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Competing Interests: U. Paetow: erhielt Honorar von der Deutschen Gesellschaft für Fettstoffwechselstörungen und ihre Folgeerkrankungen (DGFF) für Lehrtätigkeiten. O. Kordonouri: die Fr1dolin-Studie wird durch Zuwendungen der „Juvenile Diabetes Research Foundation“ (2-SRA-2016-243-Q-R), Liona M. an Harry B. Halley Charitable Trust und Sanofi Aventis Deutschland GmbH unterstützt. K.O. Schwab: ist im Vorstand der DGFF und ist als Berater für die Firmen Akcea und Novartis tätig. Dieser Beitrag beinhaltet keine Studien an Menschen oder Tieren.

Congenital disorders of lipid metabolism are characterised by LDL-C concentrations > 190 mg/dl (4.9 mM) and/or triglycerides > 200 mg/dl (2.3 mM) in young individuals after having excluded a secondary hyperlipoproteinemia. Further characteristics of this primary hyperlipoproteinemia are elevated lipid values or premature myocardial infarctions within families or xantelasms, arcus lipoides, xanthomas and abdominal pain. This overview summarises our current knowledge of etiology and pathogenesis of primary hyperlipoproteinemia., Competing Interests: F. U. B. und H. D. geben an, dass kein Interessenkonflikt besteht.W. M. ist leitender Angestellter der Synlab Holding Deutschland GmbH und erklärt den Erhalt von Forschungsunterstützung und/oder Honoraren durch AMGEN GmbH, Sanofi, Amryt Pharmaceuticals, Abbott Diagnostics, Akzea Therapeutics, Novartis Pharma GmbH, Vifor Pharma und Daiichi-Sankyo., (Thieme. All rights reserved.)

Diagnosis and Treatment of Familial Hypercholesterolemia Abstract. Familial hypercholesterolemia secondary to heterozygous mutations in the LDL receptor, Apolipoprotein B or PCSK9 gene is characterized by 2- to 3-fold elevated LDL cholesterol levels, premature atherosclerosis and extravascular cholesterol deposits (tendon xanthomata, corneal arcus). The same phenotype may occur if a person carries several LDL cholesterol rising polymorphisms (polygenic FH). Primary prevention with statins has been shown to dramatically reduce the cardiovascular burden in patients with the disease. However, it is estimated that less than 10 % of affected subjects in Switzerland have received the diagnosis, and undertreatment is frequent. Thus, clinical cardiovascular events are still the first manifestation of the disease in many cases. A correct diagnosis in index patients and cascade screening of families are mandatory to identify and treat patients before they suffer the sequelae of untreated severe hypercholesterolemia. In patients with clinical cardiovascular disease combination lipid lowering treatment with potent statins, ezetimibe and the newly available PCSK9 inhibitors will successfully lower LDL cholesterol to normal or even target levels.

Congenital disorders of lipid metabolism are caused by a wide range of variants of the genes for receptors, apolipoproteins, enzymes, transfer factors, and cellular cholesterol transporters. Clinically most relevant are autosomal dominant familial hypercholesterolemia (FH) and familial combined hyperlipoproteinemia (FCHL). FH has a prevalence of 1:250. It is due to mutations of the low density lipoprotein (LDL) receptor, less often to mutations of the apolipoprotein B (APOB), the proprotein convertase subtilisin/kexin type 9 (PCSK9), or the signal transducing adapter family member 1 (STAP1). FH often leads to early atherosclerosis. Its diagnosis can definitely be made only by molecular genetic testing. The detection of mutations of the LDLR, APOB, or PCSK9 is an indicator for extremely high cardiovascular risk, independently of the concentration of LDL cholesterol. FCHL is also common (1:100) and is seen in about 10% of patients with early myocardial infarction. It is produced by combinations of frequent genetic variants affecting triglycerides and LDL cholesterol. Other monogenic hyperlipoproteinemias (HLP) affect the catabolism of chylomicrons (familial chylomicronemia) or of remnants of triglyceride-rich lipoproteins (type III hyperlipoproteinemia). Multiple hereditary disorders in HDL metabolism - with a broad spectrum of clinical significance - are known. Currently, second generation sequencing methods are used to simultaneously analyze multiple disease-causing genes. This approach cost-neutrally provides additional information such as the genetic risk of atherosclerosis and predisposition to statin intolerance.

Genetic testing plays an increasing role in cardiovascular medicine. Advances in technology and the development of novel and more affordable (high throughput) methods have led to the identification of genetic risk factors in research and clinical practice. Also, this progress has simplified the screening of patients and individuals at risk. In case of rare monogenic diseases, diagnostics, risk stratification, and, in some cases, treatment decisions have become easier. For common, polygenic cardiovascular diseases, the situation is more complex due to interaction of modifiable external risk factors and nonmodifiable factors like genetic predisposition. Over the last few years, it has been shown that multiple genes are involved in the pathophysiology of these cardiovascular diseases rather than one single gene. In the following article, we give an overview of the genetic risk factors in polygenic cardiovascular diseases as atrial fibrillation, arterial hypertension and coronary artery disease. Furthermore, we aim to illustrate in which cases genetic testing is recommended in these diseases.

Homozygous hypercholesterolemia is an extremely rare genetic disorder caused by mutations in the LDL receptor gene or occasionally by mutations in other genes like proprotein convertase subtilisin / kexin 9 (PCSK9). Gold standard of homozygous hypercholesterolemia therapy is apheresis, accompanied by high-dose statin and ezetimibe therapy. The cholesterol-lowering effect can be supported by new agents like inhibitors of microsomal triglyceride transfer protein (lomitapide), or by enhancing LDL catabolism through inhibition of the PCSK9 activity. We present the case of a young woman with homozygous hyperlipidemia due to a mutation c.1200 C> A(p.Tyr400*) in the LDLR gene that introduces a stop-codon at amino acid position 400. This truncated LDLR cannot mediate a membrane-bound uptake of LDL cholesterol. A combined therapy including simvastatin, ezetimibe and apheresis did not lead to satisfactory LDL levels. By adding lomitapide, a dramatic receptor-independent reduction of LDL was achieved., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background and Aim: The monogenetic hypercholesterolemias (HC) are associated with a very high risk of premature coronary heart disease (CHD). We sought to assess the influence of the genetic defect and the cardiovascular risk factors on the manifestation of atherosclerotic complications in two forms of genetic HC., Patients and Methods: Data of patients with genetically defined HC (54 LDL-receptor defective familial hypercholesterolemia (FH) and 54 familial defective apolipoprotein B (FDB)) were analysed retrospectively for cardiac and extracardiac atherosclerosis., Results: Total and LDL-cholesterol were significantly higher in FH men than in FDB men, but not so in women. 41.8% of FH patients had CHD (mean age 41 years), 5.6% of FDB (mean age 52 years). Stenoses (>50% narrowing) of the internal carotid artery were verified in 15% of FH and 4% of FDB patients. Peripheral arterial disease was found in 3 FH and 2 FDB patients. Hypertension and active smoking were allotted almost equally, body weight was normal in most of the patients (BMI ≤ 25 kg/m(2)). Conlusion: Patients with genetic HC suffer from early manifestation of cardiac disease. Patients with FH seem to be affected more often than patients with FDB. Early diagnosis and early and lifelong treatment are essential and, according to the literature, lead to a delay of disease manifestation., (© Georg Thieme Verlag KG Stuttgart · New York.)

Dyslipidemia is one of the main modifiable cardiovascular risk factors. There is strong evidence for the efficacy of lipid-lowering drugs in secondary prevention, as well as in primary prevention for patients at high cardiovascular risk. In primary prevention, indication for lipid-lowering interventions should be based on an individual assessment of the cardiovascular risk and on the LDL cholesterol level, despite less strong evidence for the efficacy of drug-based interventions in low risk patients. Treatment consists of statins, as well as lifestyle modifications such as body weight control and increased physical exercise. The latter constitute the primary intervention in patients at low cardiovascular risk. Secondary dyslipidemias due to an underlying medical condition and familial dyslipidemias such as Familial Hypercholesterolemia and Familial Combined Hyperlipidemia should be identified and treated accordingly, taking into account that the risk scoring systems are not appropriate in these situations.

The family history in a sportive 49 year old patient with coronary artery disease reveals several members with cardiovascular events. The diagnosis of dyslipidemia could be made in all the patient's children. Genetic analysis of the patient shows a heterozygous mutation of the apolipoprotein B-100 genotype. An accurate family history and screening for cardiovascular risk factors are mandatory in all patients with a history of premature coronary artery disease.

Coronary heart disease (CHD) is among the leading causes for invalidity and death in industrialized countries. A prominent role of genetic factors in the onset of this disease has been documented in twin and family studies, by the use of experimental animal models, and by unravelling the genetic basis of monogenic disorders closely associated with CHD. Notwithstanding this knowledge attempts have failed to significantly improve prediction, early diagnosis and treatment of the common disorder CHD. The following will discuss the reasons for this lack of success but argue for positive perspectives that are ahead of us.

In children with familial hypercholesterolemia, coronary heart disease requires both medical theraphy and LDL apheresis. We report a case of verified occlusion of the anterior descending branch of the left coronary artery in a 10-year-old patient. The pathological findings revealed by ergometry established the diagnosis. The goal was to achieve the greatest possible reduction of lipid parameters and fibrinogen by lowering plasma viscosity employing LDL apheresis. It is astonishing that this treatment is also well tolerated by children. The basic vascular approaches suffice and shunt operations are not absolutely necessary. The efficacy of this method became vividly apparent by the changes in the skin lesions. Additional angiographic follow-up and further clinical course wil provide information on the usefulness of this treatment strategy with maximum lipid theraphy and the expected improvement in prognosis.

Nucleotide variants in genes of the lipid metabolism influence the risk of premature atherosclerosis. Ten percent of all single nucleotide substitutions in these genes involve splice sites. The effects of these changes on mRNA splicing and phenotypic severity, however, are not inherently obvious from the nucleotide sequence. This review presents various genes of lipid metabolism with splicing mutations known to influence the risk of premature atherosclerosis. Mechanisms of pre-mRNA splicing are illustrated and different models for prediction of the effect of nucleotide substitutions on splice-site function are presented. The role of information theory-based models is emphasized along with its role for prediction of splice-site function and phenotypic severity of atherosclerosis.

Heterozygous familial hypercholesterolemia (FH, prevalence 1:500) is a major cause of early atherosclerotic disease. Little is known about possible co-factors influencing individual patient's risk. We investigated this question in a large family carrying a new LDL-receptor-mutation. Genetic analysis of all exons of the LDL-receptor gene in the index case using polymerase chain reaction (PCR) and Denaturing Gradient Gel Electrophoresis (DGGE) revealed a previously unknown mutation in exon 10 (GAC > ACC, D471N, "FH Graz-1"). Investigation of 21 family members (15 females, 6 males), aged 17 to 86 years, revealed 9 female and 4 male carriers of the mutation. 7 female carriers aged 17 to 58 years show no clinical signs of macrovascular disease. An 86-year old female patient, who was asymptomatic until 85, recently suffered a transient cerebral ischemic attack. All these females were normotensive. The only hypertensive 76-year old patient (ex-smoker with a history of 15 pack years) suffers from angina pectoris. 2 male carriers of the mutation (32 and 38 years old) are asymptomatic. A 65-year old patient suffers from cardiovascular disease. A 49-year old patient had a coronary artery bypass graft after a myocardial infarction at the age of 37. Additionally he has a history of bilateral thrombendarterectomy of the carotid arteries and suffers from bilateral peripheral artery disease. This patient also carries the apoE-genotype 4/3, which might be responsible for his poor response to stain therapy, and needs extracorporal lipid elimination (LDL-C > 200 mg/dl under drug therapy). Both of his daughters are homozygous for the apoE-allele 3 and and responded well to stain therapy. Genetic analysis in patients with FH assures diagnosis, but is not sufficient to determine the individual patient's risk. A precise clinical examination remains the gold standard for individual risk evaluation.

Coronary artery stenosis with need for therapy is rarely seen in childhood. A 15-year-old girl with hypercholesterinaemia type II a was undergoing lipid aphereses therapy (once or twice a week) since she was 6 years old. The girl was seen in our hospital with stenocardia and depression of the ST-segment in the inferior ECG leads at rest. Myocardial scintigraphy with technetium 99 showed an ischemia of the infero-lateral left ventricular myocardium. During selective coronary angiography a 90% stenosis of the proximal right coronary artery over a distance of approximately 5 mm close to the ostium was found. Post stenotic dilatation of the vessel was obvious. In addition a diffuse 10% stenosis in the proximal and middle part of the right coronary artery was found. The left coronary artery appeared angiographically normal. After balloon dilatation, stent implantation was performed without complications with a 6 mm microstent. Reduction of the stenosis from 90% to 40% could be achieved. Ticlopidin 2 x 250 mg was started for thrombocyte aggregation inhibition. During the following 12 months the patient has been free of symptoms. Lipidaphareses has been continued as before. Stent implantation seems to be a successful treatment for coronary artery stenosis also in young patients.

Background: Central crystalline dystrophy of Schnyder is characterized by the deposition of unesterified cholesterol crystals and lipids in the central and paracentral corneal stroma. Classically, this disease has been described as autosomal dominantly inherited and non-progressive with cholesterol deposits found in the anterior one third of the cornea. In recent years, however, rare sporadic cases and individuals with progressive, panstromal Schnyder's dystrophy have been described. Furthermore, an association has been made between some patients with Schnyder's dystrophy and a region on the coast in southwest Finland. Among the stromal dystrophies, this disease is unique with its occasional association with genu valgum and systemic hyperlipidemia. The role of high serum cholesterol in the pathogenesis of this disorder is still unclear., Patient: A ten-year-old white male presented with a one year history of ocular irritation made worse by bright sunlight. His past medical history was significant only for attention deficit disorder for which he received methylphenidate. A brother died at four months of age secondary to an unexplained cardiac abnormality. The ocular examinations of the patient's mother and father were normal and no history of eye disease among the grandparents could be elicited. The patient's visual acuity was 20/20 +2 in the right eye and 20/15 -3 in the left eye. The external examination showed no xanthelasmas. Slit-lamp biomicroscopy revealed bilateral ring-shaped corneal opacities extending into the midperiphery but sparing the limbal zone. The ring was composed of a fine, lacy garland of crystals present primarily in the anterior aspect of the stroma just beneath Bowman's membrane. The anterior chamber and iris showed no signs of inflammation. Intraocular pressures were 20 mm Hg and the ocular examination was otherwise unremarkable. Physical exam demonstrated no genu valgum. Blood testing showed a total cholesterol of 201 mg/dl with a low density lipoprotein cholesterol (LDL-C) of 156 mg/dl. Retesting four months later revealed a total cholesterol level of 245 mg/dl and an LDL-C of 192 mg/dl. The patient was referred to the pediatric gastroenterology service where he was put on diet therapy for further management of his hypercholesterolemia., Conclusions: This case appears to represent one of the rare sporadic examples of Schnyder's corneal dystrophy. The patient's family history is negative for ocular problems and the parents deny any Scandinavian ancestry. This patient is also unique for his presentation with ocular irritation. Most patients with Schnyder's dystrophy are initially seen for diagnosis of asymptomatic cloudy corneas or for gradual, painless loss of vision although glare in bright sunlight is noted by some individuals. Perhaps the most significant finding concerning this patient are his serum cholesterol levels. The association between total and LDL cholesterol and atherosclerotic vascular disease are well known and the literature suggests that regression of coronary artery disease is possible with aggressive treatment of hypercholesterolemia. Intervention in children should be considered if total cholesterol exceeds 170 mg/dl or LDL-C exceeds 110 mg/dl. Thus, early detection may eliminate significant morbidity and mortality. We therefore advocate evaluating all patients with Schnyder's corneal dystrophy and their immediate family members for systemic hypercholesterolemia.

Familial forms of isolated hypercholesterolemia are inherited autosomal-dominantly and are caused by defects of the low-density lipoprotein (LDL) receptor protein or its ligand, the apolipoprotein B-100, the exclusive apolipoprotein moiety of the LDL particles. Mutations at the LDL receptor gene locus (more than 150 different mutations have been described up to now) lead to familial hypercholesterolemia (FH); the only mutation at the apolipoprotein B-100 gene locus described in detail so far leads to the so-called familial defective apolipoprotein B-100 (FDB). Both lipid disorders are characterized by an increased risk for premature atherosclerosis involving primarily the coronary arteries. An increased risk for coronary heart disease can be expressed statistically by the excess mortality. In particular, individuals between the age of 20 and 59 are affected by an excess mortality; coronary deaths are approximately 100 times more frequent in patients between 20 and 39 with familial forms of hypercholesterolemia than within the normal population. On the other hand, in patients with myocardial infarctions before the age of 60, the diagnosis of FH is approximately 20 to 30 times more frequent than within the normal population. A regression of cardiovascular lesions subsequent to an intensive lipid-lowering therapy has clearly been demonstrated in patients with familial forms of hypercholesterolemia. Because of the serious prognosis of untreated familial forms of isolated hypercholesterolemia with respect to longevity, it is important to identify patients and their relatives with FH and FDB as early as possible and to treat them, besides a lipid-lowering diet, intensively with lipid-lowering drugs.

This review article describes the types, pathophysiology, differential diagnosis and therapy of hypercholesterolemia. Special attention has been directed towards familiar hypercholesterolemia and familiar apolipoprotein B 100 defect. Clinically, both forms present very similar and may cause severe coronary arteriosclerosis and death before the age of 40 years. In the homozygote form CHD even develops prior to adolescence. With a frequency of 1:500 these forms of hypercholesterolemia are among the most common genetic disorders worldwide. The poor prognosis and their monogenetic dominant character emphasize the need for an exact distinction from the poligenetic forms of hypercholesterolemia and moreover underscore the necessity to screen for affected members in the family of already diagnosed cases and call for more aggressive therapeutic interventions. By dietary measures and monotherapy only 25% of patients reach the recommended cholesterol values. HMG-CoA reductase inhibitors proved to be the most effective. The remainders have to be treated with combinations of up to 3 lipid-lowering drugs. Alternative treatment such as extracorporal cholesterol elimination may become necessary.

There is general agreement that hyperlipidemic states, in particular hypercholesterolemia, should be diagnosed during childhood, and treatment should start beyond the age of 2 years. The rationale for this procedure is the fact that increased cholesterol levels have been accepted to act as major risk factors for coronary vascular disease in adult populations, and therefore the significance of cholesterol must be inferred from less direct evidence. The diagnosis of hyperlipidemias is based on reference levels for the various age groups which are mainly transferred from studies in the USA. The classification of hyperlipidemias refers to a clinical and genetic concept; thus, familial hypercholesterolemia (incidence 1:500) is the most important disorder for the pediatric age group. Treatment of affected children should include dietary restrictions, in particular for saturated fats, but substitution of animal protein by soy protein has been shown to increase the cholesterol lowering effect. It is concluded that children from families with cardiovascular disease and/or hyperlipidemias should be referred to a special metabolic clinic for appropriate diagnosis and treatment. So far, a general screening for hyperlipidemias is not recommended in the neonatal period or during childhood.

The identification of patients with monogenetic lipid disorders and a very high risk of premature coronary heart disease is the prerequisit for an intensive cholesterol lowering therapy with the goal to normalize serum cholesterol and prevent early coronary death which seems possible with the new potent drugs.

The goal of MED-PED, a worldwide program including USA and many countries of Europe, Asia and Australia aims at diagnosing at the DNA level familial hypercholesterolemia (FH). There are currently 2 genetic defects under consideration: the LDL-R defect and familial Apo-B-100 defect (FDB). Whereas currently more than 160 mutations for the LDL-receptor defect are known, which can hamper the straight foreward characterization at the DNA level, FDB is caused by a single point mutation which may be easily characterized by routine methods. Austria participates since January 1st in MED-PED with subcenters in many different regions, which are listed in this article. We expect from the MED-PED program not only an optimation of health care in our country, with respect to preventive medicine, but also as studies from the US demonstrate, a positive cost effectiveness may be reached by this program. MED-PED in Austria is just at the beginning and in a rather preliminary stage, but we hope that after finding sponsors for covering the actual costs, this project will go on to a more advanced stage.

In Austria atherosclerosis related diseases are responsible for the death of more than 50% of the population. There is a linear relationship between lowering cholesterol and the mortality of coronary heart disease. Apart from diet and drug therapy for the treatment of hypercholesterolemia we nowadays have very potent extracorporeal cholesterol lowering therapies. In combination with HMG-CoA reductase inhibitors LDL-cholesterol can be lowered by 80% with these procedures. In particular homozygote familial hypercholesterolemia is an absolute indication for extracorporeal lipid lowering. Refractory heterozygote FH and secondary hypercholesterolemia in combination with other risk factors can also be controlled by extracorporeal cholesterol elimination. Since some of these extracorporeal therapies also improve the hemorheological situation they are also being used to treat peripheral vascular disease and cerebral atherosclerosis.

While screening activities have already been performed in a wide range in adults in Austria, extensive investigations in children and juveniles have so far only been done in a very limited number. In 1094 out of 1732 juveniles attending agricultural schools all lipid parameters were fully documented and thus could be evaluated. On an average, the total cholesterol (169 mg/dl) was too high; the worst findings for lipid parameters cholesterol, HDL-cholesterol, triglycerides, apolipoprotein-A1 were found in pupils of Burgenland. The cholesterol/HDL-cholesterol ratio in Burgenland was significantly (p < 0.01) higher than in Lower Austria. Female participants had a higher total cholesterol, HDL-cholesterol, and apolipoprotein-A1, but lower triglycerides and also lower blood pressure. Juveniles with a positive family history showed lower total cholesterol, but higher triglycerides as well as HDL-cholesterol. In heavy smokers, but also in occasional smokers, a lower total cholesterol, but decreased HDL-cholesterol and apolipoprotein-A1 and increased triglycerides were found. These findings underline the high prevalence of hypercholesterolemia in juveniles justifying screening activities and possibly therapeutic intervention at this young age.

LDL-cholesterol is the leading risk factor which influences the clinical outcome of patients with preexisting coronary heart disease. Clinical trials show that diet and medication, that lower plasma LDL-cholesterol below 100 mg/dl decrease the rate of recurrent myocardial infarction and can induce regression in patients with coronary heart disease. However, in most cases of severe hypercholesterolemia with plasma LDL-cholesterol concentrations above 220 mg/dl LDL cannot be sufficiently decreased by maximal dietary and pharmacological therapy alone. Today this group of high risk CHD patients can be treated in addition with an extracorporeal procedure to eliminate LDL from the plasma circulation, the H.E.L.P.-LDL-apheresis. This method for selective removal of LDL, lipoprotein(a) and fibrinogen from plasma has been shown to be a clinically safe and very efficient method for the treatment of patients with homozygous familial hypercholesterolemia or CHD patients with severe hypercholesterolemia. Treatments with one week H.E.L.P. intervals revealed a mean reduction of minus 51% for LDL, of minus 45% for Lp(a) and of minus 46% for apo B, while HDL was increased by +12%. Fibrinogen was decreased by minus 46%. Besides the marked reduction of LDL and fibrinogen plasma concentrations the H.E.L.P.-treatment significantly improves hemorheological parameters and increases the oxygen tension in the tissue. We have also investigated the efficiency of a combined therapy, using HMG-CoA reductase inhibitors together with the H.E.L.P.-apheresis. Under this combined treatment, a reduction of the interval LDL-cholesterol levels of 70-80% has been achieved, while Lp(a) and fibrinogen were not further affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Temperature-dependence, time-course, competition studies and saturation kinetics of the binding of either 123I-LDL or 111In-LDL to peripheral blood mononuclear cells (lymphocytes and monocytes) were determined in normolipemic controls and heterozygous familial hypercholesterolemia (FH) patients. Radioligand binding studies with 123I-LDL and 111In-LDL revealed similar binding characteristics. The maximal binding capacity was significantly reduced in FH patients (p less than 0.01) whereas the binding equilibrium dissociation constant was virtually unchanged as compared to healthy controls.

It has been demonstrated in numerous studies that hypercholesterolemia is an important independent risk factor for the development of coronary heart disease. Besides exogenous factors like diet and physical exercise genetic predisposition is a major determinant of serum cholesterol levels. Apolipoprotein B-100 (apo B-100) is the protein constituent of LDL which serves as ligand to the LDL-receptor. A hypervariable region containing repetitive elements adjacent to the apo B gene was used as marker to study the role of genetic variation in this gene in the development of elevated serum lipid levels and premature coronary heart disease. A group unrelated patients with severe coronary heart disease and normal controls were studied. Using a high resolution method we could identify 14 different alleles. Alleles with a large number of repetitive elements were associated with coronary heart disease. The same alleles were weakly associated with elevated levels of serum levels of cholesterol, triglycerides and apolipoprotein B.

Twenty-eight patients were studied who required treatment for hypercholesterolemia type IIa. Familial hypercholesterolemia was found in 53%. Sixty percent of all patients had arcus senilis. When familial and non-familial hypercholesterolemia were compared the incidence of arcus senilis was 80% and 38%, respectively. The gradation of the condition was minor (n = 9), moderate (n = 4), or pronounced (n = 4); all patients with a strong degree and 7 of 8 patients with either moderate or pronounced arcus senilis had familial hypercholesterolemia. The mean cholesterol level was 345 +/- 82 in patients with familial hypercholesterolemia and 353 +/- 120 mg/dl in patients with non-familial hypercholesterolemia. Although the correlation between the cholesterol level and the degree of arcus senilis was higher in patients with familial hypercholesterolemia than in those with non-familial hypercholesterolemia (r = 0.45 versus r = 0.17), neither had clinical relevance. There was no connection between the cholesterol level, refraction or visual acuity. The mean contrast sensitivity measured for five different spatial frequencies in all patients was normal. In comparison with patients without arcus senilis, the mean values in patients with severe arcus senilis showed lower contrast sensitivity for the higher spatial frequencies.

The distinct increase in the highly atherogenic plasma low-density lipoproteins (LDL) caused by the wellknown LDL-receptor defect is considered to be responsible for the development of atherosclerosis in familial hypercholesterolemia (FH). In contrast to the atherogenic LDL, the high-density lipoproteins (HDL) are considered to have a protective effect against the development of atherosclerosis and have hitherto been insufficiently investigated in association with FH. HDL2 are assumed to be important in the removal of free cholesterol from the peripheral tissue to the liver, but this hypothesis needs to be supported by further experimental investigations. In this study 18 patients (7 men/11 women) with familial hypercholesterolemia (FH) were compared with 18 healthy controls (8 men/10 women). From fasting plasma the following parameters were determined: cholesterol, triglycerides, phospholipids, HDL-cholesterol, by rate zonal ultracentrifugation the lipoproteins VLDL (very low-density lipoproteins), IDL (intermediate-density lipoproteins), LDL (low-density lipoproteins), HDL2 and HDL3, as well as the activities of lipoprotein lipase (LPL) and hepatic lipase (HTGL). In addition, the percentage composition of the major apolipoproteins (apo) of HDL2 and HDL3 were determined by polyacrylamide disc-gel electrophoresis. In LDL of patients with FH the percentage amount of protein was significantly (p less than 0.01) smaller than in controls. Furthermore, in HDL2 of patients with FH, the percentage content of apo-A II and apo-D was significantly (both p less than 0.01) higher than in controls. In HDL3 of patients with FH a significantly smaller (p less than 0.02) amount of apo-E was revealed than in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

We present a scanning electron microscopic method for determining the quantity of the apo B,E-receptors at the surface of lymphocytes. We used human lymphocytes from venous blood. Gold particles, 50 nm in diameter, were conjugated to the receptors by indirect coupling. We visualized the gold particles by means of an electron microscope (JEM 100 S with scanning attachment ASID). The lymphocytes of control persons and of patients with primary hyperlipoproteinaemias were analysed. Scanning electron microscopic assay of labelled apo-B,E-receptors was shown to allow the rapid and accurate identification of patients with autosomal monogenic hypercholesterolaemia.

In our examinations of the new-born and their parents, of the patients with coronary heart disease and their relations, of the healthy test persons of different age and of the families of the long-lived persons we have found that in the atherogenesis genetic factors and blood lipids play a great part. In future it is perhaps possible already early to recognize in children a genetically conditioned hyperlipoproteinaemia, all the more since in the patients with hereditary load was to be observed a clear increase of the indices of lipid metabolism in comparison to the healthy test persons. Furthermore, a connection between a hyperlipoproteinaemia and the AB0 blood groups was stated. A combination of the hyperlipoproteinaemia of type IIb with the blood group A in new-born and in patients after myocardial infarction belongs to the most important risk factors for the atherogenesis. On account of these findings it is possible to establish a hyperlipoproteinaemia in childhood in children with hereditary load, which gives the possibility by means of normalization of the lipids to perform an early prophylaxis of the arteriosclerosis. The examination of the long-lived persons showed that the arteriosclerosis is not certainly an accompanying appearance of old age, for the autopsies of persons 100 years of age and more did not show any arteriosclerotic changes of the vessels.

The spontaneous and the induced change of phenotype makes the correct interpretation of disturbance of fat metabolism on the base of phenotypization by Fredrickson more difficult. This is underlined by the present international practice to divide disturbances of fat metabolism for the time by increased lipids into hypercholesterinaemiae, hypertriglyceridaemiae and hypertriglyceride-hypercholesterinaemiae. The common trend, however, aims at characterization of disturbances of fat metabolism by changes of apoproteins.

The significance of genetic factors contributing to the complex etiology of coronary heart disease is discussed using lipoprotein metabolism as an example. A radiochemical screening method was developed fro precise biochemical diagnosis of autosomal monogenic hypercholesterolemia. In this method lymphocytes are used as test material.