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Excess cholesterol originating from nonhepatic tissues is transported within HDL particles to the liver for metabolism and excretion. Cholesterol efflux is initiated by lipid-free or lipid-poor apolipoprotein A1 interacting with the transmembrane protein ABCA1, a key player in cholesterol homeostasis. Defective ABCA1 results in reduced serum levels of HDL cholesterol, deposition of cholesterol in arteries, and an increased risk of early onset CVD. Over 300 genetic variants in ABCA1 have been reported, many of which are associated with reduced HDL cholesterol levels. Only a few of these have been functionally characterized. In this study, we have analyzed 51 previously unclassified missense variants affecting the extracellular domains of ABCA1 using a sensitive, easy, and low-cost fluorescence-based assay. Among these, only 12 variants showed a distinct loss-of-function phenotype, asserting their direct association with severe HDL disorders. These findings emphasize the crucial role of functional characterization of genetic variants in pathogenicity assessment and precision medicine. The functional rescue of ABCA1 loss-of-function variants through proteasomal inhibition or by the use of the chemical chaperone 4-phenylbutyric acid was genotype specific. Genotype-specific responses were also observed for the ability of apolipoprotein A1 to stabilize the different ABCA1 variants. In view of personalized medicine, this could potentially form the basis for novel therapeutic strategies.
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Apolipoproteína A-I , Colesterol , HDL-Colesterol , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , Fluorescência , Transportador 1 de Cassete de Ligação de ATP/genética , Colesterol/metabolismo , Mutação de Sentido IncorretoRESUMO
Flavonoids, polyphenolic compounds found in plant-based diets, are associated with reduced risk of cardiovascular disease and longevity. These components are reported to reduce plasma levels of low-density lipoprotein (LDL) through an upregulation of the LDL receptor (LDLR), but the mechanism is still largely unknown. In this study, we have systematically screened the effect of 12 flavonoids from six different flavonoid subclasses on the effect on LDLR. This paper provides an in-depth analysis on how these flavonoids affect LDLR regulation and functionality. We found that most but not all of the tested flavonoids increased LDLR mRNA levels. Surprisingly, this increase was attributed to different regulatory mechanisms, such as enhanced LDLR promoter activity, LDLR mRNA stabilization, or LDLR protein stabilization, of which specific effectual parts of the flavonoid molecular structure could be assigned. These types of comparative analysis of various flavonoids enhance clarity and deepen the understanding of how the different structures of flavonoids affect LDLR regulation. Our data offer useful insights that may guide future research in developing therapeutic approaches for cardiovascular health.
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Flavonoides , Receptores de LDL , Flavonoides/farmacologia , Flavonoides/química , Receptores de LDL/metabolismo , Receptores de LDL/genética , Humanos , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Regiões Promotoras GenéticasRESUMO
The aim of this study was to explore the prevalence of likely pathogenic or pathogenic variants and assess the diagnostic yield from genetic testing for cardiac arrhythmias in Norway since 2003. Data from 1991 probands and 2782 relatives were retrospectively collected from the laboratory information management system at Unit for Cardiac and Cardiovascular Genetics, Oslo University hospital. Of 1991 probands, 57.4% were females, age at genetic testing was 33.1 (±22.7) years, and 32.5% were under the age of 18. A likely pathogenic or pathogenic variant (including 14 novel) was detected in 15.4% in total. Of the 2782 relatives, 53.7% were females, age at genetic testing was 35.6 (±22.5) years, 27.3% were under the age of 18, and 45.3% carried the family variant. Probands and relatives combined, 1/3356 persons in the Norwegian population were heterozygous for an arrhythmia-causing variant. The founder variant p.Q530X (NM_000218.2: c.1588C>T) in KCNQ1 accounted for 34% of all variants in Norway. In conclusion, genetic testing provided a genetic basis of the arrhythmia in 15.4% of the probands. Familial cascade screening identified four times as many variant-positive relatives, allowing early detection and prompt stratification of arrhythmic risk of those variant carriers.
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AIMS: This study aimed to explore the incidence of severe cardiac events in paediatric arrhythmogenic right ventricular cardiomyopathy (ARVC) patients and ARVC penetrance in paediatric relatives. Furthermore, the phenotype in childhood-onset ARVC was described. METHODS: Consecutive ARVC paediatric patients and genotype positive relatives ≤18 years of age were followed with electrocardiographic, structural, and arrhythmic characteristics according to the 2010 revised Task Force Criteria. Penetrance of ARVC disease was defined as fulfilling definite ARVC criteria and severe cardiac events were defined as cardiac death, heart transplantation (HTx) or severe ventricular arrhythmias. Childhood-onset disease was defined as meeting definite ARVC criteria ≤12 years of age. RESULTS: Among 62 individuals [age 9.8 (5.0-14.0) years, 11 probands], 20 (32%) fulfilled definite ARVC diagnosis, of which 8 (40%) had childhood-onset disease. The incidence of severe cardiac events was 23% (n = 14) by last follow-up and half of them occurred in patients ≤12 years of age. Among the eight patients with childhood-onset disease, five had biventricular involvement needing HTx and three had severe arrhythmic events. Among the 51 relatives, 6% (n = 3) met definite ARVC criteria at time of genetic diagnosis, increasing to 18% (n = 9) at end of follow-up. CONCLUSIONS: In a paediatric ARVC cohort, there was a high incidence of severe cardiac events and half of them occurred in children ≤12 years of age. The ARVC penetrance in genotype positive paediatric relatives was 18%. These findings of a high-malignant phenotype in childhood-onset ARVC indicate a need for ARVC family screening at younger age than currently recommended.
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Displasia Arritmogênica Ventricular Direita , Humanos , Displasia Arritmogênica Ventricular Direita/diagnóstico , Displasia Arritmogênica Ventricular Direita/epidemiologia , Displasia Arritmogênica Ventricular Direita/genética , Fatores de Risco , Arritmias Cardíacas/epidemiologia , Eletrocardiografia , Estudos de CoortesRESUMO
Approximately 5 % of the population have highly elevated levels of lipoprotein(a) (Lp(a)), which is a genetically determined risk factor for cardiovascular disease. Measuring lipoprotein(a) can improve cardiovascular risk stratification and have consequences for preventive measures. Treatment is targeted at reducing modifiable cardiovascular risk factors, but Lp(a)-lowering drugs are being trialled. This article reviews the management of lipoprotein(a) in clinical practice.
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Doenças Cardiovasculares , Lipoproteína(a) , Humanos , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/tratamento farmacológico , Lipoproteína(a)/sangue , Fatores de RiscoRESUMO
PURPOSE OF REVIEW: Patients with familial hypercholesterolemia (FH) have a markedly increased risk of premature cardiovascular disease. However, there are effective lipid-lowering therapies available to reduce the risk of cardiovascular disease. This makes it important to diagnose these patients. The most cost-effective strategy to diagnose patients with FH is to perform cascade screening. However, cascade screening as part of ordinary healthcare has not been very successful. Thus, there is a need to implement more efficient cascade screening strategies. RECENT FINDINGS: Cascade screening for FH should be organized at a national level and should be run by dedicated health personnel such as genetic counsellors. As part of a national organization a national registry of patients with FH needs to be established. Moreover, for cascade screening to be effective, diagnosis of FH must be based on identifying the underlying mutation. There should preferably only be one genetics centre in each country for diagnosing FH, and this genetics centre should be an integrated part of the national cascade screening program. SUMMARY: Cascade screening for FH is very effective and should be organized at a national level. Even a modest national cascade screening program can result in a large number of patients being identified.
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Doenças Cardiovasculares , Hiperlipoproteinemia Tipo II , Doenças Cardiovasculares/genética , Testes Genéticos , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Hiperlipoproteinemia Tipo II/genética , Programas de Rastreamento , MutaçãoRESUMO
BACKGROUND AND AIMS: Both the Nordic and Mediterranean diets claim to have a beneficial effect on lipid metabolism and cardiovascular prevention. The objective of this study was to compare diets consumed by children with FH at the time of diagnosis in Norway and Spain and to study their relationship with the lipid profile. METHODS AND RESULTS: In this cross-sectional study, we appraised the dietary intake in children (4-18 years old) with (n = 114) and without FH (n = 145) from Norway and Spain. We compared Nordic and Mediterranean diet composition differences and determined the association between food groups and lipid profiles. RESULTS: The Spanish FH group had a higher intake of total fats (mainly monounsaturated fatty acids (MUFAs)), cholesterol and fibre, but a lower intake of polyunsaturated fatty acids (PUFAs) compared to the Norwegian FH group. The Norwegian children consumed more rapeseed oil, low-fat margarine and whole grains and less olive oil, eggs, fatty fish, meat, legumes and nuts. In the Norwegian FH group, fat and MUFAs were directly correlated with total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B and inversely correlated with high-density lipoprotein (HDL-C). In Spanish children with FH, the intake of fats (mainly MUFAs) was directly associated with HDL-C and apolipoprotein A1. CONCLUSIONS: Despite a similar lipid phenotype, diets consumed by children with FH in Norway and Spain have significant differences at time of diagnosis. Nutrition advice should be more adapted to local intake patterns than on specific nutrient composition.
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Doenças Cardiovasculares/prevenção & controle , Dieta Saudável , Dieta Mediterrânea , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/sangue , Hiperlipoproteinemia Tipo II/dietoterapia , Adolescente , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/etnologia , Criança , Pré-Escolar , Estudos Transversais , Características Culturais , Dieta Saudável/etnologia , Dieta Mediterrânea/etnologia , Comportamento Alimentar/etnologia , Feminino , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/etnologia , Masculino , Noruega , Valor Nutritivo , EspanhaRESUMO
Background and Purpose- Familial hypercholesterolemia (FH) is a common autosomal dominant disease leading to increased level of serum LDL (low-density lipoprotein) cholesterol and risk of coronary heart disease. Whether FH increases the risk of cerebrovascular disease, including ischemic stroke, is debated. Accordingly, we studied the incidence of cerebrovascular disease in a cohort of people with genetically verified FH compared with the entire Norwegian population and examined whether people in this cohort with previous cohort had increased risk of cerebrovascular disease. Methods- Incidence rates of hospitalization for cerebrovascular disease (among 3144 people with FH) and ischemic stroke (among 3166 people with FH) were estimated by linkage of FH people to Cardiovascular Disease in Norway-a nationwide database of cardiovascular disease hospitalizations (2001-2009). We calculated standardized incidence ratios and used Cox regression to estimate hazard ratios. Results- A total of 46 cases (19 women and 27 men) of cerebrovascular disease were observed in the cohort of people with FH, with no increased risk of cerebrovascular disease compared with the general population (standardized incidence ratio, 1.0; 95% CI, 0.8-1.4). Total number of ischemic strokes in the cohort of people with FH was 26 (9 women and 17 men), with no increased risk compared with the general population (standardized incidence ratio, 1.0; 95% CI, 0.7-1.5). Prior coronary heart disease significantly increased cerebrovascular disease risk in women (hazard ratio, 3.29; 95% CI, 1.20-9.00) but not in men (hazard ratio, 1.03; 95% CI, 0.45-2.37; Pinteraction=0.04). Conclusions- In a large cohort of genetically verified FH, risks of cerebrovascular disease and ischemic stroke were not increased compared with the total Norwegian population.
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BACKGROUND: Severe hypertriglyceridemia can be caused by pathogenic variants in genes encoding proteins involved in the metabolism of triglyceride-rich lipoproteins. A key protein in this respect is lipoprotein lipase (LPL) which hydrolyzes triglycerides in these lipoproteins. Another important protein is glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) which transports LPL to the luminal side of the endothelial cells. OBJECTIVE: Our objective was to identify a genetic cause of hypertriglyceridemia in 459 consecutive unrelated subjects with levels of serum triglycerides ≥20 mmol/l. These patients had been referred for molecular genetic testing from 1998 to 2021. In addition, we wanted to study whether GPIHBP1 autoantibodies also were a cause of hypertriglyceridemia. METHODS: Molecular genetic analyses of the genes encoding LPL, GPIHBP1, apolipoprotein C2, lipase maturation factor 1 and apolipoprotein A5 as well as apolipoprotein E genotyping, were performed in all 459 patients. Serum was obtained from 132 of the patients for measurement of GPIHBP1 autoantibodies approximately nine years after molecular genetic testing was performed. RESULTS: A monogenic cause was found in four of the 459 (0.9%) patients, and nine (2.0%) patients had dyslipoproteinemia due to homozygosity for apolipoprotein E2. One of the 132 (0.8%) patients had GPIHBP1 autoantibody syndrome. CONCLUSION: Only 0.9% of the patients had monogenic hypertriglyceridemia, and only 0.8% had GPIHBP1 autoantibody syndrome. The latter figure is most likely an underestimate because serum samples were obtained approximately nine years after hypertriglyceridemia was first identified. There is a need to implement measurement of GPIHBP1 autoantibodies in clinical medicine to secure that proper therapeutic actions are taken.
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Hipertrigliceridemia , Receptores de Lipoproteínas , Humanos , Autoanticorpos , Células Endoteliais , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , Lipoproteínas , Hipertrigliceridemia/genética , Triglicerídeos/metabolismo , Biologia Molecular , ApolipoproteínasRESUMO
OBJECTIVE: The aim of the present study was to evaluate the possible effects of Q10 and selenium supplementation on statin-induced myopathy (SIM), both for subjective symptoms and muscle function. DESIGN: Patients (N = 43) who had experienced previous or ongoing SIM on atorvastatin therapy were recruited. Following a 6-week washout period during which no statins were administered, the patients were re-challenged with 10 mg of atorvastatin. Patients (N = 41) who experienced SIM continued the atorvastatin treatment and were in addition randomized to receive 12 weeks supplement of 400 mg Q10 and 200 µg selenium per day or a matching double placebo. SIM was assessed using 3 validated symptom questionnaires, and a muscle function test was performed at the beginning and at the end of the study. RESULTS: The patients receiving the active supplement experienced significant increases in their serum Q10 and selenium concentrations compared with the group receiving placebo. No statistically significant differences in symptom questionnaire scores or muscle function tests were revealed between the groups. CONCLUSIONS: Despite substantial increases in the serum Q10 and selenium levels following the oral supplementation, this study revealed no significant effects on SIM compared with the placebo.
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Antioxidantes/administração & dosagem , Ácidos Heptanoicos/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/induzido quimicamente , Doenças Musculares/tratamento farmacológico , Pirróis/efeitos adversos , Selênio/administração & dosagem , Ubiquinona/análogos & derivados , Vitaminas/administração & dosagem , Adulto , Idoso , Atorvastatina , Suplementos Nutricionais , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Ácidos Heptanoicos/administração & dosagem , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Pirróis/administração & dosagem , Inquéritos e Questionários , Resultado do Tratamento , Ubiquinona/administração & dosagemRESUMO
BACKGROUND: Many Norwegians have embraced the low-carb trend and choose butter and bacon instead of brown bread and carrots. This entails a dramatic change in the total intake of fat and the intake of saturated fat. We have investigated how a low-carb diet can affect the lipid profile in healthy adults with a normal bodyweight. MATERIAL AND METHOD: Seven healthy female participants with normal bodyweight underwent a four-week trial of a low-carb diet (< 20-25 grams of carbohydrates/day). Daily diet registrations were made during the trial period, and diet data for three randomly selected days were included in the estimates. Blood samples and weight data were collected as fasting values prior to and after the intervention. RESULTS: Standardised diet data were available for six participants. On a low-carb diet, the energy intake from carbohydrates accounted for a median of 3 (spread: 2-5) per cent of the total energy intake. The intake of fat accounted for 71 (67-78) per cent of total energy, while protein accounted for 26 (19-31) of total energy intake. At baseline, the median value of total cholesterol was 4.1 mmol/L (dispersion: 3.3-5.7) and LDL cholesterol was 2.2 (1.8-3.4) mmol/L. The values increased to 5.2 (3.7-8.8) mmol/L and 3.1 (1.9-6.2) mmol/L for total and LDL cholesterol respectively. The absolute changes correspond to a percentage increase in total cholesterol of 33 (14-71)% and in LDL cholesterol of 41 (9-84)%. Median weight change amounted to -1.2 kg (-2.8-0.6). INTERPRETATION: A diet with little carbohydrate and a great deal of protein and fat resulted in a considerably heightened level of total cholesterol and LDL cholesterol in young, healthy women with a normal bodyweight. The findings indicate that a low-carb diet may have a negative impact on individual risk profiles. However, the study is small-scale and the results must be interpreted with caution.
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HDL-Colesterol/sangue , LDL-Colesterol/sangue , Colesterol/sangue , Dieta com Restrição de Carboidratos/efeitos adversos , Triglicerídeos/sangue , Adulto , Colesterol na Dieta/sangue , Proteínas Alimentares , Ingestão de Energia , Feminino , Humanos , Lipídeos/sangue , Fatores de RiscoRESUMO
BACKGROUND: Molecular genetic testing of patients with hypobetalipoproteinemia may identify a genetic cause that can form the basis for starting proper therapy. Identifying a genetic cause may also provide novel data on the structure-function relationship of the mutant protein. OBJECTIVE: To identify a genetic cause of hypobetalipoproteinemia in a patient with levels of low density lipoprotein cholesterol at the detection limit of 0.1 mmol/l. METHODS: DNA sequencing of the translated exons with flanking intron sequences of the genes adenosine triphosphate-binding cassette transporter 1, angiopoietin-like protein 3, apolipoprotein B, apolipoprotein A1, lecithin-cholesterol acyltransferase, microsomal triglyceride transfer protein and proprotein convertase subtilisin/kexin type 9. RESULTS: The patient was homozygous for mutation Q384K (c.1150C>A) in the apolipoprotein B gene, and this mutation segregated with hypobetalipoproteinemia in the family. Residue Gln384 is located in the large lipid transfer module of apoB that has been suggested to be important for lipidation of apolipoprotein B through interaction with microsomal triglyceride transfer protein. Based on measurements of serum levels of triglycerides and apolipoprotein B-48 after an oral fat load, we conclude that the patient was able to synthesize apolipoprotein B-48 in the intestine in a seemingly normal fashion. CONCLUSION: Our data indicate that mutation Q384K severely reduces the secretion of apolipoprotein B-100 in the liver without reducing the secretion of apolipoprotein B-48 in the intestine. Possible mechanisms for the different effects of this and other missense mutations affecting the large lipid transfer module on the two forms of apoB are discussed.
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Hipobetalipoproteinemias , Mutação de Sentido Incorreto , Humanos , Apolipoproteína B-100/genética , Apolipoproteína B-48 , Apolipoproteínas B/genética , Apolipoproteínas B/metabolismo , Intestinos , Hipobetalipoproteinemias/genética , Mutação , Fígado/metabolismoAssuntos
Estenose Coronária , Adulto , Angina Pectoris/tratamento farmacológico , Angina Pectoris/etiologia , Anticolesterolemiantes/uso terapêutico , Ponte de Artéria Coronária , Estenose Coronária/complicações , Estenose Coronária/diagnóstico , Estenose Coronária/cirurgia , Stents Farmacológicos , Dispneia/etiologia , Exercício Físico , Feminino , Humanos , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Adesão à MedicaçãoRESUMO
AIMS: To describe results from genetic testing for cardiomyopathies in a national laboratory for genetic testing in Norway since 2003. METHODS AND RESULTS: Retrospective data collection from the laboratory information management system at Unit for Cardiac and Cardiovascular Genetics, Oslo University hospital. Data from 4408 probands and 3008 relatives were available. Three probands had two variants, nine had incidental findings of variants not related to their cardiomyopathy diagnosis. Of the remaining 4396 probands, 65.1% were males, age at genetic testing was 50.9 (±18.1) years and 6.1% were under the age of 18. A likely pathogenic or pathogenic variant (216 different variants including 67 novel) was detected in 574 probands, corresponding to a hit-rate of genetic testing of 13.1% in total, 11.9% in hypertrophic, 14.1% in dilated, and 14.9% in arrhythmogenic right ventricular cardiomyopathy. Of the 3008 relatives, 47.6 % were males, age at genetic testing was 39.3 (±20.5) years, 17.9% were under the age of 18, and 43.2% were positive for the variant found in their family. Probands and relatives combined, 1/2809 persons in Norway were found to be heterozygous for a cardiomyopathy variant. Next Generation Sequencing provided more findings in dilated cardiomyopathy, especially in TTN accounting for 44.2% of all variants. Otherwise, the majority of variants were found in the classical sarcomeric and desmosomal genes. CONCLUSION: Genetic testing provided a genetic basis of the cardiomyopathy in 13.1% of probands, and subsequent family testing identified almost three times as many variant-positive relatives which could be offered preventive follow-up.
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Displasia Arritmogênica Ventricular Direita , Cardiomiopatias , Masculino , Humanos , Feminino , Estudos Retrospectivos , Testes Genéticos , Cardiomiopatias/diagnóstico , Cardiomiopatias/epidemiologia , Cardiomiopatias/genética , Biologia MolecularRESUMO
Familial hypercholesterolemia (FH) is a common, inherited disease characterized by high levels of low-density lipoprotein Cholesterol (LDL-C) from birth. Any diseases associated with increased LDL-C levels including atherosclerotic cardiovascular diseases (ASCVDs) would be expected to be overrepresented among FH patients. There are several clinical scoring systems aiming to diagnose FH, however; most individuals who meet the clinical criteria for a FH diagnosis do not have a mutation causing FH. In this review, we aim to summarize the literature on the risk for the various forms of ASCVD in subjects with a proven FH-mutation (FH+). We searched for studies on FH+ and cardiovascular diseases and also included our and other groups published papers on FH + on a wide range of cardiovascular and other diseases of the heart and vessels. FH + patients are at a markedly increased risk of a broad range of ASCVD. Acute myocardial infarction (AMI) is the most common in absolute numbers, but also aortic valve stenosis is by far associated with the highest excess risk. Per thousand patients, we observed 3.6 incident AMI per year compared to 1.9 incident aortic valve stenosis, however, standardized incidence ratio (SIR) for incident AMI was 2.3 compared to 7.9 for incident aortic valve stenosis. Further, occurrence of ischemic stroke seems not to be associated with increased risk in FH+. Clinicians should be aware of the excess risk of almost all kind of ASCVD in FH+, and the neutral risk of stroke need to be studied further in FH + patients.
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BACKGROUND: The most cost-effective strategy to diagnose patients with autosomal dominant hypercholesterolemia (ADH) is to perform cascade genetic screening. OBJECTIVE: To present the cascade genetic screening program for ADH in Norway. METHODS: A national cascade genetic screening program for ADH in Norway has been operating at Unit for Cardiac and Cardiovascular Genetics, Oslo University Hospital for twenty years. This program has been run by just one genetic counsellor. We now present the main findings of this cascade genetic screening program. RESULTS: After genetic counselling, 8182 at-risk relatives have consented to genetic testing for the mutation that causes ADH in the family. Of these, 3076 (37.6%) relatives have tested positive. Among mutation-positive relatives 31.3% were on lipid-lowering therapy at the time of genetic testing. However, only 9.8% of these relatives had a value for low density lipoprotein (LDL) cholesterol below 2.5 mmol/l (97 mg/dl). At follow-up six months after genetic testing, reductions in the levels of total serum cholesterol and LDL cholesterol of 12% and 17%, respectively were observed. A total of 8811 ADH heterozygotes have been diagnosed in Norway. Thus, the number of patients diagnosed by this modest cascade genetic screening program constitutes 35% of all Norwegian ADH patients provided with a molecular genetic diagnosis. CONCLUSION: Cascade genetic screening for ADH is very effective and should be organized at a national level. Even a modest cascade genetic screening program with small resources, can result in a large number of patients being identified.
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Genes Dominantes , Testes Genéticos/economia , Testes Genéticos/métodos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/genética , Programas de Rastreamento/economia , Programas de Rastreamento/métodos , Mutação , Programas Nacionais de Saúde , LDL-Colesterol/sangue , Análise Custo-Benefício , Feminino , Seguimentos , Heterozigoto , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/epidemiologia , Masculino , Programas Nacionais de Saúde/economia , Noruega/epidemiologia , Fatores de TempoRESUMO
BACKGROUND AND AIMS: In this study, we present the status regarding molecular genetic testing for mutations in the genes encoding the low density lipoprotein receptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) as causes of autosomal dominant hypercholesterolemia (ADH) in Norway. METHODS: We have extracted data from the laboratory information management system at Unit for Cardiac and Cardiovascular Genetics, Oslo University Hospital for the period 1993-2020. This laboratory is the sole laboratory performing molecular genetic testing for ADH in Norway. RESULTS: A total of 29,449 unrelated hypercholesterolemic patients have been screened for mutations in the LDLR gene, in the APOB gene and in the PCSK9 gene. Of these, 2818 (9.6%) were heterozygotes and 11 were homozygotes or compound heterozygotes. Most of the 264 different mutations identified were found in the LDLR gene. Only two and three mutations were found in the APOB gene or in the PCSK9 gene, respectively. Several founder mutations were identified. After testing of 14,230 family members, a total of 8811 heterozygous patients have been identified. Of these, 94.0% had a mutation in the LDLR gene, 5.4% had a mutation in the APOB gene and 0.6% had a mutation in the PCSK9 gene. CONCLUSIONS: A large proportion of Norwegian ADH patients have been provided with a molecular genetic diagnosis. Norway is probably only second to the Netherlands in this respect. A molecular genetic diagnosis may form the basis for starting proper preventive measures and for identifying affected family members by cascade genetic screening.
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Hiperlipoproteinemia Tipo II , Pró-Proteína Convertase 9 , Testes Genéticos , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Hiperlipoproteinemia Tipo II/genética , Biologia Molecular , Mutação , Países Baixos , Noruega/epidemiologia , Pró-Proteína Convertase 9/genética , Receptores de LDL/genéticaRESUMO
Background Arrhythmogenic cardiomyopathy (AC) is characterized by biventricular dysfunction, exercise intolerance, and high risk of ventricular tachyarrhythmias and sudden death. Predisposing factors for left ventricular (LV) disease manifestation and its prognostic implication in AC are poorly described. We aimed to assess the associations of exercise exposure and genotype with LV dysfunction in AC, and to explore the impact of LV disease progression on adverse arrhythmic outcome. Methods and Results We included 168 patients with AC (50% probands, 45% women, 40±16 years old) with 715 echocardiographic exams (4.1±1.7 exams/patient, follow-up 7.6 [interquartile range (IQR), 5.4-10.9] years) and complete exercise and genetic data in a longitudinal study. LV function by global longitudinal strain was -18.8% [IQR, -19.2% to -18.3%] at presentation and was worse in patients with greater exercise exposure (global longitudinal strain worsening, 0.09% [IQR, 0.01%-0.17%] per 5 MET-hours/week, P=0.02). LV function by global longitudinal strain worsened, with 0.08% [IQR, 0.05%-0.12%] per year; (P<0.001), and progression was most evident in patients with desmoplakin genotype (P for interaction <0.001). Deterioration of LV function predicted incident ventricular tachyarrhythmia (aborted cardiac arrest, sustained ventricular tachycardia, or implantable cardioverter defibrillator shock) (adjusted odds ratio, 1.1 [IQR, 1.0-1.3] per 1% worsening by global longitudinal strain; P=0.02, adjusted for time and previous arrhythmic events). Conclusions Greater exercise exposure was associated with worse LV function at first visit of patients with AC but did not significantly affect the rate of LV progression during follow-up. Progression of LV dysfunction was most pronounced in patients with desmoplakin genotypes. Deterioration of LV function during follow-up predicted subsequent ventricular tachyarrhythmia and should be considered in risk stratification.
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Displasia Arritmogênica Ventricular Direita/complicações , Exercício Físico/fisiologia , Previsões , Predisposição Genética para Doença , Ventrículos do Coração/diagnóstico por imagem , Disfunção Ventricular Esquerda/etiologia , Função Ventricular Esquerda/fisiologia , Adulto , Displasia Arritmogênica Ventricular Direita/genética , Displasia Arritmogênica Ventricular Direita/fisiopatologia , Progressão da Doença , Ecocardiografia/métodos , Feminino , Seguimentos , Ventrículos do Coração/fisiopatologia , Humanos , Imagem Cinética por Ressonância Magnética/métodos , Masculino , Prognóstico , Fatores de Risco , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
BACKGROUND: Reduction of the aortic valve area (AVA) may lead to aortic valve stenosis with considerable impact on morbidity and mortality if not identified and treated. Lipoprotein (a) [Lp(a)] and also inflammatory biomarkers, including platelet derived biomarkers, have been considered risk factor for aortic stenosis; however, the association between Lp(a), inflammatory biomarkers and AVA among patients with familial hypercholesterolemia (FH) is not clear. OBJECTIVE: We aimed to investigate the relation between concentration of Lp(a), measurements of the aortic valve including velocities and valve area and circulating inflammatory biomarkers in adult FH subjects and controls. METHODS: In this cross-sectional study aortic valve measures were examined by cardiac ultrasound and inflammatory markers were analyzed in non-fasting blood samples. The study participants were 64 FH subjects with high (n = 29) or low (n = 35) Lp(a), and 14 healthy controls. RESULTS: Aortic valve peak velocity was higher (p = 0.02), and AVA was lower (p = 0.04) in the FH patients compared to controls; however, when performing multivariable linear regression, there were no significant differences. Furthermore, there were no significant differences between the high and low FH Lp(a) groups regarding the aortic valve. FH subjects had higher levels of platelet-derived markers CD40L, PF4, NAP2 and RANTES compared to controls (0.003 ≤ P ≤ 0.03). This result persisted after multiple linear regression. CONCLUSIONS: Middle-aged, intensively treated FH subjects have higher aortic valve velocity, lower AVA, and higher levels of the platelet-derived markers CD40L, PF4, NAP2 and RANTES compared to healthy control subjects. The aortic valve findings were not significant after multiple linear regression, whereas the higher levels of platelet-derived markers were maintained.