"Finnish" mutations in LDL receptor gene: a rare cause of familial hypercholesterolemia in St. Petersburg and Petrozavodsk.

The search for two mutations, FH-Helsinki and FH-North Karelia, in LDL receptor gene was carried out in patients with familial hypercholesterolemia from St. Petersburg (80 families) and Petrozavodsk (80 families) using allele-specific PCR and analysis of single-stranded DNA fragment conformation polymorphism (SSCP analysis) with subsequent sequencing. The FH-North Karelia mutation was found in one family in St. Petersburg and in one family in Petrozavodsk, while FH-Helsinki mutation was not detected in any of the samples. Hence, the two "Finnish" mutations together responsible for 2/3 familial hypercholesterolemia cases in Finland were extremely rare in the Russian regions neighboring Finland.

[Family and polygenic hypercholesteremia: similarities and differencies according to long-term clinical observations].

AIM: Detection and analysis of similarities and differences in patients with family and polygenic hypercholesterolemia (FHCE and PHCE). MATERIAL AND METHODS: The study included 100 patients with FHCE and 80 PHCE patients with LD-LP cholesterol level at least 4.3 mmol/l (170 mg/dl). RESULTS: The patients differed by age, gender, severity of hypercholesterolemia, clinical symptoms. Half of PHCE patients had myocardial infarction, 18% had angina pectoris, 29% cerebrovascular events. The disease was asymptomatic in 19% FHCE patients, 33% had myocardial infarction, 15%--angina pectoris, 12%--cerebrovascular events, 9%--aortic problems. Total mortality in both groups was similar--32 and 33%. Long-term treatment with statins reduced lethality twice both in FHCE and PHCE. Adequate statin therapy prolonged life of the patients by 11 years, on the average. CONCLUSION: Regular treatment of patients with hypercholesterolemia reduces lethality and prolong their life span.

[Familial hypercholesterolemia in St. Petersburg: diversity of mutations argues against a strong founder effect].

Examination of low-density lipoprotein (LDL) receptor, its promoter, and major exon-intron boundaries from a sample of patients with familial hypercholesterolemia (FH) from 74 probands of St. Petersburg revealed 34 mutations and 8 widely spread polymorphisms at this locus. Only four mutations were considered silent, while the other 30 are likely associated with familial hypercholesterolemia (FH). Mutations in the LDL receptor gene, inducing the disease, were identified in 41 (55%) out of 74 families with FH. Mutation R3500Q in apolipoprotein B (APOB) gene was not detected in all probands. Therefore in the families lacking mutations hypercholesterolemia was induced by mutations in the introns of the LDL receptor gene or by other genetic factors. Nineteen mutations causing disease progression were described in St. Petersburg for the first time, while 18 of them are specific for Russia. Among Ashkenazi Jews, major mutation G197del was detected in 30% (7 out of 22) of patients with FH. In the Slavic population of St. Petersburg, no major mutations were detected. Only five mutations were identified in two families, while 24 were found in isolated families. These data are indicative of the lack of a strong founder effect for FH in the St. Petersburg population.

[About dyslipidemic states characteristic for various forms of ischemic heart disease and cerebrovascular damages].

We examined 4 groups of patients younger than 70 years with atherosclerosis of coronary and/or cerebral arteries. In 98 patients the disease began as acute myocardial infarction, 65 patient from the very beginning suffered from angina of effort, 33 had ischemic cerebral stroke, and in 26 dyscirculatory encephalopathy was diagnosed. Among patients with ischemic heart disease (IHD) and cerebrovascular damages (CVD) 87 and 89%, respectively, had dyslipidemia (DLP). Disorders of lipid composition of the blood with pronounced hypercholesterolemia prevailed in patients with IHD and elevated level of triglycerides or selective decrease of antiatherogenic fraction of lipoproteides - in patients with CVD (especially in patients with stroke). When treatment is prescribed to patients with IHD and CVD at the background of DLP it is necessary to take into consideration DLP variants in order to obtain most effective action of statins and fibrates.

[Identification of novel missense mutation G571E, novel silent mutation H229H, nonsense mutation C74X, and four single nucleotide polymorphisms in the low-density lipoprotein receptor in patients with familial hypercholesterolemia from St. Petersburg]. / Identifikatsiia novoi missens-mutatsii G571E, novoi molchashchei mutatsii H229H, nonsens-mutatsii C74X i chetyrekh odnonukleotidnykh polimorfizmov v gene retsptora lipoproteinov nizkoi plotnosti u patsientov s semeinoi giperkholesterinemiei Sankt-Peterburga.

Novel missense mutation G571E (c.1775 G > A), novel silent mutation H229H (c.750 C > T), and nonsense mutation C74X (c.285 C > A), earlier described in Japan but unknown in Russia, were identified in the low-density lipoprotein (LDL) receptor gene in St. Petersburg familial hypercholesterolemia in patients. The analyzed group of patients was shown to be polymorphic in many positions of the LDL receptor gene, namely: c.1171 G/A, c.1773 T/C, c.2177 C/T, and c.2231 G/A.

[A multiexon deletion in the human low density lipoprotein receptor gene as a reason for familial hypercholesterolemia]. / Mul'tiékzonnaia deletsiia v gene retseptora lipoproteinov nizkoi plotnosti cheloveka kak prichina semeinoi giperkholesterinemii.

Inheritance of Taq I, BstE II, and Nco I restriction fragment length polymorphisms (RFLP) in three families from St. Petersburg with familial hypercholesterolemia (FH) was studied. In two of these families, polymorphic markers of the low density lipoprotein receptor (LDLR) gene cosegregated with the disease. This data confirmed FH diagnosis based on the analysis of blood plasma lipid levels. Three different RFLP haplotypes were associated with the disease, suggesting the presence of at least three point mutations in the LDLR gene in the population studied, i.e., suggesting molecular heterogeneity of FH in the St. Petersburg population.

[Molecular heterogeneity of familial hypercholesterolemia in the St. Petersburg population]. / Molekuliarnaia geterogennost' semeinoi giperkholesterinemii v populiatsii zhitelei Sankt-Peterburga.

Inheritance of Taq I, BstE II, and Nco I restriction fragment length polymorphisms (RFLP) in three families from St. Petersburg with familial hypercholesterolemia (FH) was studied. In two of these families, polymorphic markers of the low density lipoprotein receptor (LDLR) gene cosegregated with the disease. This data confirmed FH diagnosis based on the analysis of blood plasma lipid levels. Three different RFLP haplotypes were associated with the disease, suggesting the presence of at least three point mutations in the LDLR gene in the population studied, i.e., suggesting molecular heterogeneity of FH in the St. Petersburg population.

[Four new mutations and polymorphic variants of the low density lipoprotein receptor in patients with familial hypercholesterolemia in Saint Petersburg]. / Chetyre novye mutatsii i polimorfnye varianty gena retseptora lipoproteinov nizkoi plotnosti u patsientov s semeinoi giperkholesterinemiei Sankt-Peterburga.

In a collection of DNA samples from 100 unrelated patients with clinical features of familial hypercholesterolemia (FH), a search for mutations of exons 4 and 10 of the low-density lipoprotein (LDL) receptor gene was performed using heteroduplex and single-strand conformational polymorphism (SSCP) analyses followed by sequencing of amplified DNA fragments. Four new mutations of the LDL receptor gene were identified: C146R (c.499 T > C), A130P (c.451 G > C), G128G (c.477 T > C), and C188Y (c.626 G > A). Mutation A130P was assigned to the same chromosome with allele variant 447C. Two polymorphic sites in exon 10 of the LDL receptor gene (1413G/A and 1545C/T) were found in the Russian population for the first time. Based on the data obtained, familial hypercholesterolemia was confirmed in seven patients.

[Search for frequently encountered mutations in genes predisposing to breast cancer]. / Poisk chasto vstrechaiushchikhsia mutatsii v genakh predraspolozhennosti k raku molochnoi zhelezy.

DNA of oncological patients, including Ashkenazi Jews and Slavs, living in St. Petersburg was collected, and the resultant collection was screened for three common mutations of genes BRCA1 and BRCA2 by means of heteroduplex analysis. The mutation 5382insC in exon 20 of the BRCA1 gene was found in four unrelated patients, including three Slavs and one Ashkenazi Jew, with a positive family history of breast cancer. The mutations 185delAG and 6174delT in the BRCA1 and BRCA2 genes, respectively, which are typical of Ashkenazi Jewish patients with breast cancer, were not found in the patients of either ethnicity living in St. Petersburg, although the 6174delT mutation was found in the control group of Ashkenazi Jews. A new 12-nucleotide duplication g.71741ins12nt found in intron 20 of the BRCA1 gene was described. The high frequency of the 5382insC mutation in the BRCA1 gene in patients with familial breast cancer in both St. Petersburg and Moscow indicates that Russian families with the history of breast cancer should be primarily tested for this mutation.

[Apical cardiogram during bicycle ergometry as a method of assessing the contractile capacity of the myocardium in ishemic heart disease]. / Apikal'naia kardiogramma v usloviiakh veloérgometrii kak metod otsenki sokratitel'noi sposobnosti miokarda u bol'nykh ishemicheskoi bolezn'iu serdtsa.

The authors appraise a number of indices of left-ventricular apex cardiogram recorded at rest and after submaximum or threshold physical load in 52 healthy males and in 122 patients with ischemic heart disease. It was found that after physical load the electromechanic interval of the apex cardiogram of patients with ischemic heart disease is prolonged, the period of rapid filling is shortened and the period of slow filling of the left ventricle is prolonged with a general decrease in the whole diastole as compared to that which should be. An increase in the ratio of the atrial wave amplitude to the total systolic wave, which is clearly demonstrated after physical load, is one of the earliest signs of cardiodynamic disorders recorded by apex-cardiography. A parallelism was established between the degree of the pathological changes on the apex cardiogram, physical load tolerance and the pronounced character of the clinical manifestation of ischemic heart disease.

[Hyperlipemia and functional state of the myocardius according to the analysis of the polycardiograph under conditions of submaximal physical exercise]. / Giperlipidemiia i funktsional'noe sostoianie miokarda po dannym analiza polikardiogrammy v usloviiakh submaksimal'noi fizicheskoi nagruzki.

An analysis of polycardiographic parameters prior to and following treadmill exercises was conducted in 124 males, aged 39-59 years; in 57 of them the blood lipids level was normal, in 67--elevated (cholesterol level 260 mg% and higher in those aged 39--49 and 280 mg% and higher for those aged 50-59, or triglycerids--300 mg% and higher for both age-groups). In persons with elevated levels of lipids in blood during early restitution (after 2 min.) following submaximal physical exercises polycardiogrammes demonstrated a phase syndrome of hypodynamia irrespective of the fact whether an ischaemic depression of the ST segment appeared on the ECG tracings in response to the exercises or not. The functional deficiency of the myocardium in patients with hyperlipidemia is most probably explained by the hampered oxygen transport from the erythrocytes via the hyperlipidemic plasma to the heart muscle.

[Relationship between lipid and carbohydrate metabolism and hyperinsulinemia in coronary arteriosclerosis]. / O vzaimosviazi narushenii lipidnogo i uglevodnogo obmenov s giperinsulinemiei pri ateroskleroze koronarnykh arterii

The disorders in the carbohydrates metabolism were studied along with the level of insulinemia in patients with coronary atherosclerosis, and the interrelationship between the pathological shifts in the lipid and carbohydrates metabolism were clarified. The study was conducted in 45 persons: 31 patients with coronary atherosclerosis and 14 normals. The indices of the lipid (cholestrol, triglycerides, NEFA, lipoproteids) and carbohydrates metabolism (blood sugar immunoreactive insulin) were analysed on an empty stomach and after glucose provocation. Twenty of the 31 patients demonstrated hyperinsulinemia, 25--an altered tolerance of carbohydrates. The authors believe that in atherosclerosis hyperinsulinemia develops against the background of pre-existing disorders in the lipid metabolism, and correlates with the degree of the increase in atherogenic lipoproteids.

[Effect of heparin on blood lipids under conditions of endo- and exogenous hyperlipemia]. / Vliianie geparina na lipidy krovi v usloviiakh endo- i ekzegennoi giperlipemia

In 15 patients suffering from ischemic heart disease and in 5 healthy individuals (controls) the dynamics of the blood lipids content (NEFA, triglycerides and atherogenic lipoproteins) was followed up on an empty stomach, during a 18-hour fasting, after carbohydrate and fat loadings, before and after intravenous administration of heparin. Data on a quick and abrupt rise of the NEFA level and a falling triglycerides concentration, and also on a certain decline in the content of atherogenic lipoproteins following administration of heparin were obtained. In atherosclerotic patients the development of hypertriglyceridemia in response to introduction of glucose and a prolonged rise in the level of triglycerides following a fat loading were recorded. Intravenous administration of heparin with carbohydrates and fat loads contributes in atherosclerotic patients to a rapid fall of the blood plasma tryglycerides concentration.

[Characteristics of the adequate and pathological reactions to the standard treadmill test in a female population 20 to 69 years old]. / Kharakteristika adekvatnykh i patologicheskikh reaktsii na standartnyi tredmilovyi test v populiatsii zhenshchin 20--69 let.

Treadmill exercise tests were carried out in 397 women, aged 20 to 69, who were selected at random from an unorganized population. Four types of response were identified: ischemia, reduced stress tolerance due to excessively elevated systolic arterial blood pressure or other causes; reduced stress tolerance due to premature muscular fatigue or dyspnea (in less than 9 minutes of exercise) and the adequate type. The parameters of adequate response to physical stress were established. The incidence of ischemic response was relatively small in women, as compared to men. Ischemic response was only seen in women between 50 and 69 years of age, making a 4.5% rate.

[Characteristics and significance of cardiodynamic disorders in patients with stenocardia and a history of myocardial infarction]. / O kharaktere i znachenii narushenii kardiodinamiki u bol'nykh so stenokardiei i perenesennym infarktom miokarda.

To judge of the contractile function of the heart polycardiography and apical cardiography were used to study a male population aged 40-49 years and 57 patients up to 50 years with ischaemic heart disease (IHD). The investigations were made at rest and after a tread-mill test. Patients with IHD were divided into 3 groups: those who had myocardial infarction from 6 months to 3 years with high and low tolerance to exercise and persons with angina pectoris. All patients with IHD were found to have extension of the isometric contraction on the polycardiogram and enhanced amplitude of the atrial wave in relation to the main systolic wave of the apexcardiogram, and also decreased tolerance to exercise. Cardiodynamic disorders in patients with angina pectoris were manifest as clearly as in many patients who had had myocardial infarction.

[Distribution of the electrocardiographic changes characteristic of ischemic heart disease among the male population of Leningrad in comparison with the clinical biochemical indices]. / Rasprostranennost' élektrokardiograficheskikh izmenenii, svoistvennykh ishemicheskoi bolezni serdtsa, sredi muzhskogo naseleniia Leningrada v sopostavlenii s nekotorymi kliniko-biokhimicheskikh pokazateliami.

The authors studied the peculiarities of electrocardiograms recorded under conditions of rest in 1,022 males from 40 to 59 years of age, who reflected representatively a selected unorganized population of 1,250 persons. The ECG were analysed according to the Minnesota code. Among the examined persons 9.6% were found to have "coronary" ECG changes indicating to ischemic heart disease. The tread-mill test conducted in individuals chosen for scrupulous examination made it possible to make a diagnosis of ischemic heart disease in 19.6% of 219 persons (72 of whom had hyperlipidemia). A tendency toward relative decrease in high-density lipoproteins was noted in individuals with clearly manifested signs of coronary pathology on the ECG.

[Tolerance to physical exertion after myocardial infarct as a method of evaluation of coronary circulation and cardiac function]. / Tolerantnost' k fizicheskoi nagruzke u bol'nykh, perenesshikh infarkt miokarda, kak metod otsenki koronarnogo krovoobrashcheniia i funktsional'nogo sostoianiia serdtsa.

Twenty healthy individuals and 61 persons who had suffered from myocardial infarction 3 to 18 months previously were examined. They were all males under the age of 50. Tolerance of healthy persons to physical load on a treadmill (according to a standard program) was 3.6 steps of the treadmill test with maximum pulse rate of 166 +/- 2 per minute. The tolerance to load of persons who had a history of myocardial infarction was much lower and varied mainly with the severity of coronary insufficiency. An inadequate reaction of the cardiovascular system to the load was revealed in most of them.

[Clinico-epidemiological characteristics of ischemic heart disease in men of different age groups from the data of a single screening of a random population]. / Kliniko-épidemiologicheskie osobennosti ishemicheskoi bolezni serdtsa u muzhchin raznykh vozrastnykh grupp po dannym odnomomentnogo obsledovaniia neorganizovannoi populiatsii.

A total of 742 men, aged 20-69 and representative of a random male population from a Leningrad district, were investigated. The incidence of coronary disease was 3.2% in subjects aged 20-29, and 33.3% in those aged 60-69. In 40-49-year-olds, coronary disease was mostly manifested in angina of effort (57.9%), whereas painless forms reflected in ECG at rest prevailed (55-58.5% in men above 50 years of age. The frequency of ischemic response to the treadmill test increases with advancing age (8.3% in subjects aged 40-49 and 28.2% at age 60-69). The results of the WHO Questionnaire on Angina of Effort demonstrate that ECG at rest and exercise tests are mutually complementary procedures for epidemiologic diagnosis of coronary disease, their combination ensuring the fullest possible identification of coronary disease in population screenings.

[Myocardial 99mTc-pyrophosphate scintigraphy during bicycle ergometry as a method of evaluating the severity of chronic ischemic heart disease]. / Stsintigrafiia miokarda 99mTc-pirofosfatom v usloviiakh veloérgometrii kak sposob otsenki tiazhesti techeniia khronicheskoi ishemicheskoi bolezni serdtsa.

The time course of myocardial 99mTc-pyrophosphate accumulation 1 hour after a bicycle ergometric test versus the resting scintigraphic findings was correlated with the severity of chronic coronary heart disease (CHD) and long-term prognosis. A group of the patients who had higher radiotracer accumulation following the exercise showed the most severe disease and unfavorable prognosis (in this group 19.4% deaths were observed during a three-year follow-up). A single administration of 99mTc-pyrophosphate followed by scintigraphy 2 hours after bicycle ergometry and repeated scintigraphy 1 hour later allows one to assess the time course of myocardial radiotracer accumulation and to judge how the myocardium is supplied by blood.

[Cardiac contractility in males with post-infarction cardiac sclerosis as evidenced by ultrasonic scanning]. / Kontraktil'naia funktsiia serdtsa u muzhchin s postinfarktnym kardiosclrozom po rezul'tatam ul'trazvukovogo skanirovaniia.

The relationship was examined between the severity of heart failure, the degree of asynergy and exercise tolerance in 40 males under 60 years with postinfarction cardiosclerosis. Fifteen healthy males were matched for as a control. Echocardiography was performed before and after bicycle ergometer exercise test, allowing the patients to be divided into 4 groups: Groups 1 and 2 without an ischemic response in the absence or presence of akinesia or dyskinesia, respectively; Groups 3 and 4 with an ischemic response in the absence or presence of akinesia or dyskinesia, respectively. The lowest exercise tolerance was observed in Group 4. Echographic findings showed that the overall left ventricular contractility was diminished in all the patients; there was no noticeable quantitative difference in the values between the groups. No differences were found in segmental ejection fractions. The combination of ischemic response to exercise tolerance and akinesia-dyskinesia asynergy indicates a more severe disease of the coronary bed and myocardium.