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1. Transcriptomic profile helps to identify high-risk heterozygous familial hypercholesterolemia patients

Author

Pirbay, T., primary, Carreau, V., additional, Guérin, M., additional, Frisdal, E., additional, Lesnik, P., additional, Mondelli, A., additional, Giral, P., additional, Bluteau, O., additional, Georget, M., additional, Bittar, R., additional, Bonnefont-Rousselot, D., additional, Bruckert, E., additional, Redheuil, A., additional, Carrié, A., additional, Le Goff, W., additional, and Gallo, A., additional

Published
2024
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2. High burden of recurrent cardiovascular events in heterozygous familial hypercholesterolemia: The French Familial Hypercholesterolemia Registry

Author

Angoulvant, D., Béliard, S., Benlian, P., Boileau, C., Boccara, F., Bruckert, E., Cariou, B., Carreau, V., Carrié, A., Charrière, S., Di Filippo, M., Ducluzeau, P.H., Dulong, S., Durlach, V., Farnier, M., Ferrari, E., Ferrières, J., Gallo, A., Girardet, J.P., Hankard, R., Krempf, M., Lalau, J.D., Lefort, B., Lemale, J., Moulin, P., Paillard, F., Peretti, N., Pradignac, A., Pucheu, Y., Rabès, J.P., Saheb, S., Sultan, A., Tounian, P., Valéro, R., Varret, M., Vergès, B., Yelnik, C., Ziegler, O., Béliard, Sophie, Boccara, Franck, Cariou, Bertrand, Carrié, Alain, Collet, Xavier, Farnier, Michel, Ferrières, Jean, Krempf, Michael, Peretti, Noël, Rabès, Jean-Pierre, Varret, Mathilde, Vimont, Alexandre, Charrière, Sybil, and Bruckert, Eric

Published
2018
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6. Towards a readjustment of diagnostic criteria for familial hypercholesterolemia in France and doors open to a combined biochemical and molecular score

Author

Bluteau, O., primary, Lapidus, N., additional, Giral, P., additional, Beliard, S., additional, Carreau, V., additional, Bittar, R., additional, Kalmykova, O., additional, Dourmap, C., additional, Couvert, P., additional, Chtioui, H., additional, Robillard, L., additional, Le Goff, W., additional, Guérin, M., additional, Lacorte, J.-M., additional, Bonnefont-Rousselot, D., additional, Paillard, F., additional, Bruckert, E., additional, Valéro, R., additional, Gallo, A., additional, and Carrié, A., additional

Published
2023
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8. Whole exome/genome sequencing joint analysis in a family with oligogenic familial hypercholesterolemia

Author

Ghaleb, Y., El Bitar, S., Philippi, A., El Khoury, P., Azar, Y., Andrianirina, M., Loste, A., Abou-Khalil, Y., Nicolas, G., Le Borgne, M., Moulin, P., Di Filippo, M., Charriere, S., Farnier, M., Yelnik, C., Carreau, V., Ferrières, J., Lecerf, J.-M., Derksen, A., Bernard, G., Gauthier, M.-S., Coulombe, B., Luetjohann, D., Finn, B., Boland, A., Olaso, R., Deleuze, J.-F., Rabès, J.-P., Boileau, C., Abifadel, M., and Varret, M.

Published
2022
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10. Combined Photobleaching and Temperature Effects on 1550 nm Radiation-Induced Attenuation of Germanosilicate Optical Fiber

Author

Roche, M., Morana, A., Balcon, N., Aubry, M., Carreau, V., Mariojouls, S., Boukenter, A., Campanella, C., Ouerdane, Y., Marin, E., Durnez, C., Rousselet, M., and Girard, S.

Abstract

Combined temperature and photobleaching (PB) effects on the 1550 nm radiation-induced attenuation (RIA) levels and kinetics of a commercial Ge-doped single-mode optical fiber (OF) have been investigated. The main goal of this study was to evaluate if synergetic effects could impact the performances of free-space optical communication links in space. For this, we performed accelerated (0.5 Gy(SiO2)/s) irradiation runs with 100 kV X-rays up to the total ionizing dose of 150 kGy(SiO2), varying the irradiation temperature between −80 °C and 80 °C. First, we evaluate the irradiation temperature effects: infrared RIA largely increases at negative temperatures. Second, the effects of injecting different optical powers at different temperatures have been characterized: if at temperatures exceeding room temperature (RT), PB effects are almost negligible, a PB effect is clearly observable at lower temperatures where the germanosilicate OF present large RIA levels due to the contribution of metastable defects absorbing at 1550 nm. Increasing the injected powers allows for reducing the concentration of these radiation-induced unstable defects, but not as much as thermal treatment consecutive to the irradiation. These results highlight the complex physics of radiation-induced defects absorbing at 1550 nm in Ge-doped OF, but also the vulnerability of this class of fiber for space telecommunication links. Regarding the unstable nature of point defects causing the RIA at a lower temperature, it seems possible to mitigate the loss excess by thermal cycles at RT or higher temperatures. We also could expect that our accelerated tests represent a worst-case scenario in terms of RIA levels at the maximum dose.

Published
2023
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16. The U2-spliceosome and its interactors regulate the levels and activity of the LDL receptor in humans

Author

Zanoni, P., primary, Panteloglou, G., additional, Othman, A., additional, Haas, J.T., additional, Meier, R., additional, Rimbert, A., additional, Futema, M., additional, Khalil, Y. Abou, additional, Norrelykke, S.F., additional, Rzepiela, A.J., additional, Stoma, S., additional, Stebler, M., additional, Van Dijk, F., additional, Wijers, M., additional, Wolters, J.C., additional, Dalila, N., additional, Huijkman, N., additional, Smit, M., additional, Gallo, A., additional, Carreau, V., additional, Philippi, A., additional, Rabès, J.-P., additional, Boileau, C., additional, Visentin, M., additional, Vonghia, L., additional, Weyler, J., additional, Francque, S.M., additional, Verrijken, A., additional, Verhaegen, A., additional, Van Gaal, L., additional, Van Der Graaf, A., additional, Van Rosmalen, B.V., additional, Velagapudi, S., additional, Yalcinkaya, M., additional, Keel, M., additional, Radosavljevic, S., additional, Geier, A., additional, Tybjærg-Hansen, A., additional, Varret, M., additional, Rohrer, L., additional, Humphries, S.E., additional, Staels, B., additional, Van De Sluis, B., additional, Kuivenhoven, J.A., additional, and Von Eckardstein, A., additional

Published
2020
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17. Analysis of the genetic variants associated with circulating levels of sgp130. Results from the IMPROVE study

Author

Bonomi, A., Veglia, F., Baldassarre, D., Strawbridge, R. J., Golabkesh, Z., Sennblad, B., Leander, K., Smit, A. J., Giral, P., Humphries, S. E., Tremoli, E., Hamsten, A., de Faire, U., Gigante, B., Sirtori, C. R., Castelnuovo, S., Calabresi, L., Amato, M., Frigerio, B., Ravani, A., Sansaro, D., Coggi, D., Tedesco, C. C., Eriksson, P., Silveira, A., Laguzzi, F., Cooper, J., Acharya, J., Huttunen, K., Rauramaa, E., Pekkarinen, H., Penttila, I. M., Torronen, J., Rauramaa, R., van Gessel, A. I., van Roon, A. M., Teune, G. C., Kuipers, W. D., Bruin, M., Nicolai, A., Haarsma-Jorritsma, P., Mulder, D. J., Bilo, H. J. G., Smeets, G. H., Beaudeux, J. L., Kahn, J. F., Carreau, V., Kontush, A., Karppi, J., Nurmi, T., Nyyssonen, K., Salonen, R., Tuomainen, T. P., Tuomainen, J., Kauhanen, J., Kurl, S., Vaudo, G., Alaeddin, A., Siepi, D., Lupattelli, G., Mannarino, E., Groningen Kidney Center (GKC), Lifestyle Medicine (LM), and Translational Immunology Groningen (TRIGR)

Subjects
Male, Carotid Intima-Media Thickness, Polymorphism, Single Nucleotide, INTIMA-MEDIA THICKNESS, Article, Gene Frequency, Risk Factors, Cytokine Receptor gp130, Humans, Genetic Predisposition to Disease, POPULATION, Aged, Medicinsk genetik, RISK, VASCULAR EVENTS, Interleukin-6, GENOME-WIDE, Genetic Variation, SIGNAL TRANSDUCER GP130, Middle Aged, Atherosclerosis, POLYMORPHISM, Genetic Loci, INTERLEUKIN-6 RECEPTOR, SOLUBLE GP130, Cytokines, Female, Medical Genetics, 4 SUBUNITS, Biomarkers
Abstract

The genes regulating circulating levels of soluble gp130 (sgp130), the antagonist of the inflammatory response in atherosclerosis driven by interleukin 6, are largely unknown. Aims of the present study were to identify genetic loci associated with circulating sgp130 and to explore the potential association between variants associated with sgp130 and markers of subclinical atherosclerosis. The study is based on IMPROVE (n = 3703), a cardiovascular multicentre study designed to investigate the determinants of carotid intima media thickness, a measure of subclinical atherosclerosis. Genomic DNA was genotyped by the CardioMetaboChip and ImmunoChip. About 360,842 SNPs were tested for association with log-transformed sgp130, using linear regression adjusted for age, gender, and population stratification using PLINK v1.07. A p value of 1 × 10−5 was chosen as threshold for significance value. In an exploratory analysis, SNPs associated with sgp130 were tested for association with c-IMT measures. We identified two SNPs significantly associated with sgp130 levels and 24 showing suggestive association with sgp130 levels. One SNP (rs17688225) on chromosome 14 was positively associated with sgp130 serum levels (β = 0.03 SE = 0.007, p = 4.77 × 10−5) and inversely associated with c-IMT (c-IMTmean–max β = −0.001 SE = 0.005, p = 0.0342). Our data indicate that multiple loci regulate sgp130 levels and suggest a possible common pathway between sgp130 and c-IMT measures.

Published
2020

18. Alcohol consumption in relation to carotid subclinical atherosclerosis and its progression: results from a European longitudinal multicentre study

Author

Laguzzi, F., Baldassarre, D., Veglia, F., Strawbridge, R. J., Humphries, S. E., Rauramaa, R., Smit, A. J., Giral, P., Silveira, A., Tremoli, E., Hamsten, A., de Faire, U., Frumento, P., Leander, K., Sirtori, C. R., Castelnuovo, S., Amato, M., Frigerio, B., Ravani, A., Sansaro, D., Tedesco, C., Coggi, D., Bonomi, A., Eriksson, M. J., Cooper, J., Acharya, J., Huttunen, K., Rauramaa, E., Pekkarinen, H., Penttila, I. M., Torronen, J., van Gessel, A. I., van Roon, A. M., Teune, G. C., Kuipers, W. D., Bruin, M., Nicolai, A., Haarsma-Jorritsma, P., Mulder, D. J., Bilo, H. J. G., Smeets, G. H., Beaudeux, J. L., Kahn, J. F., Carreau, V., Kontush, A., Karppi, J., Nurmi, T., Nyyssonen, K., Salonen, R., Tuomainen, T. P., Tuomainen, J., Kauhanen, J., Vaudo, G., Alaeddin, A., Siepi, D., Lupattelli, G., Mannarino, E., Groningen Kidney Center (GKC), The Institute of Environmental Medicine [Stockholm] (IMM), Karolinska Institutet [Stockholm], Università degli Studi di Milano [Milano] (UNIMI), Centro Cardiologico Monzino [Milano], Dpt di Scienze Cliniche e di Comunità [Milano] (DISCCO), Università degli Studi di Milano [Milano] (UNIMI)-Università degli Studi di Milano [Milano] (UNIMI)-Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), University of Glasgow, Institute of Cardiovascular and Medical Sciences [Glasgow], University College of London [London] (UCL), University of Kuopio, University Medical Center Groningen [Groningen] (UMCG), University of Groningen [Groningen], Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Karolinska University Hospital [Stockholm]

Subjects
Male, medicine.medical_specialty, Epidemiology, [SDV]Life Sciences [q-bio], Physical activity, Medicine (miscellaneous), Alcohol drinking, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, medicine.artery, Internal medicine, medicine, Humans, 030212 general & internal medicine, Carotid intima-media thickness, Finland, Netherlands, Sweden, Nutrition and Dietetics, Progression, business.industry, Confounding, European population, Original Contribution, Atherosclerosis, 3. Good health, Italy, Subclinical atherosclerosis, Cardiology, Female, France, Internal carotid artery, business, Alcohol consumption, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background/Aim The association between alcohol consumption and subclinical atherosclerosis is still unclear. Using data from a European multicentre study, we assess subclinical atherosclerosis and its 30-month progression by carotid intima-media thickness (C-IMT) measurements, and correlate this information with self-reported data on alcohol consumption. Methods Between 2002–2004, 1772 men and 1931 women aged 54–79 years with at least three risk factors for cardiovascular disease (CVD) were recruited in Italy, France, Netherlands, Sweden, and Finland. Self-reported alcohol consumption, assessed at baseline, was categorized as follows: none (0 g/d), very-low (0 − 5 g/d), low (> 5 to ≤ 10 g/d), moderate (> 10 to ≤ 20 g/d for women, > 10 to ≤ 30 g/d for men) and high (> 20 g/d for women, > 30 g/d for men). C-IMT was measured in millimeters at baseline and after 30 months. Measurements consisted of the mean and maximum values of the common carotids (CC), internal carotid artery (ICA), and bifurcations (Bif) and whole carotid tree. We used quantile regression to describe the associations between C-IMT measures and alcohol consumption categories, adjusting for sex, age, physical activity, education, smoking, diet, and latitude. Results Adjusted differences between median C-IMT values in different levels of alcohol consumption (vs. very-low) showed that moderate alcohol consumption was associated with lower C-IMTmax[− 0.17(95%CI − 0.32; − 0.02)], and Bif-IMTmean[− 0.07(95%CI − 0.13; − 0.01)] at baseline and decreasing C-IMTmean[− 0.006 (95%CI − 0.011; − 0.000)], Bif-IMTmean[− 0.016(95%CI − 0.027; − 0.005)], ICA-IMTmean[− 0.009(95% − 0.016; − 0.002)] and ICA-IMTmax[− 0.016(95%: − 0.032; − 0.000)] after 30 months. There was no evidence of departure from linearity in the association between alcohol consumption and C-IMT. Conclusion In this European population at high risk of CVD, findings show an inverse relation between moderate alcohol consumption and carotid subclinical atherosclerosis and its 30-month progression, independently of several potential confounders.

Published
2020
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20. High burden of recurrent cardiovascular events in heterozygous familial hypercholesterolemia: The French Familial Hypercholesterolemia Registry

Author

Béliard, Sophie, primary, Boccara, Franck, additional, Cariou, Bertrand, additional, Carrié, Alain, additional, Collet, Xavier, additional, Farnier, Michel, additional, Ferrières, Jean, additional, Krempf, Michael, additional, Peretti, Noël, additional, Rabès, Jean-Pierre, additional, Varret, Mathilde, additional, Vimont, Alexandre, additional, Charrière, Sybil, additional, Bruckert, Eric, additional, Angoulvant, D., additional, Béliard, S., additional, Benlian, P., additional, Boileau, C., additional, Boccara, F., additional, Bruckert, E., additional, Cariou, B., additional, Carreau, V., additional, Carrié, A., additional, Charrière, S., additional, Di Filippo, M., additional, Ducluzeau, P.H., additional, Dulong, S., additional, Durlach, V., additional, Farnier, M., additional, Ferrari, E., additional, Ferrières, J., additional, Gallo, A., additional, Girardet, J.P., additional, Hankard, R., additional, Krempf, M., additional, Lalau, J.D., additional, Lefort, B., additional, Lemale, J., additional, Moulin, P., additional, Paillard, F., additional, Peretti, N., additional, Pradignac, A., additional, Pucheu, Y., additional, Rabès, J.P., additional, Saheb, S., additional, Sultan, A., additional, Tounian, P., additional, Valéro, R., additional, Varret, M., additional, Vergès, B., additional, Yelnik, C., additional, and Ziegler, O., additional

Published
2018
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22. Electro-optical characterizations for robustness assessment of automotive qualified white LEDs multichip modules: failure analysis and packaging influence

Author

Chambion, B., Mendizabal, L., Gasse, A., Bechou, L., Deshayes, Y., Carreau, V., Laboratoire de l'intégration, du matériau au système (IMS), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Technocentre Renault [Guyancourt], RENAULT, and Bord, Isabelle

Subjects
[SPI.TRON] Engineering Sciences [physics]/Electronics, ComputingMilieux_MISCELLANEOUS, [SPI.TRON]Engineering Sciences [physics]/Electronics
Abstract

International audience

Published
2013

23. Eclairage Automobile: Les conséquences de l'intégration de DEL blanches de puissance sur la stratégie des tests de fiabilité

Author

Chambion, B., Mendizabal, L., Bechou, L., Carreau, V., Deshayes, Y., Gasse, A., Bord, Isabelle, Laboratoire de l'intégration, du matériau au système (IMS), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Technocentre Renault [Guyancourt], and RENAULT

Subjects
ComputingMilieux_MISCELLANEOUS, [SPI.TRON] Engineering Sciences [physics]/Electronics, [SPI.TRON]Engineering Sciences [physics]/Electronics
Abstract

National audience

Published
2012

24. Cu grain growth in damascene narrow trenches

Author

Maitrejean, S., Carreau, V., Thomas, O., Labat, S., Kaouache, B., Verdier, M., Lepinoux, J., Brechet, Y., Legros, Marc, Douin, Joël, Cayron, C., Sicardy, O., Weygand, D., Dubreuil, O., Normandon, P., Science et Ingénierie des Matériaux et Procédés (SIMaP), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SPI.GPROC]Engineering Sciences [physics]/Chemical and Process Engineering, [CHIM.MATE]Chemical Sciences/Material chemistry, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2008

25. Experimental characterization of the overburden effect

Author

Carreau, V., Maitrejean, S., Brechet, Y., Verdier, M., Bouchu, D., Toffoli, A., Passemard, G., Science et Ingénierie des Matériaux et Procédés (SIMaP), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SPI.GPROC]Engineering Sciences [physics]/Chemical and Process Engineering, [CHIM.MATE]Chemical Sciences/Material chemistry, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2008

26. 43 NEW GAIN OF FUNCTIONS MUTATIONS IN PCSK9 AND THEIR IMPACT IN FAMILIAL HYPERCHOLESTEROLEMIA

Author

AbiFadel, M., primary, Rabès, J.-P., additional, Guérin, M., additional, Carreau, V., additional, Carrié, A., additional, Varret, M., additional, Samson-Bouma, M.-E., additional, Tosolini, L., additional, Erlich, D., additional, Couvert, P., additional, Bonnefont-Rousselot, D., additional, Bruckert, E., additional, Prat, A., additional, Seidah, N., additional, and Boileau, C., additional

Published
2011
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27. MS91 PCSK9: FROM GENE AND VARIANTS TO PROTEIN AND PLASMA LEVELS

Author

AbiFadel, M., primary, Rabès, J.-P., additional, Varret, M., additional, Samson-Bouma, M.-E., additional, Bruckert, E., additional, Devillers, M., additional, Carreau, V., additional, Tosolini, L., additional, Marduel, M., additional, Marques, A., additional, Couvert, P., additional, Bonnefont-Rousselot, D., additional, Guérin, M., additional, Carrié, A., additional, Prat, A., additional, Seidah, N., additional, and Boileau, C., additional

Published
2010
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30. Electro-optical strength assessment of white LEDs multichip modules for automotive forward-lighting application: Failure analysis and packaging influence.

Author

Chambion, B., Mendizabal, L., Bechou, L., Gasse, A., Deshayes, Y., and Carreau, V.

Abstract

Performances of Lighting Emitting Diode (LED) are now suitable for automotive high beam / low beam lighting applications. Due to high brightness light sources needs in automotive, LEDs are packaged in multichip module (e.g. 4 chips in series), to deliver up to 1000 lumens at 1A. Currently, different packaging strategies have been implemented in term of chip configuration, bonding, down conversion phosphor layer and mechanical protection to optimize performances. Beyond the performances, and from an automotive point of view, it is crucial to know the exact behavior and reliability of these optoelectronic devices in an automotive context. Current reference documents such as automotive regulations and qualification test (Automotive Electronics Council, AEC-Q101) do not take all of the automotive mission profile into consideration. In this context, a methodology is proposed to define and anticipate failure behaviors of each LEDs module through a robustness study (over-stress). A setup measurement has been developed focusing on the monitoring of electrical, optical, and thermal parameters of these modules during thermal and electrical step-stress robustness tests. A specific methodology and physical measurement issues on a multichip configuration are detailed. Indeed, these new multichip optoelectronic devices force to overall characterizations (chips in series) and drive the emergency of a new behavior to be considered, the partial failure: how could we estimate the failure of a single chip into a multichip configuration? Secondly, based on these results, we extract the strength and weakness of each LEDs module packaging strategy against thermal or electrical over-shots allowing defining a safe operating area of such devices. Failure modes, failure mechanisms and related physical phenomena are investigated considering the overall LEDs module architecture. [ABSTRACT FROM PUBLISHER]

Published
2013

33. Cu grain growth in damascene narrow trenches

Author

Maitrejean, S., Carreau, V., Thomas, O., Labat, S., Kaouache, B., Verdier, M., Lepinoux, J., Bréchet, Y., Legros, M., Douin, J., Brandstetter, S., Cayron, C., Sicardy, O., Weygand, D., Dubreuil, O., and Normandon, P.

Subjects
Interconnects, Cu, Grain growth
Abstract

Since the end of the last century, Cu damascene integration scheme has been the favoured choice for advanced interconnect technologies. Indeed, due to the lowest Cu bulk resistivity and to it higher resistance to electromigration, performances enhancement with respect to Al have been obtained. Nevertheless, dimensional scaling considerably reduces these performances. At line width below 150nm, grain size is usually measured around line dimension and thus decreases with down scaling. Moreover, columnar grain morphology perpendicular to line sidewall is frequently observed. This results in a large increase of Cu resistivity and in degradation of resistance to electromigration. Optimization of Cu microstructure in damascene architecture is then required. This is the topic of this work. Direct measurements of microstructure through electron microscopy (TEM, EBSD) and X ray diffraction methods are performed. Indirect measurement of grain size evolutions via resistivity characterization is done. Complementary grain growth simulations are performed using vertex method. It is observed that, depending on line dimension, anneal conditions and electrolyte, different type of microstructures are achieved. As expected, certainly due grain boundary pinning on sidewall, for long time anneal, a stable situation is reached. We evidence that Cu line microstructure results from an interaction between grain growth inside the trenches and grain growth in the Cu overburden. On one hand, for the larger lines, the grain size is directly related to the grain growth in the overburden, on the other hand, for the narrowest lines, interfaces limit the impact of this layer on the inline grain growth. A quantitative measurement of overburden microstructure extension in trenches is reported. It could be used to optimize the in-line microstructure with respect to resistivity and electromigration resistance. © 2009 American Institute of Physics.

34. Génomique de la légumineuse modèle Medicago truncatula : état des lieux et perspectives

Author

Journet Etienne-Pascal, Carreau Véronique, Gouzy Jérome, Thoquet Philippe, Rosenberg Charles, Barker David, Huguet Thierry, Denarie Jean, and Gamas Pascal

Subjects
Medicago truncatula, root symbioses, crop legumes, plant genomics, bioinformatics, Oils, fats, and waxes, TP670-699
Abstract

Depuis une vingtaine d’années, les nombreuses recherches focalisées sur la plante modèle Arabidopsis thaliana ont permis des progrès considérables dans notre connaissance des bases moléculaires de la biologie des plantes. Avec l’achèvement du séquençage du génome d’Arabidopsis [1], la palette complète des outils de génétique et de génomique maintenant disponibles devrait encore accélérer le rythme des découvertes. De son côté, le riz fait l’objet de rapides développements génomiques en tant que modèle pour les monocotylédones. Cependant, il est clair que ces deux espèces ne suffisent pas pour représenter le monde végétal dans toute sa diversité biologique [2]. Ce fait est particulièrement bien illustré par le cas des Légumineuses (Fabacées) qui représentent l’un des taxons végétaux les plus importants, tant du point de vue de la biologie et de l’écologie fondamentales que du point de vue agronomique et environnemental.

Published
2001
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35. Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)

Author

Jie Lin, Snejana Tisheva, Ishwar C. Verma, Francesco Cipollone, Liam R. Brunham, Florentina Predica, Perla A.C. Gonzalez, Jocelyne Inamo, André R. Miserez, Belma Pojskic, Michel Farnier, Avishay Ellis, Katia Bonomo, Ibrahim Al-Zakwani, Maria Grazia Zenti, Humberto A. Lopez, Khairul Shafiq Ibrahim, Erkin M. Mirrakhimov, Alexey Meshkov, Jose P. de Moura, Muthukkaruppan Annamalai, Raul D. Santos, F. Paillard, Maria Del Ben, Jan Lacko, Miguel T. Rico, Ximena Reyes, Laura E.G. de Leon, Noor Shafina Mohd Nor, Ulrich Julius, Mohammed A. Batais, Dieter Böhm, Ta-Chen Su, Takuya Kobayashi, Magdalena Chmara, Marco Gebauer, Marcos M. Lima-Martínez, Ravshanbek D. Kurbanov, Daisaku Masuda, Amro El-Hadidy, Melanie Schüler, Francisco Fuentes, Florian J. Mayer, Helena Vaverkova, F. Ulrich Beil, Juraj Bujdak, Mario Stoll, Isabelle Ruel, Elena Dorn, Thomas M. Stulnig, Abubaker Elfatih, Rano B. Alieva, Jiri Vesely, Valérie Carreau, Cristina M. Sibaja, Sophie Béliard, Olivier Ziegler, Adriana Branchi, Daniel Schurr, G.B. John Mancini, Tai E. Shyong, Eric L.T. Siang, Mafalda Bourbon, Zerrin Yigit, Meral Kayıkçıoğlu, Jacques Genest, Wei Yu, Michal Vrablík, Shavkat U. Hoshimov, Dan Gaita, Antonio Pipolo, Ashraf H.A. AlQudaimi, Walter Speidl, Gianfranco Parati, Zaliha Ismail, Victoria M. Zubieta, René Valéro, Tomas Salek, Hana Halamkova, Gustavs Latkovskis, Nicole Allendorf-Ostwald, Agnes Perrin, Vladimir Soska, Anastasia Garoufi, Francisco Araujo, Nacu C. Portilla, Thomas Segiet, Charalambos Koumaras, Hila Knobler, Fatih Sivri, Hani Altaradi, Ivan Pećin, Long Jiang, Alexander Dressel, Marlena Woś, Jana Franekova, D. Agapakis, Quitéria Rato, Dirk J. Blom, Marcin A. Bartlomiejczyk, Krzysztof Dyrbuś, Maurizio Averna, Phivos Symeonides, Yung A. Chua, Asim Rana, András Nagy, Juan C.G. Cuellar, Alexander Jäkel, Maya Safarova, Neama Luqman, Amalia-Despoina Koutsogianni, Patrick Tounian, Jose A. Alvarez, Ada Cuevas, Corinna Richter, Sybil Charrieres, Vitaliy Zafiraki, Michalis Doumas, Angela Lux, Thanh Huong Truong, Elaine Chow, José Luis Díaz-Díaz, Jesus R.H. Almada, Sabine Füllgraf-Horst, Gustavo G. Retana, Claudio Borghi, Gianni Biolo, Ivajlo Tzvetkov, Patrícia Pais, Mehmet Akbulut, Kumiko Nagahama, Oner Ozdogan, Frank Leistikow, Jianxun He, Alexander R.M. Lyons, Poranee Ganokroj, Luis E.S. Mendia, Ann-Cathrin Koschker, Gabriela A.G. Ramirez, Dainus Gilis, Karin Balinth, José Ramiro Cruz, Paolo Calabrò, Alberico L. Catapano, Emmanouil Skalidis, Hamida Al-Barwani, Genovefa Kolovou, Carolyn S.P. Lam, Yoto Yotov, Yaacov Henkin, Gabriella Iannuzzo, Aimi Z. Razman, Alma B.M. Rodriguez, Hans Dieplinger, Darlington E. Obaseki, Ursulo J. Herrera, Arcangelo Iannuzzi, Christoph Säly, Elena Olmastroni, Francisco G. Padilla, S.A. Nazli, Ioanna Gouni-Berthold, Miriam Kozárová, Urh Groselj, Igor Shaposhnik, Lorenzo Iughetti, Nawal Rwaili, Cinthia E. Jannes, Andrea Bartuli, Mikhail Voevoda, Marat V. Ezhov, Yanyu Duan, Alper Sonmez, Mustafa Yenercag, Ariane Sultan, Natasza Gilis-Malinowska, Tavintharan Subramaniam, Mohamed Ashraf, Jing Pang, Kota Matsuki, Tao Jiang, Gerald Klose, Eduardo A.R. Rodriguez, Lucie Solcova, Riccardo Sarzani, Mahmoud Traina, Alejandra Vázquez Cárdenas, Gordon A. Francis, Adolat V. Ziyaeva, Ronen Durst, Maciej Banach, Francisco Silva, Heribert Schunkert, Børge G. Nordestgaard, Ziyou Liu, Ahmad Bakhtiar Md Radzi, Hana Rosolova, Andrea Bäßler, Abdulhalim Jamal Kinsara, Noël Peretti, Victor Gurevich, Margarita T. Tamayo, Abdullah Tuncez, Florian Höllerl, Ljubica Stosic, Jianguang Qi, Anja Kirschbaum, Jitendra P.S. Sawhney, Michael Scholl, Kausik K. Ray, Mohamed Bendary, Hapizah Nawawi, Adrienne Tarr, Barbora Nussbaumerova, B.C. Brice, Kurt Huber, Noor Alicezah Mohd Kasim, A. Rahman A. Jamal, Vaclava Palanova, Giacomo Biasucci, Pucong Ye, Eva Cubova, Roopa Mehta, Rüdiger Schweizer, Veronica Zampoleri, Jacek Jóźwiak, Alyaa Al-Khateeb, Jing Hong, Katarina Raslova, Kirsten B. Holven, Tatiana Rozkova, Reinhold Busch, Alexander Klabnik, Konrad Hein, Eloy A.Z. Carrillo, Robin Urbanek, Livia Pisciotta, Fatma Y. Coskun, Jose J.G. Garcia, Valerio Pecchioli, Azra D. Nalbantic, Weerapan Khovidhunkit, Jernej Kovac, Michaela Kadurova, Mohammed Al-Jarallah, Vita Saripo, Christos V. Rizos, Jie Peng, Ang L. Chua, Dorothee Deiss, Nor A.A. Murad, Aneta Stróżyk, See Kwok, Gökhan Alici, Gillian J. Pilcher, John J.P. Kastelein, Dmitry Duplyakov, Calin Lengher, Milena Budikova, C. Azzopardi, Christina Antza, Luis E.V. Arroyo, Khalid Al-Jumaily, Ahmad Al-Sarraf, Carlos A. Aguilar-Salinas, Erkayim Bektasheva, Arta Upena-RozeMicena, Qian Wang, Xumin Wang, Leah Leavit, Radzi Rahmat, Selim Topcu, Željko Reiner, Lorenzo Maroni, Matija Cevc, Elizabeth R. Cooremans, Masatsune Ogura, Tevfik Sabuncu, Ruy D Arjona Villicaña, Andrea Giaccari, Xuesong Fan, Auryan Szalat, Sanjaya Dissanayake, Etienne Khoury, Anja Vogt, Hermann Toplak, Alexis Baass, Isabel Palma, Gaelle Sablon, Dana A. Hay, Ya Yang, Margus Viigimaa, Erik S.G. Stroes, Dror Harats, Konstantin Krychtiuk, Zesen Liu, Aleksandra Parczewska, Yves Cottin, Yichen Qu, Mathilde Di-Fillipo, Agnieszka Konopka, Lamija Pojskic, Guadalupe J. Dominguez, Ahmet Temizhan, Roberto C. Chacon, Ibrahim E. Dural, Qiang Yong, G. Kees Hovingh, Kang Meng, Sandra Kutkiene, Julie Lemale, Reinhold Innerhofer, Alexandros D. Tselepis, Handrean Soran, Wolfgang König, Bassam Atallah, Olena Mitchenko, Jana Cepova, Eduardo M. Rodriguez, Ulrich Laufs, Norhidayah Rosman, Alena Lubasova, V. Durlach, Frederick J. Raal, Elyor Khodzhiboboev, Cristina Pederiva, Hui Yuan, Ashraf Reda, Fahad Alnouri, Konstantinos Tziomalos, Thanh T. Le, Jana Sirotiakova, Régis Hankard, Hector E.A. Cazares, Betsabel Rodriguez, Lenka Pavlickova, Assen Goudev, Julius Katzmann, Diana Boger, Wael Almahmeed, Katarina T. Podkrajsek, Sabina Zambon, Fahri Bayram, Nadia Citroni, Samir Rafla, Vincent Rigalleau, Aleksandr B. Shek, Hani Sabbour, Berenice G. Guzman, Shoshi Shpitzen, Eric Tarantino, Ahmed Bendary, Fedya Nikolov, Jean Bergeron, Stefan Kopf, Iva Rasulic, Gerald F. Watts, Muhammad I.A. Hafidz, Mehmet B. Yilmaz, Kathrin Biolik, Ira A. Haack, Robert A. Hegele, Sonia Dulong, Bartosz Wasąg, Osama Sanad, Susana Correia, Zhenjia Wang, Dana Biedermann, Christel König, Helena Podzimkova, Ihab Daoud, Mohammad Alghamdi, Dražen Perica, László Márk, Iosif Koutagiar, Volkan Dogan, Vladimir Blaha, Chandrashekhar K. Ponde, Katerina Valoskova, Amer A. Jabbar, Azhari Rosman, Sazzli Kasim, Mesut Demir, Ulugbek I. Nizamov, Aldo Ferreira-Hermosillo, Dilek Yesilbursa, Atef Elbahry, Arshad Abdulrasheed, Omer A. Elamin, Vasileios Athyros, Joanna Lewek, Gergely Nagy, Ursula Kassner, Jian Jiao, Klaus G. Parhofer, Charlotte Nzeyimana, Marcin Pajkowski, Stanislav Zemek, Jose J.C. Macías, Cornelius Müller, G. Sfikas, Leopoldo Pérez de Isla, Yulia Ragino, Fahad Al-Zadjali, Abdul Rais Sanusi, Anna Rita Roscini, Jean Ferrières, Selim Jambart, Jean Pierre Rabes, Laura Schreier, Hofit Cohen, Olivier S. Descamps, N. Lalic, Christine Stumpp, Antonio J. Vallejo-Vaz, Jutta Christmann, Manuela Casula, Mariko Harada-Shiba, Olga Lunegova, Ewa Starostecka, Nicolas D. Oca, Alain Carrié, Achilleas Attilakos, Savas Ozer, Andreea Dumitrescu, Jürgen Merke, Urte Aliosaitiene, Evangelos Liberopoulos, Manuel O. De los Rios Ibarra, Maria J. Virtuoso, Alessandro Lupi, Panagiotis Anagnostis, Ruth Agar, Dorota Ferrieres, George Liamis, José Eduardo Krieger, Mariann Harangi, Fouzia Sadiq, Francois Schiele, Saif Kamal, Mária Audikovszky, Peter Baumgartner, Marta Gazzotti, Daniel Gaudet, Ashanty F. Ortega, Marcin Gruchała, Philippe Moulin, Ljiljana Popovic, Luca Bonanni, E. Kiouri, Mika Hori, Chiara Trenti, Elena Repetti, Carlo Sabbà, Sophie Bernard, Alejandro R. Zazueta, Mirac Vural, Jesus R. Gonzalez, C. Stevens, Francesca Carubbi, Wenhui Wen, Sabri Demircan, Kanika I. Dharmayat, Anne Tybjærg-Hansen, Elizabete Terauda, Claudia Zemmrich, Alphonsus Isara, Fabiola L. Sobrevilla, Anell Hernandez Garcia, Ibrahim Sisic, Justin T. I-Shing, Yvonne Winhofer-Stöckl, Luya Wang, Manfred Mayer, Mohanad Al-ageedi, Judith Wiener, Mohammed Al-Kindi, Anis Safura Ramli, Yan Chen, Denis Angoulvant, Aytekin Oguz, K.H. Wolmarans, Claudio Ferri, Tomáš Freiberger, Lubomira Cermakova, Julieta D.M. Portano, Pierre Henri Ducluzeau, Katerina Vonaskova, Levent H. Can, Mario H.F. Andrade, György Paragh, C. Ebenbichler, Karina J.A. Rivera, Alia Khudari, Elisabeth Steinhagen-Thiessen, Ana C. Alves, Victoria Korneva, Sandra Singh, Georgia Anastasiou, Nur S. Hamzan, Massimo Federici, Lale Tokgozoglu, Hector G. Alcala, Oana Moldovan, Giuseppe Mandraffino, Swarup A.V. Shah, Lukas Burda, Ersel Onrat, Manuel de los Reyes Barrera Bustillo, Mirjana Radovic, Arman Postadzhiyan, Nien-Tzu Chang, Aylin Yildirir, Martin Mäser, Bruno Fink, Svetlana Mosteoru, Ulrike Schatz, Luis A.V. Talavera, Magdalena Dusejovska, Richard Ceska, Faisal A. Al-Allaf, T.F. Ashavaid, Gereon Böll, Sona Machacova, Gonzalo C. Vargas, Antonio Gallo, Elina Pantchechnikova, Lukas Tichy, Gersina Rega-Kaun, Moses Elisaf, Branislav Vohnout, Antonio Bossi, Suad Al-Mukhaini, Natasa Rajkovic, Ursa Sustar, Merih Kutlu, Mohamed Sobhy, Britta Otte, Ana M. Medeiros, Borut Jug, Patrick Couture, Rodrigo Alonso, Wolfgang Seeger, Guzal J. Abdullaeva, Ahmet Celik, Nasreen Al-Sayed, Béla Benczúr, Petra E. Khoury, Rafezah Razali, Ma L.R. Osorio, Ruiying Zhang, Monica M.N. Usme, Humberto Garcia Aguilar, Ceyhun Ceyhan, Antje Spens, Christoph J. Binder, Volker Schrader, Terrance C.S. Jin, Neftali E.A. Villa, Aleksandra Michalska-Grzonkowska, Francesco Purrello, Marshima M. Rosli, Vincent Maher, Dilshad Rasul, Ines Colaço, Ornella Guardamagna, Giuliana Mombelli, Khalid F. AlHabib, Fahmi Alkaf, Marianne Benn, Youmna Ghaleb, Arsenio V. Vazquez, Lakshmi L. Reddy, Salih Kilic, Siti Hamimah Sheikh Abdul Kadir, E. Bilianou, Rossella Marcucci, Sandro Muntoni, Kurt Widhalm, Evangelos A. Zacharis, Kuznetsova T. Yu, Eric Bruckert, Antonia Sonntag, Katerina Rehouskova, Josè Pablo Werba, Leobardo Sauque-Reyna, Myra Tilney, Dov Gavishv, A.M. Fiorenza, Zdenka Krejsova, Hong A. Le, Andrey V. Susekov, Isabel Klein, Mai N.T. Nguyen, Andrejs Erglis, Muge Ildizli, Diane Brisson, Salmi Razali, Winfried März, Ovidio Muñiz-Grijalvo, Justyna Borowiec-Wolna, Ingrid Buganova, Ngoc T. Kim, Yue Wu, István Reiber, Jose C.A. Martinez, Pavel Malina, Sandy Elbitar, Stephan Matthias, Ali F. Abdalsahib, Zlatko Fras, Wilson E Sadoh, Lucas Kleemann, Tayfun Sahin, Martin P. Bogsrud, Fabio Pellegatta, Mohamed A. Shafy, Yuntao Li, Martine Paquette, Zuhier Awan, Arturo Pujia, Xiantao Song, Renata Cifkova, Alexandre C. Pereira, Ioannis Skoumas, Roman Cibulka, Tadej Battelino, Mariusz Gąsior, Ghada Kazamel, Lahore S.U. Shah, Eran Leitersdorf, Niki Katsiki, Daniel Elías-López, Khalid Al-Rasadi, Grete Talviste, Sarka Mala, Rocio M. Alvarado, Pavel Kraml, Gerret Paulsen, Angelina Passaro, Zsolt Karányi, Carine Ayoub, Vera Adamkova, Ivo Petrov, Turky H. Almigbal, Rohana Abdul Ghani, Franck Boccara, Brian W. McCrindle, François Martin, Jamshed J. Dalal, Shitong Cheng, Khalid Al-Waili, Chaoyi Zhang, Ramon M. Prado, Lubica Cibickova, Lubomira Fabryova, Tobias Wiesner, Thuhairah Hasrah Abdul Rahman, Tan J. Le, Marcello Arca, Sabine Scholl-Bürgi, Juan R. Saucedo, Georgijs Nesterovics, Carla V.M. Valencia, Alexander Stadelmann, Vasileios Kotsis, Lina Badimon, Shizuya Yamashita, Jose C.M. Oyervides, Lay K. Teh, Susanne Greber-Platzer, Marianne Abifadel, Ruta Meiere, Wibke Reinhard, Pablo Corral, Nina Schmidt, Alain Pradignac, A. David Marais, Marta Jordanova, Marzena Romanowska-Kocejko, Johannes Scholl, Brian Tomlinson, Laura G.G. Herrera, Loukianos S. Rallidis, Pedro Mata, Sameh Emil, Matej Mlinaric, Emile Ferrari, Suraya Abdul Razak, Alexandra Ershova, Andrie G. Panayiotou, Alinna Y.R. Garcia, Kairat Davletov, Katarina Lalic, Doan L. Do, Krzysztof Chlebus, Ricardo A. Carrera, Daniel I.P. Vazquez, Nikolaos Sakkas, Liyuan Xu, Mays Altaey, Aysa Hacioglu, Alexandro J. Martagon, Marta Żarczyńska-Buchowiecka, Michael Schömig, Jürgen Homberger, Andrea Benso, Bertrand Cariou, Ardon Rubinstein, Omer Gedikli, Emre Durakoglugil, Mei Chong, Bahadir Kirilmaz, Suhaila Abd Muid, Jose M. Salgado, Berenice P. Aparicio, Mutaz Alkhnifsawi, Bruno Vergès, Cécile Yelnik, Goreti Lobarinhas, Zaneta Petrulioniene, Sylvia Asenjo, Aytul B. Yildirim, László Bajnok, Vallejo-Vaz A.J., Stevens C.A.T., Lyons A.R.M., Dharmayat K.I., Freiberger T., Hovingh G.K., Mata P., Raal F.J., Santos R.D., Soran H., Watts G.F., Abifadel M., Aguilar-Salinas C.A., Alhabib K.F., Alkhnifsawi M., Almahmeed W., Alnouri F., Alonso R., Al-Rasadi K., Al-Sarraf A., Al-Sayed N., Araujo F., Ashavaid T.F., Banach M., Beliard S., Benn M., Binder C.J., Bogsrud M.P., Bourbon M., Chlebus K., Corral P., Davletov K., Descamps O.S., Durst R., Ezhov M., Gaita D., Genest J., Groselj U., Harada-Shiba M., Holven K.B., Kayikcioglu M., Khovidhunkit W., Lalic K., Latkovskis G., Laufs U., Liberopoulos E., Lima-Martinez M.M., Lin J., Maher V., Marais A.D., Marz W., Mirrakhimov E., Miserez A.R., Mitchenko O., Nawawi H., Nordestgaard B.G., Panayiotou A.G., Paragh G., Petrulioniene Z., Pojskic B., Postadzhiyan A., Raslova K., Reda A., Reiner, Sadiq F., Sadoh W.E., Schunkert H., Shek A.B., Stoll M., Stroes E., Su T.-C., Subramaniam T., Susekov A.V., Tilney M., Tomlinson B., Truong T.H., Tselepis A.D., Tybjaerg-Hansen A., Vazquez Cardenas A., Viigimaa M., Wang L., Yamashita S., Kastelein J.J.P., Bruckert E., Vohnout B., Schreier L., Pang J., Ebenbichler C., Dieplinger H., Innerhofer R., Winhofer-Stockl Y., Greber-Platzer S., Krychtiuk K., Speidl W., Toplak H., Widhalm K., Stulnig T., Huber K., Hollerl F., Rega-Kaun G., Kleemann L., Maser M., Scholl-Burgi S., Saly C., Mayer F.J., Sablon G., Tarantino E., Nzeyimana C., Pojskic L., Sisic I., Nalbantic A.D., Jannes C.E., Pereira A.C., Krieger J.E., Petrov I., Goudev A., Nikolov F., Tisheva S., Yotov Y., Tzvetkov I., Baass A., Bergeron J., Bernard S., Brisson D., Brunham L.R., Cermakova L., Couture P., Francis G.A., Gaudet D., Hegele R.A., Khoury E., Mancini G.B.J., McCrindle B.W., Paquette M., Ruel I., Cuevas A., Asenjo S., Wang X., Meng K., Song X., Yong Q., Jiang T., Liu Z., Duan Y., Hong J., Ye P., Chen Y., Qi J., Li Y., Zhang C., Peng J., Yang Y., Yu W., Wang Q., Yuan H., Cheng S., Jiang L., Chong M., Jiao J., Wu Y., Wen W., Xu L., Zhang R., Qu Y., He J., Fan X., Wang Z., Chow E., Pecin I., Perica D., Symeonides P., Vrablik M., Ceska R., Soska V., Tichy L., Adamkova V., Franekova J., Cifkova R., Kraml P., Vonaskova K., Cepova J., Dusejovska M., Pavlickova L., Blaha V., Rosolova H., Nussbaumerova B., Cibulka R., Vaverkova H., Cibickova L., Krejsova Z., Rehouskova K., Malina P., Budikova M., Palanova V., Solcova L., Lubasova A., Podzimkova H., Bujdak J., Vesely J., Jordanova M., Salek T., Urbanek R., Zemek S., Lacko J., Halamkova H., Machacova S., Mala S., Cubova E., Valoskova K., Burda L., Bendary A., Daoud I., Emil S., Elbahry A., Rafla S., Sanad O., Kazamel G., Ashraf M., Sobhy M., El-Hadidy A., Shafy M.A., Kamal S., Bendary M., Talviste G., Angoulvant D., Boccara F., Cariou B., Carreau V., Carrie A., Charrieres S., Cottin Y., Di-Fillipo M., Ducluzeau P.H., Dulong S., Durlach V., Farnier M., Ferrari E., Ferrieres D., Ferrieres J., Gallo A., hankard R., Inamo J., Lemale J., Moulin P., Paillard F., Peretti N., Perrin A., Pradignac A., Rabes J.P., Rigalleau V., Sultan A., Schiele F., Tounian P., Valero R., Verges B., Yelnik C., Ziegler O., Haack I.A., Schmidt N., Dressel A., Klein I., Christmann J., Sonntag A., Stumpp C., Boger D., Biedermann D., Usme M.M.N., Beil F.U., Klose G., Konig C., Gouni-Berthold I., Otte B., Boll G., Kirschbaum A., Merke J., Scholl J., Segiet T., Gebauer M., Predica F., Mayer M., Leistikow F., Fullgraf-Horst S., Muller C., Schuler M., Wiener J., Hein K., Baumgartner P., Kopf S., Busch R., Schomig M., Matthias S., Allendorf-Ostwald N., Fink B., Bohm D., Jakel A., Koschker A.-C., Schweizer R., Vogt A., Parhofer K., Konig W., Reinhard W., Bassler A., Stadelmann A., Schrader V., Katzmann J., Tarr A., Steinhagen-Thiessen E., Kassner U., Paulsen G., Homberger J., Zemmrich C., Seeger W., Biolik K., Deiss D., Richter C., Pantchechnikova E., Dorn E., Schatz U., Julius U., Spens A., Wiesner T., Scholl M., Rizos C.V., Sakkas N., Elisaf M., Skoumas I., Tziomalos K., Rallidis L., Kotsis V., Doumas M., Athyros V., Skalidis E., Kolovou G., Garoufi A., Bilianou E., Koutagiar I., Agapakis D., Kiouri E., Antza C., Katsiki N., Zacharis E., Attilakos A., Sfikas G., Koumaras C., Anagnostis P., Anastasiou G., Liamis G., Koutsogianni A.-D., Karanyi Z., Harangi M., Bajnok L., Audikovszky M., Mark L., Benczur B., Reiber I., Nagy G., Nagy A., Reddy L.L., Shah S.A.V., Ponde C.K., Dalal J.J., Sawhney J.P.S., Verma I.C., Altaey M., Al-Jumaily K., Rasul D., Abdalsahib A.F., Jabbar A.A., Al-ageedi M., Agar R., Cohen H., Ellis A., Gavishv D., Harats D., Henkin Y., Knobler H., Leavit L., Leitersdorf E., Rubinstein A., Schurr D., Shpitzen S., Szalat A., Casula M., Zampoleri V., Gazzotti M., Olmastroni E., Sarzani R., Ferri C., Repetti E., Sabba C., Bossi A.C., Borghi C., Muntoni S., Cipollone F., Purrello F., Pujia A., Passaro A., Marcucci R., Pecchioli V., Pisciotta L., Mandraffino G., Pellegatta F., Mombelli G., Branchi A., Fiorenza A.M., Pederiva C., Werba J.P., Parati G., Carubbi F., Iughetti L., Iannuzzi A., Iannuzzo G., Calabro P., Averna M, Biasucci G., Zambon S., Roscini A.R., Trenti C., Arca M., Federici M., Del Ben M., Bartuli A., Giaccari A., Pipolo A., Citroni N., Guardamagna O., Bonomo K., Benso A., Biolo G., Maroni L., Lupi A., Bonanni L., Zenti M.G., Matsuki K., Hori M., Ogura M., Masuda D., Kobayashi T., Nagahama K., Al-Jarallah M., Radovic M., Lunegova O., Bektasheva E., Khodzhiboboev E., Erglis A., Gilis D., Nesterovics G., Saripo V., Meiere R., Upena-RozeMicena A., Terauda E., Jambart S., Khoury P.E., Elbitar S., Ayoub C., Ghaleb Y., Aliosaitiene U., Kutkiene S., Kasim N.A.M., Nor N.S.M., Ramli A.S., Razak S.A., Al-Khateeb A., Kadir S.H.S.A., Muid S.A., Rahman T.A., Kasim S.S., Radzi A.B.M., Ibrahim K.S., Razali S., Ismail Z., Ghani R.A., Hafidz M.I.A., Chua A.L., Rosli M.M., Annamalai M., Teh L.K., Razali R., Chua Y.A., Rosman A., Sanusi A.R., Murad N.A.A., Jamal A.R.A., Nazli S.A., Razman A.Z., Rosman N., Rahmat R., Hamzan N.S., Azzopardi C., Mehta R., Martagon A.J., Ramirez G.A.G., Villa N.E.A., Vazquez A.V., Elias-Lopez D., Retana G.G., Rodriguez B., Macias J.J.C., Zazueta A.R., Alvarado R.M., Portano J.D.M., Lopez H.A., Sauque-Reyna L., Herrera L.G.G., Mendia L.E.S., Aguilar H.G., Cooremans E.R., Aparicio B.P., Zubieta V.M., Gonzalez P.A.C., Ferreira-Hermosillo A., Portilla N.C., Dominguez G.J., Garcia A.Y.R., Cazares H.E.A., Gonzalez J.R., Valencia C.V.M., Padilla F.G., Prado R.M., De los Rios Ibarra M.O., Villicana R.D.A., Rivera K.J.A., Carrera R.A., Alvarez J.A., Martinez J.C.A., de los Reyes Barrera Bustillo M., Vargas G.C., Chacon R.C., Andrade M.H.F., Ortega A.F., Alcala H.G., de Leon L.E.G., Guzman B.G., Garcia J.J.G., Cuellar J.C.G., Cruz J.R.G., Garcia A.H., Almada J.R.H., Herrera U.J., Sobrevilla F.L., Rodriguez E.M., Sibaja C.M., Rodriguez A.B.M., Oyervides J.C.M., Vazquez D.I.P., Rodriguez E.A.R., Osorio M.L.R., Saucedo J.R., Tamayo M.T., Talavera L.A.V., Arroyo L.E.V., 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V., Sakkas, N., Elisaf, M., Skoumas, I., Tziomalos, K., Rallidis, L., Kotsis, V., Doumas, M., Athyros, V., Skalidis, E., Kolovou, G., Garoufi, A., Bilianou, E., Koutagiar, I., Agapakis, D., Kiouri, E., Antza, C., Katsiki, N., Zacharis, E., Attilakos, A., Sfikas, G., Koumaras, C., Anagnostis, P., Anastasiou, G., Liamis, G., Koutsogianni, A. -D., Karanyi, Z., Harangi, M., Bajnok, L., Audikovszky, M., Mark, L., Benczur, B., Reiber, I., Nagy, G., Nagy, A., Reddy, L. L., Shah, S. A. V., Ponde, C. K., Dalal, J. J., Sawhney, J. P. S., Verma, I. C., Altaey, M., Al-Jumaily, K., Rasul, D., Abdalsahib, A. F., Jabbar, A. A., Al-ageedi, M., Agar, R., Cohen, H., Ellis, A., Gavishv, D., Harats, D., Henkin, Y., Knobler, H., Leavit, L., Leitersdorf, E., Rubinstein, A., Schurr, D., Shpitzen, S., Szalat, A., Casula, M., Zampoleri, V., Gazzotti, M., Olmastroni, E., Sarzani, R., Ferri, C., Repetti, E., Sabba, C., Bossi, A. C., Borghi, C., Muntoni, S., Cipollone, F., Purrello, F., Pujia, A., Passaro, A., Marcucci, R., Pecchioli, V., Pisciotta, L., Mandraffino, G., Pellegatta, F., Mombelli, G., Branchi, A., Fiorenza, A. M., Pederiva, C., Werba, J. P., Parati, G., Carubbi, F., Iughetti, L., Iannuzzi, A., Iannuzzo, G., Calabro, P., Averna, M., Biasucci, G., Zambon, S., Roscini, A. R., Trenti, C., Arca, M., Federici, M., Del Ben, M., Bartuli, A., Giaccari, A., Pipolo, A., Citroni, N., Guardamagna, O., Bonomo, K., Benso, A., Biolo, G., Maroni, L., Lupi, A., Bonanni, L., Zenti, M. G., Matsuki, K., Hori, M., Ogura, M., Masuda, D., Kobayashi, T., Nagahama, K., Al-Jarallah, M., Radovic, M., Lunegova, O., Bektasheva, E., Khodzhiboboev, E., Erglis, A., Gilis, D., Nesterovics, G., Saripo, V., Meiere, R., Upena-RozeMicena, A., Terauda, E., Jambart, S., Khoury, P. E., Elbitar, S., Ayoub, C., Ghaleb, Y., Aliosaitiene, U., Kutkiene, S., Kasim, N. A. M., Nor, N. S. M., Ramli, A. S., Razak, S. A., Al-Khateeb, A., Kadir, S. H. S. A., Muid, S. A., Rahman, T. A., Kasim, S. S., Radzi, A. B. M., Ibrahim, K. S., Razali, S., Ismail, Z., Ghani, R. A., Hafidz, M. I. A., Chua, A. L., Rosli, M. M., Annamalai, M., Teh, L. K., Razali, R., Chua, Y. A., Rosman, A., Sanusi, A. R., Murad, N. A. A., Jamal, A. R. A., Nazli, S. A., Razman, A. Z., Rosman, N., Rahmat, R., Hamzan, N. S., Azzopardi, C., Mehta, R., Martagon, A. J., Ramirez, G. A. G., Villa, N. E. A., Vazquez, A. V., Elias-Lopez, D., Retana, G. G., Rodriguez, B., Macias, J. J. C., Zazueta, A. R., Alvarado, R. M., Portano, J. D. M., Lopez, H. A., Sauque-Reyna, L., Herrera, L. G. G., Mendia, L. E. S., Aguilar, H. G., Cooremans, E. R., Aparicio, B. P., Zubieta, V. M., Gonzalez, P. A. C., Ferreira-Hermosillo, A., Portilla, N. C., Dominguez, G. J., Garcia, A. Y. R., Cazares, H. E. A., Gonzalez, J. R., Valencia, C. V. M., Padilla, F. G., Prado, R. M., De los Rios Ibarra, M. O., Villicana, R. D. A., Rivera, K. J. A., Carrera, R. A., Alvarez, J. A., Martinez, J. C. A., de los Reyes Barrera Bustillo, M., Vargas, G. C., Chacon, R. C., Andrade, M. H. F., Ortega, A. F., Alcala, H. G., de Leon, L. E. G., Guzman, B. G., Garcia, J. J. G., Cuellar, J. C. G., Cruz, J. R. G., Garcia, A. H., Almada, J. R. H., Herrera, U. J., Sobrevilla, F. L., Rodriguez, E. M., Sibaja, C. M., Rodriguez, A. B. M., Oyervides, J. C. M., Vazquez, D. I. P., Rodriguez, E. A. R., Osorio, M. L. R., Saucedo, J. R., Tamayo, M. T., Talavera, L. A. V., Arroyo, L. E. V., Carrillo, E. A. Z., Isara, A., Obaseki, D. E., Al-Waili, K., Al-Zadjali, F., Al-Zakwani, I., Al-Kindi, M., Al-Mukhaini, S., Al-Barwani, H., Rana, A., Shah, L. S. U., Starostecka, E., Konopka, A., Lewek, J., Bartlomiejczyk, M., Gasior, M., Dyrbus, K., Jozwiak, J., Gruchala, M., Pajkowski, M., Romanowska-Kocejko, M., Zarczynska-Buchowiecka, M., Chmara, M., Wasag, B., Parczewska, A., Gilis-Malinowska, N., Borowiec-Wolna, J., Strozyk, A., Wos, M., Michalska-Grzonkowska, A., Medeiros, A. M., Alves, A. C., Silva, F., Lobarinhas, G., Palma, I., de Moura, J. P., Rico, M. T., Rato, Q., Pais, P., Correia, S., Moldovan, O., Virtuoso, M. J., Salgado, J. M., Colaco, I., Dumitrescu, A., Lengher, C., Mosteoru, S., Meshkov, A., Ershova, A., Rozkova, T., Korneva, V., Yu, K. T., Zafiraki, V., Voevoda, M., Gurevich, V., Duplyakov, D., Ragino, Y., Safarova, M., Shaposhnik, I., Alkaf, F., Khudari, A., Rwaili, N., Al-Allaf, F., Alghamdi, M., Batais, M. A., Almigbal, T. H., Kinsara, A., Alqudaimi, A. H. A., Awan, Z., Elamin, O. A., Altaradi, H., Rajkovic, N., Popovic, L., Singh, S., Stosic, L., Rasulic, I., Lalic, N. M., Lam, C., Le, T. J., Siang, E. L. T., Dissanayake, S., I-Shing, J. T., Shyong, T. E., Jin, T. C. S., Balinth, K., Buganova, I., Fabryova, L., Kadurova, M., Klabnik, A., Kozarova, M., Sirotiakova, J., Battelino, T., Kovac, J., Mlinaric, M., Sustar, U., Podkrajsek, K. T., Fras, Z., Jug, B., Cevc, M., Pilcher, G. J., Blom, D. J., Wolmarans, K. H., Brice, B. C., Muniz-Grijalvo, O., Diaz-Diaz, J. L., de Isla, L. P., Fuentes, F., Badimon, L., Martin, F., Lux, A., Chang, N. -T., Ganokroj, P., Akbulut, M., Alici, G., Bayram, F., Can, L. H., Celik, A., Ceyhan, C., Coskun, F. Y., Demir, M., Demircan, S., Dogan, V., Durakoglugil, E., Dural, I. E., Gedikli, O., Hacioglu, A., Ildizli, M., Kilic, S., Kirilmaz, B., Kutlu, M., Oguz, A., Ozdogan, O., Onrat, E., Ozer, S., Sabuncu, T., Sahin, T., Sivri, F., Sonmez, A., Temizhan, A., Topcu, S., Tuncez, A., Vural, M., Yenercag, M., Yesilbursa, D., Yigit, Z., Yildirim, A. B., Yildirir, A., Yilmaz, M. B., Atallah, B., Traina, M., Sabbour, H., Hay, D. A., Luqman, N., Elfatih, A., Abdulrasheed, A., Kwok, S., Oca, N. D., Reyes, X., Alieva, R. B., Kurbanov, R. D., Hoshimov, S. U., Nizamov, U. I., Ziyaeva, A. V., Abdullaeva, G. J., Do, D. L., Nguyen, M. N. T., Kim, N. T., Le, T. T., Le, H. A., Tokgozoglu, L., Catapano, A. L., Ray, K. K., and EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC), Borghi C

Subjects
Male, Settore MED/09 - Medicina Interna, Arterial disease, Cross-sectional study, Adult population, Coronary Disease, Disease, Global Health, Medical and Health Sciences, Doenças Cardio e Cérebro-vasculares, Anticholesteremic Agent, Monoclonal, Prevalence, Registries, Familial Hypercholesterolemia, Humanized, Stroke, 11 Medical and Health Sciences, LS2_9, Studies Collaboration, Anticholesteremic Agents, General Medicine, Heart Disease Risk Factor, Middle Aged, FHSC global registry data, Europe, Treatment Outcome, Lower prevalence, Guidance, lipids (amino acids, peptides, and proteins), Female, Proprotein Convertase 9, Familial hypercholesterolaemia, Life Sciences & Biomedicine, Human, Adult, medicine.medical_specialty, Combination therapy, FHSC global registry, heterozygous familial hypercholesterolaemia, Cardiovascular risk factors, Antibodies, Monoclonal, Humanized, Insights, Antibodies, NO, Hyperlipoproteinemia Type II, Clinician, Medicine, General & Internal, Internal medicine, General & Internal Medicine, Health Sciences, medicine, Humans, EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC), Cross-Sectional Studie, Science & Technology, Global Perspective, business.industry, Cholesterol, LDL, medicine.disease, Cross-Sectional Studies, Heart Disease Risk Factors, Hydroxymethylglutaryl-CoA Reductase Inhibitor, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business
Abstract

Background The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally. Methods Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Data were assessed overall and by WHO regions, sex, and index versus non-index cases. Findings Of the 61 612 individuals in the registry, 42 167 adults (21 999 [53.6%] women) from 56 countries were included in the study. Of these, 31 798 (75.4%) were diagnosed with the Dutch Lipid Clinic Network criteria, and 35 490 (84.2%) were from the WHO region of Europe. Median age of participants at entry in the registry was 46.2 years (IQR 34.3-58.0); median age at diagnosis of familial hypercholesterolaemia was 44.4 years (32.5-56.5), with 40.2% of participants younger than 40 years when diagnosed. Prevalence of cardiovascular risk factors increased progressively with age and varied by WHO region. Prevalence of coronary disease was 17.4% (2.1% for stroke and 5.2% for peripheral artery disease), increasing with concentrations of untreated LDL cholesterol, and was about two times lower in women than in men. Among patients receiving lipid-lowering medications, 16 803 (81.1%) were receiving statins and 3691 (21.2%) were on combination therapy, with greater use of more potent lipid-lowering medication in men than in women. Median LDL cholesterol was 5.43 mmol/L (IQR 4.32-6.72) among patients not taking lipid-lowering medications and 4.23 mmol/L (3.20-5.66) among those taking them. Among patients taking lipid-lowering medications, 2.7% had LDL cholesterol lower than 1.8 mmol/L; the use of combination therapy, particularly with three drugs and with proprotein convertase subtilisin-kexin type 9 inhibitors, was associated with a higher proportion and greater odds of having LDL cholesterol lower than 1.8 mmol/L. Compared with index cases, patients who were non-index cases were younger, with lower LDL cholesterol and lower prevalence of cardiovascular risk factors and cardiovascular diseases (all p, Pfizer Independent Grant for Learning Change [16157823]; Amgen; Merck Sharp Dohme; Sanofi-Aventis; Daiichi Sankyo; Regeneron; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK; NIHR; Czech Ministry of Health [NU20-02-00261]; Canadian Institutes of Health Research; Austrian Heart Foundation; Tyrolean Regional Government; Gulf Heart Association, The EAS FHSC is an academic initiative that has received funding from a Pfizer Independent Grant for Learning & Change 2014 (16157823) and from investigator-initiated research grants to the European Atherosclerosis Society-Imperial College London from Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron. KKR acknowledges support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK. KID acknowledges support from a PhD Studentship from NIHR under the Applied Health Research programme for Northwest London, UK (the views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health). TF was supported by a grant from the Czech Ministry of Health (NU20-02-00261). JG receives support from the Canadian Institutes of Health Research. The Austrian Familial Hypercholesterolaemia registry has been supported by funds from the Austrian Heart Foundation and the Tyrolean Regional Government. The Gulf Familial Hypercholesterolaemia registry was done under the auspices of the Gulf Heart Association.

Published
2021
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36. APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia.

Author

Abou Khalil Y, Marmontel O, Ferrières J, Paillard F, Yelnik C, Carreau V, Charrière S, Bruckert E, Gallo A, Giral P, Philippi A, Bluteau O, Boileau C, Abifadel M, Di-Filippo M, Carrié A, Rabès JP, and Varret M

Subjects
Cholesterol, LDL genetics, Cholesterol, LDL metabolism, Humans, Apolipoproteins E genetics, Apolipoproteins E metabolism, Hyperlipoproteinemia Type II genetics, Hyperlipoproteinemia Type II metabolism, Proprotein Convertase 9 genetics, Proprotein Convertase 9 metabolism
Abstract

Primary hypercholesterolemia is characterized by elevated LDL-cholesterol (LDL-C) levels isolated in autosomal dominant hypercholesterolemia (ADH) or associated with elevated triglyceride levels in familial combined hyperlipidemia (FCHL). Rare APOE variants are known in ADH and FCHL. We explored the APOE molecular spectrum in a French ADH/FCHL cohort of 5743 unrelated probands. The sequencing of LDLR , PCSK9 , APOB , and APOE revealed 76 carriers of a rare APOE variant, with no mutation in LDLR , PCSK9, or APOB . Among the 31 APOE variants identified here, 15 are described in ADH, 10 in FCHL, and 6 in both probands. Five were previously reported with dyslipidemia and 26 are novel, including 12 missense, 5 synonymous, 2 intronic, and 7 variants in regulatory regions. Sixteen variants were predicted as pathogenic or likely pathogenic, and their carriers had significantly lower polygenic risk scores (wPRS) than carriers of predicted benign variants. We observed no correlation between LDL-C levels and wPRS, suggesting a major effect of APOE variants. Carriers of p.Leu167del were associated with a severe phenotype. The analysis of 11 probands suggests that carriers of an APOE variant respond better to statins than carriers of a LDLR mutation. Altogether, we show that the APOE variants account for a significant contribution to ADH and FCHL.

Published
2022
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37. Whole Exome/Genome Sequencing Joint Analysis of a Family with Oligogenic Familial Hypercholesterolemia.

Author

Ghaleb Y, Elbitar S, Philippi A, El Khoury P, Azar Y, Andrianirina M, Loste A, Abou-Khalil Y, Nicolas G, Le Borgne M, Moulin P, Di-Filippo M, Charrière S, Farnier M, Yelnick C, Carreau V, Ferrières J, Lecerf JM, Derksen A, Bernard G, Gauthier MS, Coulombe B, Lütjohann D, Fin B, Boland A, Olaso R, Deleuze JF, Rabès JP, Boileau C, Abifadel M, and Varret M

Abstract

Autosomal Dominant Hypercholesterolemia (ADH) is a genetic disorder caused by pathogenic variants in LDLR , APOB , PCSK9 and APOE genes. We sought to identify new candidate genes responsible for the ADH phenotype in patients without pathogenic variants in the known ADH-causing genes by focusing on a French family with affected and non-affected members who presented a high ADH polygenic risk score (wPRS). Linkage analysis, whole exome and whole genome sequencing resulted in the identification of variants p.(Pro398Ala) in CYP7A1 , p.(Val1382Phe) in LRP6 and p.(Ser202His) in LDLRAP1 . A total of 6 other variants were identified in 6 of 160 unrelated ADH probands: p.(Ala13Val) and p.(Aps347Asn) in CYP7A1 ; p.(Tyr972Cys), p.(Thr1479Ile) and p.(Ser1612Phe) in LRP6 ; and p.(Ser202LeufsTer19) in LDLRAP1 . All six probands presented a moderate wPRS. Serum analyses of carriers of the p.(Pro398Ala) variant in CYP7A1 showed no differences in the synthesis of bile acids compared to the serums of non-carriers. Functional studies of the four LRP6 mutants in HEK293T cells resulted in contradictory results excluding a major effect of each variant alone. Within the family, none of the heterozygous for only the LDLRAP1 p.(Ser202His) variant presented ADH. Altogether, each variant individually does not result in elevated LDL-C; however, the oligogenic combination of two or three variants reveals the ADH phenotype.

Published
2022
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38. Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome.

Author

Zanoni P, Panteloglou G, Othman A, Haas JT, Meier R, Rimbert A, Futema M, Abou Khalil Y, Norrelykke SF, Rzepiela AJ, Stoma S, Stebler M, van Dijk F, Wijers M, Wolters JC, Dalila N, Huijkman NCA, Smit M, Gallo A, Carreau V, Philippi A, Rabès JP, Boileau C, Visentin M, Vonghia L, Weyler J, Francque S, Verrijken A, Verhaegen A, Van Gaal L, van der Graaf A, van Rosmalen BV, Robert J, Velagapudi S, Yalcinkaya M, Keel M, Radosavljevic S, Geier A, Tybjaerg-Hansen A, Varret M, Rohrer L, Humphries SE, Staels B, van de Sluis B, Kuivenhoven JA, and von Eckardstein A

Subjects
Cholesterol metabolism, HEK293 Cells, Hep G2 Cells, Humans, Lipoproteins, LDL metabolism, Liver metabolism, Mutation, Nuclear Proteins genetics, Receptors, LDL metabolism, Spliceosomes metabolism, Nuclear Proteins metabolism, RNA Splicing, Receptors, LDL genetics
Abstract

Background: The LDLR (low-density lipoprotein receptor) in the liver is the major determinant of LDL-cholesterol levels in human plasma. The discovery of genes that regulate the activity of LDLR helps to identify pathomechanisms of hypercholesterolemia and novel therapeutic targets against atherosclerotic cardiovascular disease., Methods: We performed a genome-wide RNA interference screen for genes limiting the uptake of fluorescent LDL into Huh-7 hepatocarcinoma cells. Top hit genes were validated by in vitro experiments as well as analyses of data sets on gene expression and variants in human populations., Results: The knockdown of 54 genes significantly inhibited LDL uptake. Fifteen of them encode for components or interactors of the U2-spliceosome. Knocking down any one of 11 out of 15 genes resulted in the selective retention of intron 3 of LDLR . The translated LDLR fragment lacks 88% of the full length LDLR and is detectable neither in nontransfected cells nor in human plasma. The hepatic expression of the intron 3 retention transcript is increased in nonalcoholic fatty liver disease as well as after bariatric surgery. Its expression in blood cells correlates with LDL-cholesterol and age. Single nucleotide polymorphisms and 3 rare variants of one spliceosome gene, RBM25 , are associated with LDL-cholesterol in the population and familial hypercholesterolemia, respectively. Compared with overexpression of wild-type RBM25 , overexpression of the 3 rare RBM25 mutants in Huh-7 cells led to lower LDL uptake., Conclusions: We identified a novel mechanism of posttranscriptional regulation of LDLR activity in humans and associations of genetic variants of RBM25 with LDL-cholesterol levels.

Published
2022
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39. Myocardial fibrosis assessed by magnetic resonance imaging in asymptomatic heterozygous familial hypercholesterolemia: the cholcoeur study.

Author

Gallo A, Giral P, Rosenbaum D, Mattina A, Kilinc A, Giron A, Bouazizi K, Gueda Moussa M, Salem JE, Carrié A, Carreau V, Béliard S, Bittar R, Cluzel P, Bruckert E, Redheuil A, and Kachenoura N

Subjects
Adult, Case-Control Studies, Female, Fibrosis, Humans, Male, Middle Aged, Predictive Value of Tests, Prevalence, Prospective Studies, Hyperlipoproteinemia Type II diagnostic imaging, Magnetic Resonance Imaging, Cine methods, Myocardium pathology
Abstract

Background: Familial Hypercholesterolemia (FH) is an underdiagnosed condition with an increased cardiovascular risk. It is unknown whether lipid accumulation plays a role in structural myocardial changes. Cardiovascular Magnetic Resonance (CMR) is the reference technique for the morpho-functional evaluation of heart chambers through cine sequences and for myocardial tissue characterization through late gadolinium enhancement (LGE) and T1 mapping images. We aimed to assess the prevalence of myocardial fibrosis in FH patients., Methods: Seventy-two asymptomatic subjects with genetically confirmed FH (mean age 49·24, range 40 to 60 years) were prospectively recruited along with 31 controls without dyslipidaemia matched for age, sex, BMI, and other cardiovascular risk factors. All underwent CMR including cine, LGE, pre- and post-contrast T1 mapping. Extracellular volume (ECV) and enhancement rate of the myocardium (ERM = difference between pre- and post-contrast myocardial T1, normalized by pre-contrast myocardial T1) were calculated., Findings: Five FH patients and none of the controls had intramyocardial LGE (p= 0·188). While no changes in Native T1 and ECV were found, post-contrast T1 was significantly lower (430·6 ± 55ms vs. 476·1 ± 43ms, p<0·001) and ERM was higher (57·44± 5·99 % vs 53·04±4·88, p=0·005) in HeFH patients compared to controls. Moreover, low post-contrast T1 was independently associated with the presence of xanthoma (HR 5·221 [1·04-26·28], p= 0·045). A composite score combining the presence of LGE, high native T1 and high ERM (defined as ≥ mean ± 1·5 SD) was found in 20·8% of the HeFH patients vs. 0% in controls (p<0·000, after adjustment for main confounders)., Interpretation: CMR revealed early changes in myocardial tissue characteristics in HeFH patients, that should foster further work to better understand and prevent the underlying pathophysiological processes., Competing Interests: Declaration of Competing Interest AG declares having received honoraria from Akcea Therapeutics, AMGEN, Sanofi and Regeneron, Novartis, MSD; DR declares having received honoraria from AMGEN (Research Grant), Sanofi, Novartis, Roche, AMGEN, Daiichi Sankyo, MSD (Fees for lecture/consulting and travel grants); AC has received honoraria from Amgen SAS and Alexion Pharma France SAS, and is currently receiving a grant from Alexion Pharma France SAS; SB declares having received honoraria from Amgen, Sanofi; EB declares having received honoraria from, AstraZeneca, AMGEN, Genfit, MSD, Sanofi and Regeneron, Danone, Aegerion, Lilly, Ionis-pharmaceuticals. Remaining authors have nothing to disclose., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2021
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40. SAFEHEART risk-equation and cholesterol-year-score are powerful predictors of cardiovascular events in French patients with familial hypercholesterolemia.

Author

Gallo A, Charriere S, Vimont A, Chapman MJ, Angoulvant D, Boccara F, Cariou B, Carreau V, Carrié A, Bruckert E, and Béliard S

Subjects
Cholesterol, Cholesterol, LDL, Cohort Studies, Humans, Risk Assessment, Cardiovascular Diseases diagnosis, Cardiovascular Diseases epidemiology, Hyperlipoproteinemia Type II diagnosis, Hyperlipoproteinemia Type II epidemiology, Hyperlipoproteinemia Type II genetics
Abstract

Background and Aims: Patients with heterozygous familial hypercholesterolemia (HeFH) present elevated cardiovascular (CV) risk. Current CV risk stratification algorithms developed for the general population are not adapted for heFH patients. It is therefore of singular importance to develop and validate CV prediction tools, which are dedicated to the HeFH population., Methods: Our first objective was to validate the Spanish SAFEHEART-risk equation (RE) in the French HeFH cohort (REFERCHOL), and the second to compare SAFEHEART-RE with the low-density-lipoprotein-cholesterol (LDL-C)-year-score for the prediction of CV events in the HeFH French population., Results: We included HeFH (n = 1473) patients with a genetic or clinical diagnosis (DLCN score ≥8). Among them, 512 patients with a 5-year follow-up were included to validate the 5 year-CV-RE. A total of 152 events (10.3%) occurred in the entire population of 1473 patients during a mean follow-up of 3.9 years. Over the five-year follow-up, non-fatal CV events occurred in 103 patients (20.2%). Almost all the parameters used in the SAFEHEART-RE were confirmed as strong predictors of CV events in the REFERCHOL cohort. The C-statistic revealed a satisfactory performance of both the SAFEHEART-RE and LDL-C-year-scores in predicting CV events for all the patients (primary and secondary prevention) (C-index 0.77 and 0.70, respectively) as well as for those in primary prevention at inclusion (C-index 0.78 and 0.77, respectively)., Conclusions: This analysis represents the first external validation of the SAFEHEART-RE and demonstrated that both SAFEHEART-RE and the LDL-C-year-score are good predictors of CV events in primary prevention HeFH patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Published
2020
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41. Usefulness of the genetic risk score to identify phenocopies in families with familial hypercholesterolemia?

Author

Ghaleb Y, Elbitar S, El Khoury P, Bruckert E, Carreau V, Carrié A, Moulin P, Di-Filippo M, Charriere S, Iliozer H, Farnier M, Luc G, Rabès JP, Boileau C, Abifadel M, and Varret M

Subjects
Apolipoprotein B-100 genetics, Apolipoproteins E genetics, Humans, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Proprotein Convertase 9 genetics, Genetic Predisposition to Disease, Genetic Testing standards, Hypercholesterolemia genetics, Phenotype
Abstract

Familial hypercholesterolemia (FH) is caused by mutations in LDLR (low-density lipoprotein receptor), APOB (apolipoprotein B), PCSK9 (proprotein convertase subtilisin/kexin type 9), or APOE (apolipoprotein E) genes in approximately 80% of the cases. Polygenic forms of hypercholesterolemia may be present among patients clinically diagnosed with FH but with no identified mutation (FH mutation-negative (FH/M-)). To address whether polygenic forms may explain phenocopies in FH families, we calculated a 6-single-nucleotide polymorphism (SNP) genetic risk score (GRS) in all members from five French FH families where a mutation was identified (FH/M+) as well as some phenocopies (FH/M-). In two families, three FH/M- patients present a high GRS suggesting a polygenic hypercholesterolemia for these phenocopies. However, a high GRS is also observed in nine FH/M+ patients and in four unaffected relatives from three families. These observations indicate that the GRS does not seem to be a good diagnostic tool at the individual level. Nevertheless, the GRS seems to be a contributor of the severity of hypercholesterolemia since patients who cumulate a mutation and a high GRS exhibit higher low-density lipoprotein cholesterol levels when compared to patients with only FH (p = 0.054) or only polygenic hypercholesterolemia (p = 0.0039). In conclusion, the GRS can be used as a marker of the severity of hypercholesterolemia but does not seem to be a reliable tool to distinguish phenocopies within FH families.

Published
2018
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42. New Sequencing technologies help revealing unexpected mutations in Autosomal Dominant Hypercholesterolemia.

Author

Elbitar S, Susan-Resiga D, Ghaleb Y, El Khoury P, Peloso G, Stitziel N, Rabès JP, Carreau V, Hamelin J, Ben-Djoudi-Ouadda A, Bruckert E, Boileau C, Seidah NG, Varret M, and Abifadel M

Subjects
Apolipoproteins B genetics, Chromosome Segregation genetics, Family, Female, HEK293 Cells, Heterozygote, Humans, Male, Pedigree, Proprotein Convertase 9 genetics, High-Throughput Nucleotide Sequencing methods, Hyperlipoproteinemia Type II genetics, Mutation genetics
Abstract

Autosomal dominant hypercholesterolemia (ADH) is characterized by elevated LDL-C levels leading to coronary heart disease. Four genes are implicated in ADH: LDLR, APOB, PCSK9 and APOE. Our aim was to identify new mutations in known genes, or in new genes implicated in ADH. Thirteen French families with ADH were recruited and studied by exome sequencing after exclusion, in their probands, of mutations in the LDLR, PCSK9 and APOE genes and fragments of exons 26 and 29 of APOB gene. We identified in one family a p.Arg50Gln mutation in the APOB gene, which occurs in a region not usually associated with ADH. Segregation and in-silico analysis suggested that this mutation is disease causing in the family. We identified in another family with the p.Ala3396Thr mutation of APOB, one patient with a severe phenotype carrying also a mutation in PCSK9: p.Arg96Cys. This is the first compound heterozygote reported with a mutation in APOB and PCSK9. Functional studies proved that the p.Arg96Cys mutation leads to increased LDL receptor degradation. This work shows that Next-Generation Sequencing (exome, genome or targeted sequencing) are powerful tools to find new mutations and identify compound heterozygotes, which will lead to better diagnosis and treatment of ADH.

Published
2018
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43. Early coronary calcifications are related to cholesterol burden in heterozygous familial hypercholesterolemia.

Author

Gallo A, Giral P, Carrié A, Carreau V, Béliard S, Bittar R, Maranghi M, Arca M, Cluzel P, Redheuil A, Bruckert E, and Rosenbaum D

Subjects
Adult, Female, Humans, Hyperlipoproteinemia Type II genetics, Male, Middle Aged, Young Adult, Calcinosis complications, Cholesterol metabolism, Coronary Artery Disease complications, Heterozygote, Hyperlipoproteinemia Type II complications, Hyperlipoproteinemia Type II metabolism
Abstract

Background: The identification of high-risk patients with heterozygous familial hypercholesterolemia (HeFH) that may benefit from early treatment is challenging. Coronary Artery Calcification (CAC) score accounts for coronary atherosclerotic burden. It has proven its accuracy in cardiovascular risk assessment in the general population but data in HeFH are lacking., Objective: The aim of our study was to assess CAC prevalence and its relationship with lifelong cholesterol exposure, calculated by total cholesterol burden (TCB) in patients with HeFH., Methods: A total of 112 HeFH patients (50% males, median age 45 years) regularly followed-up since diagnosis were prospectively recruited at Pitié-Salpêtrière Hospital, Paris, France. CAC score was assessed using noncontrast multi-detector computed tomography. TCB was calculated as total cholesterol (TC) × age at diagnosis plus annually assessed TC., Results: The prevalence of CAC was 58%. Patients without CAC showed lower TCB than patients with CAC (298 ± 110 vs 417.9 ± 89 mmol-years/L, P < .001). Among patients aged <45 years (n = 56), 39% exhibited CAC and a higher TCB compared with patients without CAC (352 ± 71 vs 255 ± 88 mmol-years/L, P < .001) due to higher TC levels at diagnosis (10.2 ± 2 vs 8.7 ± 2 mmol/L, P = .01). Multivariate analysis indicated that TCB was independently associated to CAC., Conclusions: Asymptomatic HeFH subjects exhibit early coronary atherosclerosis directly associated with TCB burden. CAC score may be useful to identify higher risk HeFH patients who can benefit from earlier and more aggressive treatment., (Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Published
2017
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44. Long-term outcome in 53 patients with homozygous familial hypercholesterolaemia in a single centre in France.

Author

Bruckert E, Kalmykova O, Bittar R, Carreau V, Béliard S, Saheb S, Rosenbaum D, Bonnefont-Rousselot D, Thomas D, Emery C, Khoshnood B, and Carrié A

Subjects
Adolescent, Angina Pectoris genetics, Angina Pectoris prevention & control, Biomarkers blood, Cardiovascular Diseases genetics, Cardiovascular Diseases mortality, Child, Child, Preschool, DNA Mutational Analysis, Disease-Free Survival, Early Diagnosis, Female, France, Genetic Predisposition to Disease, Heredity, Humans, Hyperlipoproteinemia Type II blood, Hyperlipoproteinemia Type II genetics, Hyperlipoproteinemia Type II mortality, Infant, Infant, Newborn, Kaplan-Meier Estimate, Male, Myocardial Infarction genetics, Myocardial Infarction prevention & control, Pedigree, Phenotype, Predictive Value of Tests, Retrospective Studies, Risk Factors, Time Factors, Treatment Outcome, Anticholesteremic Agents therapeutic use, Blood Component Removal, Cardiovascular Diseases prevention & control, Cholesterol, LDL blood, Homozygote, Hyperlipoproteinemia Type II therapy, Mutation, Receptors, LDL genetics
Abstract

Background and Aims: Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited condition characterized by elevated plasma low-density lipoprotein-cholesterol (LDL-C) levels, severe, accelerated atherosclerosis and premature coronary heart disease. We evaluated cardiovascular complications in HoFH patients over extended follow-up and investigated their association with changes in cholesterol over time, as well as total cholesterol burden., Methods: In this retrospective single-centre study, 53 patients (baseline mean ± standard deviation [SD], total cholesterol 15.5 ± 3.7 mmol/L and LDL-C 13.2 ± 2.6 mmol/L) were followed for up to 38 years (21.2 ± 10 years). The primary outcome was an adverse clinical event, defined as cardiovascular death, nonfatal myocardial infarction, or angina., Results: Twenty-eight patients experienced an event, of whom 8 died due to complications of major surgery (4), myocardial infarction (3) or stroke (1). While total cholesterol levels were comparable in patients with and without an event at baseline (20 mmol/L), those who subsequently experienced an event showed a slower decline in total cholesterol. Cumulative total cholesterol (i.e. total-cholesterol year score) was highly associated with the incidence of an adverse clinical event in a linear dose-response relation. A 100 mmol/L increase in cumulative total cholesterol (i.e. an average exposure of 10 mmol/L per 10 years or 20 mmol/L per 5 years) was associated with a doubling of the risk of a cardiovascular event (age-adjusted incidence rate ratio: 1.99, 95% CI, 1.16-3.41)., Conclusions: Our findings reinforce the importance of early diagnosis and initiation of maximal treatment, including lipoprotein apheresis, to ensure long-term reduction in the cholesterol burden, expressed as the total-cholesterol year score, and risk of cardiovascular complications in HoFH., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Published
2017
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45. The very high cardiovascular risk in heterozygous familial hypercholesterolemia: Analysis of 734 French patients.

Author

Béliard S, Millier A, Carreau V, Carrié A, Moulin P, Fredenrich A, Farnier M, Luc G, Rosenbaum D, Toumi M, and Bruckert E

Subjects
Adult, Aged, Anticholesteremic Agents therapeutic use, Body Mass Index, Cardiovascular Diseases epidemiology, Carotid Arteries physiopathology, Cholesterol blood, Cholesterol, LDL blood, Cross-Sectional Studies, Female, France epidemiology, Humans, Hyperlipoproteinemia Type II complications, Hyperlipoproteinemia Type II drug therapy, Male, Middle Aged, Plaque, Atherosclerotic, Retrospective Studies, Risk Factors, Cardiovascular Diseases etiology, Hyperlipoproteinemia Type II pathology
Abstract

Background: Heterozygous familial hypercholesterolemia (heFH) is a genetic disease causing high levels of low-density lipoprotein cholesterol (LDL-C). Although this population is at high cardiovascular (CV) risk, the risk is variable within patients depending on additional risk factors. CV disease risk groups have been defined by the Nouvelle Société Francophone d'Athérosclérose (NSFA) and by the National Lipid Association recommendations., Objectives: The study aimed to describe a sample of French heFH patients, comparing patients at very high risk (VHR) and patients at high risk in terms of demographic and clinical characteristics as well as biological measurements and disease management., Methods: Cross-sectional retrospective analysis on 734 patients hospitalized after 2005 in 5 academic centers., Results: When considering NSFA classification, 550 (74.9%) patients belonged to the VHR group. Most patients in the VHR group presented more than 1 risk factor, the most prevalent ones being Lp(a) > 50 mg/dL and smoking. Patients in the VHR group were older (50.6 vs 45.0 years old, P = .0002), and presented a higher body mass index (25.5 kg/m(2) vs 23.3 kg/m(2), P < .0001). The proportion of patients with carotid arterial plaque was higher in the VHR group (59.8% vs 48.6%, P = .06). Total cholesterol (2.41 g/L on average) and LDL-C (1.65 g/L on average) were not found to be significantly different. Maximum level of lipid-lowering treatments were used in 34% of cases in the VHR group, significantly higher than 16% in the high-risk group (P = .001). Very similar results were found when using the National Lipid Association recommendations., Conclusion: This study provides a detailed description of French heFH patients according to their CV risk. Patients with very high CV risk had usually more advanced carotid plaques and were treated with heavier lipid-lowering drugs although their LDL-C level remained similar. This highlights the significant burden of this population., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Published
2016
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46. Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody.

Author

Hopkins PN, Defesche J, Fouchier SW, Bruckert E, Luc G, Cariou B, Sjouke B, Leren TP, Harada-Shiba M, Mabuchi H, Rabès JP, Carrié A, van Heyningen C, Carreau V, Farnier M, Teoh YP, Bourbon M, Kawashiri MA, Nohara A, Soran H, Marais AD, Tada H, Abifadel M, Boileau C, Chanu B, Katsuda S, Kishimoto I, Lambert G, Makino H, Miyamoto Y, Pichelin M, Yagi K, Yamagishi M, Zair Y, Mellis S, Yancopoulos GD, Stahl N, Mendoza J, Du Y, Hamon S, Krempf M, and Swergold GD

Subjects
Adolescent, Adult, Aged, Antibodies, Monoclonal, Humanized, Double-Blind Method, Female, Humans, Male, Middle Aged, Proprotein Convertase 9, Antibodies, Monoclonal administration & dosage, Cholesterol, LDL blood, Coronary Artery Disease blood, Coronary Artery Disease drug therapy, Coronary Artery Disease genetics, Hyperlipoproteinemia Type II blood, Hyperlipoproteinemia Type II drug therapy, Hyperlipoproteinemia Type II genetics, Mutation, Proprotein Convertases antagonists & inhibitors, Proprotein Convertases genetics, Proprotein Convertases metabolism, Serine Endopeptidases genetics, Serine Endopeptidases metabolism
Abstract

Background: Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic distribution are lacking. Furthermore, no randomized treatment study in this population has been reported., Methods and Results: We compiled clinical characteristics of PCSK9 GOF mutation carriers in a multinational retrospective, cross-sectional, observational study. We then performed a randomized placebo-phase, double-blind study of alirocumab 150 mg administered subcutaneously every 2 weeks to 13 patients representing 4 different PCSK9 GOF mutations with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL on their current lipid-lowering therapies at baseline. Observational study: among 164 patients, 16 different PCSK9 GOF mutations distributed throughout the gene were associated with varying severity of untreated LDL-C levels. Coronary artery disease was common (33%; average age of onset, 49.4 years), and untreated LDL-C concentrations were higher compared with matched carriers of mutations in the LDLR (n=2126) or apolipoprotein B (n=470) genes. Intervention study: in PCSK9 GOF mutation patients randomly assigned to receive alirocumab, mean percent reduction in LDL-C at 2 weeks was 62.5% (P<0.0001) from baseline, 53.7% compared with placebo-treated PCSK9 GOF mutation patients (P=0.0009; primary end point). After all subjects received 8 weeks of alirocumab treatment, LDL-C was reduced by 73% from baseline (P<0.0001)., Conclusions: PCSK9 GOF mutation carriers have elevated LDL-C levels and are at high risk of premature cardiovascular disease. Alirocumab, a PCSK9 antibody, markedly lowers LDL-C levels and seems to be well tolerated in these patients., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01604824., (© 2015 The Authors.)

Published
2015
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47. Identification and characterization of new gain-of-function mutations in the PCSK9 gene responsible for autosomal dominant hypercholesterolemia.

Author

Abifadel M, Guerin M, Benjannet S, Rabès JP, Le Goff W, Julia Z, Hamelin J, Carreau V, Varret M, Bruckert E, Tosolini L, Meilhac O, Couvert P, Bonnefont-Rousselot D, Chapman J, Carrié A, Michel JB, Prat A, Seidah NG, and Boileau C

Subjects
Apolipoproteins B genetics, Apolipoproteins B metabolism, Biomarkers blood, Cholesterol, HDL blood, DNA Mutational Analysis, Female, Genetic Predisposition to Disease, HEK293 Cells, Hep G2 Cells, Humans, Hyperlipoproteinemia Type II blood, Hyperlipoproteinemia Type II metabolism, Male, Paris, Pedigree, Phenotype, Proprotein Convertase 9, Proprotein Convertases metabolism, Receptors, LDL genetics, Receptors, LDL metabolism, Serine Endopeptidases metabolism, Transfection, Hyperlipoproteinemia Type II genetics, Mutation, Proprotein Convertases genetics, Serine Endopeptidases genetics
Abstract

Background: The identification of mutations in PCSK9 (proprotein convertase subtilisin kexin9) in autosomal dominant hypercholesterolemia (ADH), has revealed the existence of a new player in cholesterol homeostasis. PCSK9 has been shown to enhance the degradation of the LDL receptor (LDLR) at the cell surface. Gain-of-function mutations of PCSK9 induce ADH and are very rare, but their identification is crucial in studying PCSK9's role in hypercholesterolemia, its detailed trafficking pathway and its impact on the LDLR., Methods: In order to identify new mutations and understand the exact mechanisms of action of mutated PCSK9, PCSK9 was sequenced in 75 ADH patients with no mutations in the LDLR or APOB genes. Functional analyses in cell culture were conducted and the impact of novel PCSK9 mutations on the quantitative and qualitative features of lipoprotein particles and on the HDL-mediated cellular cholesterol efflux was studied., Results: Among these 75 ADH probands with no mutations in the LDLR or APOB genes, four gain-of-function mutations of PCSK9 were identified, of which two were novel: the p.Leu108Arg and the p.Asp35Tyr substitutions. In vitro studies of their consequences on the activity of PCSK9 on cell surface levels of LDLR showed that the p.Leu108Arg mutation clearly results in a gain-of-function, while the p.Asp35Tyr mutation created a novel Tyr-sulfation site, which may enhance the intracellular activity of PCSK9., Conclusion: These data further contribute to the characterization of PCSK9 mutations and to better understanding of the impact on cholesterol metabolism of this new therapeutic target., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Published
2012
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48. Long-term follow-up of statin treatment in a cohort of children with familial hypercholesterolemia: efficacy and tolerability.

Author

Carreau V, Girardet JP, and Bruckert E

Subjects
Adolescent, Child, Child, Preschool, Cohort Studies, Female, Follow-Up Studies, France, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects, Hyperlipoproteinemia Type II physiopathology, Male, Pravastatin adverse effects, Severity of Illness Index, Time Factors, Young Adult, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Hyperlipoproteinemia Type II drug therapy, Pravastatin therapeutic use
Abstract

Background: Early identification of children with familial hypercholesterolemia (FH) makes it possible to start lipid-lowering therapy at a young age in order to prevent cardiovascular disease. Numerous randomized, often placebo-controlled, studies have assessed the efficacy and safety of statins in children with FH., Objective: The aim of this pragmatic observational study was to evaluate pravastatin treatment efficacy and tolerability for a long period of time, and to assess how these results translate in 'real-life' clinical practice., Methods: We analyzed all medical files of young hypercholesterolemic patients referred to two specialized French centers. This population of 185 pravastatin-treated children with FH, with a mean baseline cholesterol level above 300 mg/dL, in most of whom genetic diagnosis was achieved, was followed-up for a mean duration of 2 years 2 months. The mean age for starting pravastatin was 11 years; in one of five children, treatment was started before the age of 8 years, mostly because of severe hypercholesterolemia or a family history of coronary heart disease., Results: A 16.9-19.2% decrease in total cholesterol level (21-24% for low-density lipoprotein cholesterol) was observed. Growth and puberty were not affected by statin treatment. A review of the medical files showed that 13% of children had side effects, most of which were minor; four of these children had muscular symptoms possibly related to the treatment. This frequency is lower than that observed in adults, and comparable to other studies in children., Conclusions: In this large cohort of FH children, the efficacy and tolerability of pravastatin therapy in real-life conditions was demonstrated to be similar to that in randomized controlled studies.

Published
2011
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49. Molecular spectrum of autosomal dominant hypercholesterolemia in France.

Author

Marduel M, Carrié A, Sassolas A, Devillers M, Carreau V, Di Filippo M, Erlich D, Abifadel M, Marques-Pinheiro A, Munnich A, Junien C, Boileau C, Varret M, and Rabès JP

Subjects
Apolipoproteins B genetics, Cholesterol blood, Cohort Studies, DNA Mutational Analysis, Female, France, Genetic Variation, Humans, Hyperlipoproteinemia Type II blood, Male, Proprotein Convertase 9, Proprotein Convertases, Receptors, LDL chemistry, Receptors, LDL genetics, Serine Endopeptidases genetics, Hyperlipoproteinemia Type II genetics, Mutation
Abstract

Autosomal Dominant Hypercholesterolemia (ADH), characterized by isolated elevation of plasmatic LDL cholesterol and premature cardiovascular complications, is associated with mutations in 3 major genes: LDLR (LDL receptor), APOB (apolipoprotein B) and PCSK9(proprotein convertase subtilisin-kexin type 9). Through the French ADH Research Network, we collected molecular data from 1358 French probands from eleven different regions in France.Mutations in the LDLR gene were identified in 1003 subjects representing 391 unique events with 46.0% missense, 14.6% frameshift, 13.6% splice, and 11.3% nonsense mutations, 9.7% major rearrangements, 3.8% small in frame deletions/insertions, and 1.0% UTR mutations. Interestingly,175 are novel mutational events and represent 45% of the unique events we identified, highlighting a specificity of the LDLR mutation spectrum in France. Furthermore, mutations in the APOB gene were identified in 89 probands and in the PCSK9 gene in 10 probands. Comparison of available clinical and biochemical data showed a gradient of severity for ADH-causing mutations:FH=PCSK9>FDB>«Others» genes. The respective contribution of each known gene to ADH inthis French cohort is: LDLR 73.9%, APOB 6.6%, PCSK9 0.7%. Finally, in 19.0% of the probands,no mutation was found, thus underscoring the existence of ADH mutations located in still unknown genes., (©2010 Wiley-Liss, Inc.)

Published
2010
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50. Hypothyroidism is not associated with increased carotid atherosclerosis when cardiovascular risk factors are accounted for in hyperlipidemic patients.

Author

Chiche F, Jublanc C, Coudert M, Carreau V, Kahn JF, and Bruckert E

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Case-Control Studies, Female, Humans, Male, Middle Aged, Multivariate Analysis, Risk Factors, Cardiovascular Diseases diagnosis, Carotid Artery Diseases complications, Hyperlipidemias complications, Hyperlipidemias drug therapy, Hypothyroidism complications
Abstract

Overt hypothyroidism is associated with an increased prevalence of cardiovascular heart disease (CHD). The role of subclinical hypothyroidism as risk factor for cardiovascular diseases is supported by recent meta-analysis. However it still remains to be established whether hypothyroidism favors atherosclerosis independently of its effects on cardiovascular risk factors, such as hypercholesterolemia or hypertension. To assess whether hypothyroidism might be a risk factor per se, we analyzed carotid lesions assessed by US examination in two large populations with similar risk factors and displaying hypo- or euthyroidism. We selected, among a population of patients referred for assessment of hyperlipidemia, 794 hypothyroid patients (TSH>4mU/L), and 1588 euthyroid patients matched for the main cardiovascular risk factors (age, gender, lipid levels, hypertension, diabetes, smoking habits and obesity). All the patients had evaluation of their arterial carotid plaques, and about half of them had measurement of carotid intima-media thickness (IMT). Our hypothyroid population included 90% of patients with normal FT4 levels (subclinical hypothyroidism). We found that neither prevalence nor severity of carotid plaques nor carotid IMT were significantly different between hypothyroid patients and controls. To assess whether thyroid hormones may predict carotid atherosclerosis, we performed multivariate regression analyses, and we showed that, in both populations of hypothyroid and euthyroid patients, neither the TSH values nor the FT4 concentrations were independent risk factors for carotid atherosclerosis. In conclusion, we showed that, among a population of hyperlipidemic patients, hypothyroidism is not associated with an increased risk for carotid atherosclerosis when cardiovascular risk factors are accounted for.

Published
2009
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