alcohol abuse and stress can contribute to high blood cholesterol levels.
  1. 25. Breast milk contains a lot of “good cholesterol” and the fat in breast milk is easily and efficiently absorbed by the baby. In infants, cholesterol helps reduce the risk of cardiovascular disease and plays an important role in the development of a child’s brain.

90,000 Apheresis SAFETY FOR HIGH RISK PATIENTS

What is apheresis?

Apheresis essentially means the separation of plasma from the rest of the blood. Therapeutic apheresis (therapeutic plasmapheresis, lipoprotein apheresis, immune apheresis) removes pathogens from the blood in the treatment of chronic metabolic diseases that do not respond to conservative treatment and is symptomatic therapy.

Therapeutic apheresis

Until now, the most common procedure around the world is therapeutic plasmapheresis, in which the separated plasma is removed and replaced with an albumin solution. It is carried out mainly in cases of autoimmune diseases (for example, rheumatoid arthritis) and sepsis (blood poisoning), but is not suitable for long-term chronic treatment due to the loss of a wide range of plasma proteins. An appropriate therapeutic apheresis procedure for chronic procedures is lipoprotein apheresis, which removes lipoproteins (blood lipids such as LDL cholesterol) directly from the blood or plasma to treat cardiovascular disease.Lipoprotein apheresis is between semi-selective and selective lipoprotein apheresis. In the case of semi-selective lipoprotein apheresis (cascade or double filtration), plasma proteins are filtered out in a second step without differentiating between pathogens or desired plasma constituents.

H.E.L.P. LDL apheresis

Abbreviation H.E.L.P. means:
H eparin-induced – heparin-induced
E xtracorporal – extracorporeal
L ipoprotein / fibrinogen – lipoprotein / fibrinogen
P recipitation – precipitation.

During treatment, the patient’s blood plasma is separated from the blood cells. The separated plasma is mixed with an acetate buffer saturated with heparin, which lowers the acidity (pH) of the plasma to 5.12. Together with heparin supplementation, plasma lipoproteins form insoluble precipitates that can be removed from the plasma during the filtration step. Unused excess heparin is retained in a separate adsorber, then ultrafiltration with bicarbonate dialysis is used to restore the purified plasma to a physiologically acceptable level.The selectively purified plasma is then mixed with the remaining blood components and returned to the patient. During H.E.L.P. apheresis, these four stages (plasma separation, sedimentation followed by filtration, heparin adsorption and ultrafiltration) are performed by one apparatus – PLASMAT Futura.

Cardiovascular diseases

H.E.L.P. apheresis is used mainly for patients with hereditary hypercholesterolemia, which leads to cardiovascular disorders that are refractory to therapy.

What is cardiovascular disease?

In a broad sense, cardiovascular diseases refer to disorders in the work of the heart and blood circulation. Extremely diverse in nature, cardiovascular diseases can affect coronary vessels (coronary heart disease), heart muscle (heart failure), heart valves (aortic valve insufficiency, aortic stenosis, etc.), heart rhythm (arrhythmia, fibrillation, etc.) etc.) or endocardium (infectious or rheumatic endocarditis).

What Causes Cardiovascular Disease?

Cardiovascular diseases have a number of causes that affect various parts of the cardiovascular system (blood vessels, heart). Diseases of the blood vessels often include arteriosclerotic diseases and associated risks, such as hypercholesterolemia, arterial hypertension, diabetes mellitus, smoking, etc. heart attack), the brain (stroke), the lower extremities (peripheral obstructive arterial disease), or, less commonly, the inner ear (microcirculation disorders lead to acute hearing loss).

What are the potential consequences of cardiovascular disease?

The consequences of cardiovascular diseases are very diverse. They can vary, for example, between high blood pressure, heart failure, arrhythmias, and heart attack, depending on which part of the cardiovascular system is affected. The consequences are usually associated with arteriosclerotic changes in blood vessels (calcification). Arteriosclerosis includes an inflammatory change in the inner walls of blood vessels.Excessively high cholesterol levels in patients with cardiovascular disease are due to a genetic metabolic disorder of the liver. Excess cholesterol is deposited on the walls of blood vessels, where it leads to plaque formation. If a stable plaque becomes unstable and ruptures, the affected organ – usually the heart – suffers from a heart attack.

Treatment of cardiovascular diseases

An LDL concentration of up to 160 mg / dl blood is considered acceptable for healthy people.For patients with cardiovascular disease, the recommended LDL concentration limit is 100 mg / dL (70 mg / dL for patients with diabetes). If the patient is unable to achieve their goal by making lifestyle changes, dietary choices, and medications designed to lower blood lipid levels, the patient is advised to H.E.L.P. apheresis. H.E.L.P. apheresis reduces the level of lipids in the blood by more than 60% per therapy session in combination with adherence to the drug intake – up to 80%.H.E.L.P. thus improves blood microcirculation in capillary vessels.

.