Author: "Etienne Khoury" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Etienne Khoury"' showing total 34 results

Start Over Author "Etienne Khoury"

34 results on '"Etienne Khoury"'

1. Discovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen

Author: Jenna Giubilaro, Doris A. Schuetz, Tomasz M. Stepniewski, Yoon Namkung, Etienne Khoury, Mónica Lara-Márquez, Shirley Campbell, Alexandre Beautrait, Sylvain Armando, Olivier Radresa, Jean Duchaine, Nathalie Lamarche-Vane, Audrey Claing, Jana Selent, Michel Bouvier, Anne Marinier, and Stéphane A. Laporte
Subjects: Science
Abstract: While Ras is a promising target for cancer therapy, development of inhibitors targeting Ras signaling has proven challenging. Here, the authors report the discovery of Rasarfin, a small molecule from a phenotypic screen on G protein-coupled receptor (GPCR) endocytosis that acts as a dual Ras and ARF6 inhibitor.
Published: 2021
Full Text: View/download PDF

2. A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling

Author: Alexandre Beautrait, Justine S. Paradis, Brandon Zimmerman, Jenna Giubilaro, Ljiljana Nikolajev, Sylvain Armando, Hiroyuki Kobayashi, Lama Yamani, Yoon Namkung, Franziska M. Heydenreich, Etienne Khoury, Martin Audet, Philippe P. Roux, Dmitry B. Veprintsev, Stéphane A. Laporte, and Michel Bouvier
Subjects: Science
Abstract: Beta-arrestins play central roles in the mechanisms regulating GPCR signalling and trafficking. Here the authors identify a selective inhibitor of the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP-2, which they use to dissect the role of the β-arrestin/β2-adaptin interaction in GPCR signalling.
Published: 2017
Full Text: View/download PDF

3. Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing.

Author: James S Floyd, Katarzyna M Bloch, Jennifer A Brody, Cyrielle Maroteau, Moneeza K Siddiqui, Richard Gregory, Daniel F Carr, Mariam Molokhia, Xiaoming Liu, Joshua C Bis, Ammar Ahmed, Xuan Liu, Pär Hallberg, Qun-Ying Yue, Patrik K E Magnusson, Diane Brisson, Kerri L Wiggins, Alanna C Morrison, Etienne Khoury, Paul McKeigue, Bruno H Stricker, Maryse Lapeyre-Mestre, Susan R Heckbert, Arlene M Gallagher, Hector Chinoy, Richard A Gibbs, Emmanuelle Bondon-Guitton, Russell Tracy, Eric Boerwinkle, Daniel Gaudet, Anita Conforti, Tjeerd van Staa, Colleen M Sitlani, Kenneth M Rice, Anke-Hilse Maitland-van der Zee, Mia Wadelius, Andrew P Morris, Munir Pirmohamed, Colin A N Palmer, Bruce M Psaty, Ana Alfirevic, and PREDICTION-ADR Consortium and EUDRAGENE
Subjects: Medicine, Science
Abstract: AimsStatin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM.Methods and resultsSRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance.ConclusionsIn this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.
Published: 2019
Full Text: View/download PDF

4. Monitoring G protein-coupled receptor and β-arrestin trafficking in live cells using enhanced bystander BRET

Author: Yoon Namkung, Christian Le Gouill, Viktoria Lukashova, Hiroyuki Kobayashi, Mireille Hogue, Etienne Khoury, Mideum Song, Michel Bouvier, and Stéphane A. Laporte
Subjects: Science
Abstract: Cellular signaling processes often involve trafficking of receptors and other proteins between subcellular compartments. Here the authors demonstrate a method based on the concept of Enhanced bystander Bioluminescence Resonance Energy Transfer (EbBRET) that allows efficient real time monitoring of endocytosis and trafficking.
Published: 2016
Full Text: View/download PDF

5. Correlation between chylomicronemia diagnosis scores and post-heparin lipoprotein lipase activity

Author: Diane Brisson, Miriam Larouche, Jasmine Chebli, Etienne Khoury, and Daniel Gaudet
Subjects: Clinical Biochemistry, General Medicine
Published: 2023

6. Lessons learned from the evinacumab trials in the treatment of homozygous familial hypercholesterolemia

Author: Etienne Khoury, Laurent Croteau, Alex Lauzière, and Daniel Gaudet
Subjects: Homozygous Familial Hypercholesterolemia, Angiopoietin-like Proteins, Receptors, LDL, Anticholesteremic Agents, Antibodies, Monoclonal, Humans, Molecular Medicine, lipids (amino acids, peptides, and proteins), Cholesterol, LDL, Cardiology and Cardiovascular Medicine, Angiopoietin-Like Protein 3
Abstract: Homozygous familial hypercholesterolemia (HoFH) is a life-threatening disease characterized by extremely elevated LDL cholesterol (LDL-C) levels which result in premature atherosclerotic cardiovascular disease. As conventional lipid-lowering therapies, which mainly depend on LDL receptors for LDL particle clearance, remain insufficient for reaching the recommended LDL-C levels in HoFH, agents acting independently of LDL receptors, such as ANGPTL3 inhibitors, constitute a promising target. Evinacumab, a monoclonal antibody directed against ANGPTL3, was approved in the USA in 2021 for treating patients with HoFH. Evinacumab has shown an adequate safety profile with strong LDL-lowering efficacy. This review highlights the development path of evinacumab and provides insight on the lessons learned from trials as well as the hurdles facing accessibility.Homozygous familial hypercholesterolemia (HoFH) is a life-threatening rare genetic disorder characterized by extremely elevated ‘bad’ cholesterol and resulting in heart disease at a young age. As the current treatments that tend to lower the levels of ‘bad’ cholesterol remain insufficient for treating patients with this disease, emerging agents, such as inhibitors of the protein ANGPTL3, follow different biological pathways than the ones targeted by the traditional therapies and constitute a promising target for HoFH. Evinacumab, which is highly selective for ANGPTL3 inhibition, was approved in the USA in 2021 for treating patients with HoFH. Evinacumab has been shown to be safe and well tolerated, with a strong effect on decreasing ‘bad’ cholesterol levels. This review highlights the development path of evinacumab and provides insight into the lessons learned from trials as well as the hurdles facing accessibility.
Published: 2022

7. Atherosclerotic plaque regression in homozygous familial hypercholesterolaemia: a case report of a long-term lipid-lowering therapy involving LDL-receptor-independent mechanisms

Author: Etienne Khoury, Alex Lauzière, Frederick J Raal, John Mancini, and Daniel Gaudet
Subjects: Cardiology and Cardiovascular Medicine
Abstract: Background Homozygous familial hypercholesterolaemia (HoFH) is a rare and life-threatening genetic disease characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels, important xanthomatosis and increased risk of premature atherosclerotic cardiovascular disease. Management of HoFH at an early stage is recommended but conventional lipid-lowering therapies (LLTs) dependent on the LDL-receptor for clearance of LDL particles, are usually not sufficient. However, agents acting independently of the LDL-receptor, such as inhibitors of microsomal triglyceride transfer protein (MTP) or angiopoietin-like protein 3 (ANGPTL3), administered in combination, on top of standard-of-care LLT constitute a promising therapy for HoFH. Case summary The present case describes a long-term (>10 years) follow-up of a 52-year-old woman with severe HoFH, who was treated with conventional lipid-lowering medications (i.e. statins and ezetimibe) for several years before experiencing the risks and benefits that were encountered with the use of LDL-receptor-independent agents (MTP and ANGPTL3 inhibitors). This combination therapy demonstrated a good long-term safety and efficacy profile, while continuous monitoring of hepatic enzymes (sometimes requiring dose adjustments) and fat accumulation is recommended when using lomitapide. Discussion Treating this HoFH patient with an LLT involving the combination of MTP and ANGPTL3 LDL-receptor-independent inhibitors (lomitapide and evinacumab, respectively) showed remarkable improvement in LDL-C levels, disappearance of xanthomatosis and regression in atherosclerotic plaques. In addition to safety and efficacy, one should question the affordability and access hurdle that emerging combination of expensive therapies might constitute in the future for the payers. These challenges could eventually limit the clinical use of those innovative treatments despite their clinical benefit.
Published: 2022

8. Lomitapide for treatment of homozygous familial hypercholesterolemia: The Québec experience

Author: Isabelle Ruel, Zubin Lahijanian, Daniel Gaudet, Alexandre M. Bélanger, Jacques Genest, Jean Bergeron, Alexis Baass, Etienne Khoury, Latifah Alothman, Diane Brisson, Patrick Couture, Sumayah Aljenedil, and Leslie Brown
Subjects: Adult, 0301 basic medicine, Canada, medicine.medical_specialty, Statin, medicine.drug_class, Familial hypercholesterolemia, Disease, 030204 cardiovascular system & hematology, Hyperlipoproteinemia Type II, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Ezetimibe, Internal medicine, Humans, Medicine, Retrospective Studies, business.industry, Anticholesteremic Agents, Homozygote, Quebec, Middle Aged, medicine.disease, Lomitapide, Discontinuation, 030104 developmental biology, chemistry, LDL apheresis, Benzimidazoles, Cardiology and Cardiovascular Medicine, business, medicine.drug, Lipidology
Abstract: Background and aims Homozygous familial hypercholesterolemia (HoFH) is an orphan disease, most often caused by bi-allelic mutations of the LDLR gene. Patients with HoFH have elevated LDL-C levels >13 mmol/L, tendinous xanthomata and severe, premature atherosclerotic cardiovascular disease (ASCVD). Untreated, most HoFH patients die of ASCVD in youth. New therapeutic modalities include lomitapide, an inhibitor of microsomal triglyceride transfer protein that lowers hepatic LDL-C production. We have recently identified 79 Canadian patients with HoFH. Here, we describe our experience with lomitapide in the province of Quebec, a geographic area known to have a high prevalence of HoFH. Methods This is a retrospective case series of 12 HoFH patients followed at three lipidology centers in the province of Quebec. Results Mean age of the patients was 44 ± 18 years; age at time of HoFH diagnosis ranged from 2 to 59 years. All patients were on a statin and ezetimibe 10 mg/day and five patients were treated with LDL apheresis. Treatment with lomitapide reduced LDL-C levels by 38% (intention-to-treat). Intolerable gastrointestinal side effects were observed in 3/12 patients and were the main reason for treatment discontinuation. Three patients tolerated lomitapide at doses ranging between 5 and 30 mg/day without major side effects. Downwards drug titration was necessary in the 6 remaining patients because of gastrointestinal side effects (n = 5) and elevated liver enzymes (n = 1), and 2 of them finally discontinued treatment. Conclusions Lomitapide may be used to further decrease LDL-C in HoFH patients; gastrointestinal side effects and hepatic toxicity may limit adherence.
Published: 2020

9. Identifying Markers of Cardiovascular Event-Free Survival in Familial Hypercholesterolemia

Author: Nathalie Roy, Gérald Tremblay, Etienne Khoury, Diane Brisson, and Daniel Gaudet
Subjects: medicine.medical_specialty, lcsh:Medicine, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Logistic regression, Article, 03 medical and health sciences, cardiovascular events, 0302 clinical medicine, Internal medicine, medicine, cardioprotective markers, 030212 general & internal medicine, Young adult, Adiponectin, familial hypercholesterolemia, business.industry, septuagenarians, lcsh:R, Autosomal dominant trait, General Medicine, Odds ratio, medicine.disease, Cohort, business, Lipoprotein
Abstract: Familial hypercholesterolemia (FH) is an autosomal dominant trait characterized by elevated low-density lipoprotein-cholesterol (LDL-C) concentrations appearing at birth and is associated with increased risk of premature atherosclerotic cardiovascular disease (CVD). However, in some cases, FH subjects over 70 years of age have surprisingly never experienced any CVD symptoms throughout their entire lives. The objective of this study consists of identifying biological and environmental markers acting as cardioprotective factors and associated with unexpected survival in FH. Upon age and reported cardiovascular events (CVE) stratification, we identified a total of 458 French&ndash, Canadian FH subjects with premature reported CVE, and 1297 young adults as well as 24 elderly subjects (&ge, 70 years) who have never reported CVE requiring hospitalization. Logistic regression models were used to depict cardioprotective markers among FH survivors (&ge, 70 years). Regression analyses of the FH cohort showed that female sex (odds ratio (OR) = 12.92 (4.23&ndash, 39.46), p &lt, 0.0001), high levels of high-density lipoprotein (HDL)-C (OR = 6.76 (2.43&ndash, 18.79), p = 0.0002) and elevated concentrations of adiponectin (OR = 71.40 (5.20&ndash, 980.47), p = 0.001) were significant contributory factors in reducing FH-related CVD risk. Notably, female (OR = 11.45 (1.25&ndash, 105.98), p = 0.031) and high HDL-C (OR = 9.78 (1.75&ndash, 54.67), p = 0.009) were shown to be significant covariates associated with survival in FH. Non-smoking (OR = 11.73 (4.36&ndash, 31.56), 0.0001) was also identified as an environmental factor associated with CVE-free survival. Based on this configured model of premature CVE occurrence, these results demonstrated that, beyond LDL-C levels, female sex, high HDL-C, elevated adiponectin and non-smoking are important markers that contribute to a reduced risk of CVD and CVE-free survival in FH.
Published: 2021

10. Influence of the LDL-Receptor Genotype on Statin Response in Heterozygous Familial Hypercholesterolemia: Insights From the Canadian FH Registry

Author: Jean Bergeron, Nathalie Laflamme, Brooke A. Kennedy, Patrick Couture, Jacques Genest, Alexis Baass, Lubomira Cermakova, Robert A. Hegele, Etienne Khoury, Daniel Gaudet, Gabrielle Roy, Jean-Philippe Drouin-Chartier, Liam R. Brunham, Isabelle Ruel, and Diane Brisson
Subjects: Male, medicine.medical_specialty, Canada, Heterozygote, Statin, Apolipoprotein B, medicine.drug_class, Familial hypercholesterolemia, Gastroenterology, Hyperlipoproteinemia Type II, Internal medicine, Genotype, medicine, Humans, Longitudinal Studies, biology, business.industry, nutritional and metabolic diseases, Cholesterol, LDL, Genetic Profile, Middle Aged, medicine.disease, Lipid Metabolism, Confidence interval, Pharmacogenomic Testing, Receptors, LDL, LDL receptor, HMG-CoA reductase, Mutation, biology.protein, lipids (amino acids, peptides, and proteins), Female, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiology and Cardiovascular Medicine, business, Body mass index
Abstract: Whether low-density lipoprotein (LDL) receptor (LDLR) residual activity influences the LDL-lowering effect of statins in heterozygous familial hypercholesterolemia (HeFH) remains unclear. The objective of this study was to investigate the relationship between the LDLR genotype and statin-induced LDL cholesterol (LDL-C) reductions in HeFH.A total of 615 individuals with HeFH (receptor-defective [RD] genotype: n = 226; receptor-negative [RN] genotype: n = 389) from 7 lipid clinics across Canada who initiated statin monotherapy were included in this retrospective longitudinal study. Statin-induced reductions in LDL-C among individuals with RD and RN genotypes were compared with the use of linear models.There were 334 women and 281 men with a mean untreated LDL-C concentrations of 6.97 ± 1.65 mmol/L. Untreated and on-statin LDL-C levels where higher among patients with an RN genotype: untreated: RN 7.24 (95% confidence interval [CI] 6.98-7.50) mmol/L vs RD 6.70 (95% CI 6.41-6.98) mmol/L (P = 0.0002); on-statin: RN 4.50 (95% CI 4.31-4.70) vs RD 4.05 (95% CI 3.84-4.26) mmol/L (P = 0.0004). After adjustments for age, sex, smoking status, untreated LDL-C concentrations, statin type and dose, as well as the clinic where the patients were treated, the LDL-C-lowering effect of statins was significantly weaker for individuals with an RN mutation than for individuals with an RD mutation: RN: -31.1% (95% CI -34.7% to -27.4) vs RD -36.5% (95% CI -40.4% to -32.6%); P0.0001. The LDLR genotype was the strongest nonmodifiable independent correlate of statin-induced LDL-C reductions (RThe LDLR genotype is significantly associated with statin-induced reductions in LDL-C concentrations in HeFH.
Published: 2021

11. Coronary Atheroma Regression From Infusions of Autologous Selectively Delipidated Preβ-HDL-Enriched Plasma in Homozygous Familial Hypercholesterolemia

Author: H. Bryan Brewer, Prediman K. Shah, Ernst J. Schaefer, Daniel Gaudet, Steven R. Jones, Brian B. Ghoshhajra, Etienne Khoury, Borek Foldyna, Ron Waksman, and Steven R. Sloan
Subjects: Adult, Male, medicine.medical_specialty, Computed Tomography Angiography, Coronary Artery Disease, Familial hypercholesterolemia, High-Density Lipoproteins, Pre-beta, Coronary Angiography, Hyperlipoproteinemia Type II, Plasma, Internal medicine, medicine, Humans, Preβ hdl, Infusions, Intravenous, business.industry, medicine.disease, Coronary Vessels, Plaque, Atherosclerotic, Lipoproteins, LDL, Treatment Outcome, Endocrinology, CORONARY ATHEROMA, Female, Cardiology and Cardiovascular Medicine, business
Published: 2020

12. Discovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen

Author: Jean Duchaine, Stéphane A. Laporte, Etienne Khoury, Alexandre Beautrait, Yoon Namkung, Michel Bouvier, Mónica Lara-Márquez, Tomasz Maciej Stepniewski, Doris A. Schuetz, Audrey Claing, Olivier Radresa, Sylvain Armando, Anne Marinier, Nathalie Lamarche-Vane, Jana Selent, Jenna Giubilaro, and Shirley Campbell
Subjects: MAPK/ERK pathway, Bioluminescence Resonance Energy Transfer Techniques, Science, media_common.quotation_subject, General Physics and Astronomy, Small G Protein, Hormone receptors, Molecular Dynamics Simulation, Endocytosis, General Biochemistry, Genetics and Molecular Biology, Article, Receptors, G-Protein-Coupled, Cell Line, Tumor, Drug Discovery, Humans, Enzyme Inhibitors, Receptor, Internalization, Protein kinase B, G protein-coupled receptor, media_common, Cell Proliferation, Multidisciplinary, Binding Sites, Chemistry, ADP-Ribosylation Factors, Receptor Protein-Tyrosine Kinases, General Chemistry, Angiotensin II, Cell biology, HEK293 Cells, ADP-Ribosylation Factor 6, Screening, ras Proteins, Signal Transduction
Abstract: Internalization and intracellular trafficking of G protein-coupled receptors (GPCRs) play pivotal roles in cell responsiveness. Dysregulation in receptor trafficking can lead to aberrant signaling and cell behavior. Here, using an endosomal BRET-based assay in a high-throughput screen with the prototypical GPCR angiotensin II type 1 receptor (AT1R), we sought to identify receptor trafficking inhibitors from a library of ~115,000 small molecules. We identified a novel dual Ras and ARF6 inhibitor, which we named Rasarfin, that blocks agonist-mediated internalization of AT1R and other GPCRs. Rasarfin also potently inhibits agonist-induced ERK1/2 signaling by GPCRs, and MAPK and Akt signaling by EGFR, as well as prevents cancer cell proliferation. In silico modeling and in vitro studies reveal a unique binding modality of Rasarfin within the SOS-binding domain of Ras. Our findings unveil a class of dual small G protein inhibitors for receptor trafficking and signaling, useful for the inhibition of oncogenic cellular responses., While Ras is a promising target for cancer therapy, development of inhibitors targeting Ras signaling has proven challenging. Here, the authors report the discovery of Rasarfin, a small molecule from a phenotypic screen on G protein-coupled receptor (GPCR) endocytosis that acts as a dual Ras and ARF6 inhibitor.
Published: 2021

13. Review of the long-term safety of lomitapide: a microsomal triglycerides transfer protein inhibitor for treating homozygous familial hypercholesterolemia

Author: Daniel Gaudet, Etienne Khoury, Gérald Tremblay, Nathalie Roy, and Diane Brisson
Subjects: medicine.medical_specialty, Time Factors, Lipid disorder, Proteinase inhibitor, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Hyperlipoproteinemia Type II, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Humans, Pharmacology (medical), business.industry, Anticholesteremic Agents, Cholesterol, LDL, General Medicine, medicine.disease, Lomitapide, Endocrinology, Receptors, LDL, chemistry, 030220 oncology & carcinogenesis, Blood Component Removal, Microsome, Benzimidazoles, lipids (amino acids, peptides, and proteins), Long term safety, Carrier Proteins, business
Abstract: Homozygous familial hypercholesterolemia (HoFH) is a rare and life-threatening lipid disorder characterized by extremely elevated low-density lipoprotein-cholesterol (LDL-C) concentrations and premature atherosclerotic cardiovascular disease (CVD). Conventional lipid-lowering agents remain insufficient in managing this disease, which emphasize the unmet medical need for potential therapies capable of lowering LDL-C and decreasing CVD risk in this patient population.Novel LDL receptor (LDLR) independent drugs have been recently approved or are in development for the treatment of HoFH, including lomitapide (Juxtapid®). This oral microsomal triglyceride transfer protein (MTP) inhibitor was approved in 2012 in several countries as an adjunct to a low-fat diet and other lipid-lowering drugs with or without LDL apheresis to treat patients with HoFH. This review summarizes key safety and efficacy data of lomitapide from clinical trials and 'real-life' experience.While lomitapide is an interesting therapy for treating HoFH, long-term safety, as well as cardiovascular outcome data, are yet to be provided. Precision medicine has recently contributed to the development of several agents designed to address the unmet medical need of HoFH. However, combining safety, efficacy, accessibility, and affordability in a single therapy constitutes very challenging individual and societal paradigms in HoFH treatment.
Published: 2019

14. 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., 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., 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., 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., 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

15. Discovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen

Author: Jenna Giubilaro, Doris Schuetz, Yoon Namkung, Etienne Khoury, Monica Marquez, Shirley Campbell, Alexandre Beautrait, Sylvain Armando, Olivier Radresa, Jean Duchaine, Nathalie Lamarche-Vane, Audrey Claing, Michel Bouvier, Anne Marinier, and Stéphane Laporte
Abstract: Internalization and intracellular trafficking of hormone receptors, like receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs), play pivotal roles in cell responsiveness homeostasis. Dysregulation in receptor trafficking can lead to aberrant signaling and cell behavior, prevalent in cancer. Here, using an endosomal BRET-based assay in a high-throughput screen with the prototypical GPCR angiotensin II type 1 receptor (AT1R), we sought to identify inhibitors of receptor trafficking from a library of ~115,000 small molecules. We identified a novel dual Ras and ARF6 inhibitor that blocks agonist-mediated internalization of AT1R and other GPCRs, which we named Rasarfin. Rasarfin also potently inhibited agonist-induced ERK1/2 signaling by GPCRs, and MAPK and Akt signaling by EGFR, as well as prevented cancer cell proliferation. In silico modeling and in vitro studies revealed a unique binding modality of Rasarfin within the SOS-binding domain of Ras. Our findings unveil a new class of dual small G protein inhibitors for receptor trafficking and signaling, useful for the inhibition of oncogenic cellular responses.
Published: 2020

16. Dissection of Clinical and Gene Expression Signatures of Familial versus Multifactorial Chylomicronemia

Author: Karine Tremblay, Etienne Khoury, Daniel Gaudet, and Diane Brisson
Subjects: 0301 basic medicine, medicine.medical_specialty, Apolipoprotein B, Endocrinology, Diabetes and Metabolism, 030204 cardiovascular system & hematology, lipoprotein lipase deficiency, 03 medical and health sciences, Lipoprotein lipase deficiency, 0302 clinical medicine, Internal medicine, Mole, Gene expression, medicine, biology, Receiver operating characteristic, business.industry, Brief Report, medicine.disease, 030104 developmental biology, Endocrinology, Postprandial, biology.protein, gene expression, Pancreatitis, lipids (amino acids, peptides, and proteins), business, Body mass index, AcademicSubjects/MED00250, chylomicronemia
Abstract: Familial chylomicronemia syndrome (FCS) is a rare disorder associated with chylomicronemia (CM) and an increased risk of pancreatitis. Most individuals with CM do not have FCS but exhibit multifactorial CM (MCM), which differs from FCS in terms of risk and disease management. This study aimed to investigate clinical and gene expression profiles of FCS and MCM patients. Anthropometrics, clinical, and biochemical variables were analyzed in 57 FCS and 353 MCM patients. Gene expression analyses were performed in a subsample of 19 FCS, 28 MCM, and 15 normolipidemic controls. Receiver operating characteristic (ROC) curve analyses were performed to analyze the capacity of variables to discriminate FCS from MCM. Sustained fasting triglycerides ≥20 mmol/L (>15 mmol/L with eruptive xanthomas), history of pancreatitis, poor response to fibrates, diagnosis of CM at childhood, body mass index
Published: 2020

17. Preclinical discovery and development of evolocumab for the treatment of hypercholesterolemia

Author: Diane Brisson, Daniel Gaudet, and Etienne Khoury
Subjects: animal structures, Cost-Benefit Analysis, Hypercholesterolemia, Familial hypercholesterolemia, Pharmacology, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, 0302 clinical medicine, Drug Development, Drug Discovery, medicine, Animals, Humans, 030304 developmental biology, Serine protease, 0303 health sciences, biology, Chemistry, PCSK9, Anticholesteremic Agents, fungi, PCSK9 Inhibitors, Subtilisin, Cholesterol, LDL, Proprotein convertase, medicine.disease, Atherosclerosis, Evolocumab, 030220 oncology & carcinogenesis, LDL receptor, biology.protein, Kexin, lipids (amino acids, peptides, and proteins)
Abstract: Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that binds and promotes the lysosomal degradation of the low-density lipoprotein receptors (LDLR). Upon its ...
Published: 2020

18. Familial hypercholesterolemia in Canada: Initial results from the FH Canada national registry

Author: Dianne Brisson, Gordon A. Francis, G.B. John Mancini, James M. Brophy, Jacques Genest, Etienne Khoury, Robert Dufour, Jean Bergeron, Robert A. Hegele, Alexis Baass, Patrick Couture, Lubomira Cermakova, Liam R. Brunham, Isabelle Ruel, and Daniel Gaudet
Subjects: Adult, Male, Canada, medicine.medical_specialty, Heredity, Serine Proteinase Inhibitors, Time Factors, Databases, Factual, Down-Regulation, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Risk Assessment, Hyperlipoproteinemia Type II, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Prevalence, Humans, Medicine, Genetic Predisposition to Disease, Registries, 030212 general & internal medicine, Imputation (statistics), Ldl cholesterol, business.industry, Anticholesteremic Agents, PCSK9 Inhibitors, Cholesterol, LDL, Middle Aged, medicine.disease, Pedigree, Phenotype, Treatment Outcome, Cardiovascular Diseases, Family medicine, Drug Therapy, Combination, Female, National registry, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, business, Biomarkers
Abstract: Background and aims Familial hypercholesterolemia (FH) is under-diagnosed and under-treated in most of the world, including Canada. National registries play a key role in identifying patients with FH, understanding gaps in care, and advancing the science of FH to better treat these patients. Methods FH Canada has established a national registry across 19 academic sites acting as “hubs” in Canada to increase awareness and access to standard-of-care therapies. Results To-date, more than 3000 patients with FH have been entered into a secure, web-based database. Early outcomes of this initiative include a greater understanding of treatment gaps for patients with FH in Canada, the development of a new, simplified Canadian definition of FH, and tools to aid in the diagnosis of FH, including imputation of baseline levels of LDL cholesterol. Conclusions As the national registry expands in size and scope, further learning will emerge with ultimate benefit for the diagnosis and treatment of FH in Canada.
Published: 2018

19. 4944The contribution of familial hypercholesterolemia (FH) to premature coronary artery disease decreased by 2-fold between 1998 and 2018 in a founder population with high prevalence of FH

Author: M. Barabas, G Tremblay, Diane Brisson, Etienne Khoury, S Bedard, Daniel Gaudet, and A. Lauziere
Subjects: medicine.medical_specialty, High prevalence, business.industry, Internal medicine, Cardiology, medicine, Premature coronary artery disease, Familial hypercholesterolemia, Cardiology and Cardiovascular Medicine, business, medicine.disease, Founder effect
Abstract: Background Familial hypercholesterolemia (FH) is an autosomal dominant trait associated with high risk of premature coronary artery disease (CAD). The worldwide prevalence of FH is estimated at 1:250 to 1:500. In certain populations, including French Canadians (FC), the prevalence is significantly higher however. From 1995 to 1998, FH contributed to 9.6% of angiographically proven CAD in a FC founder population, the burden being the highest in men aged Purpose To compare the burden of FH twenty years apart in FC patients hospitalized for CAD. Methods Lipid profiles, cardiovascular risk factors and FH status of 1,132 FC patients who were hospitalized for a CAD event and who consecutively attended the cardiovascular disease clinic in 2017 and 2018 were compared to those of 2,506 who consecutively presented angiographically proven CAD two decades ago. FH status was based on Simon Broome and FH Canada definitions. In 1998, all consenting CAD patients were also molecularly screened for the most prevalent FH causing mutations in FC. Comparisons between groups were performed using Chi-square and independent samples Student's t-test. Results Most patients in both cohorts were males (74.5% vs 73.9% in 1998 vs. 2018, respectively). At admission, mean LDL-C (± SD) was 3.99±1.67 in 1998 vs. 2.22±1.06 in 2018 (p5.0 mmol/L at admission compared to 4.2% in 2018. Definite FH was diagnosed in 9.6% of patients in the 1998 cohort compared to 4.7% in the 2018 cohort (p Conclusions Over a period of 20 years, in a founder population with a high prevalence of FH, the contribution of FH to hospitalizations for CAD decreased by 2-fold and affected patients now tend to be hospitalized at an older age than 2 decades ago. This suggests that early diagnosis and more effective management of FH in the last 2 decades have contributed to significantly decrease its burden. Acknowledgement/Funding ECOGENE-21, Amgen, Sanofi
Published: 2019

20. Palmar striated xanthomas expression beyond type III dysbetalipoproteinemia

Author: Nathalie Roy, Diane Brisson, Daniel Gaudet, and Etienne Khoury
Subjects: Pathology, medicine.medical_specialty, Expression (architecture), medicine, Biology, Cardiology and Cardiovascular Medicine
Published: 2020

21. Correlation between chylomicronemia diagnosis scores and post-heparin lipoprotein lipase activity

Author: Daniel Gaudet, Diane Brisson, and Etienne Khoury
Subjects: medicine.medical_specialty, Nutrition and Dietetics, Endocrinology, business.industry, Endocrinology, Diabetes and Metabolism, Internal medicine, Internal Medicine, Medicine, Heparin, Cardiology and Cardiovascular Medicine, business, Lipoprotein lipase activity, medicine.drug
Published: 2019

22. 5938Efficacy of evinacumab in homozygous familial hypercholesterolemia patients with null or non-null LDL-receptor mutations and on various background therapies

Author: G.K. Hovingh, Daniel Gaudet, Daniel A. Gipe, K.Y. Chyu, Robert Pordy, Marina Cuchel, Etienne Khoury, Kuo-Chen Chan, Z. Ahmad, William J. Sasiela, and Parth K. Shah
Subjects: medicine.medical_specialty, Endocrinology, business.industry, Internal medicine, Evinacumab, Null (mathematics), LDL receptor, Medicine, Familial hypercholesterolemia, Cardiology and Cardiovascular Medicine, business, medicine.disease
Published: 2017

23. A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling

Author: Philippe P. Roux, Sylvain Armando, Etienne Khoury, Alexandre Beautrait, Hiroyuki Kobayashi, Michel Bouvier, Justine S. Paradis, Brandon Zimmerman, Franziska M. Heydenreich, Yoon Namkung, Dmitry B. Veprintsev, Stéphane A. Laporte, Martin Audet, Lama Yamani, Jenna Giubilaro, and Ljiljana Nikolajev
Subjects: 0301 basic medicine, genetic structures, Science, media_common.quotation_subject, Endocytic cycle, General Physics and Astronomy, Endocytosis, Clathrin, Models, Biological, General Biochemistry, Genetics and Molecular Biology, Article, Receptors, G-Protein-Coupled, Small Molecule Libraries, 03 medical and health sciences, 0302 clinical medicine, Arrestin, Cyclic AMP, Animals, Humans, Adaptor Protein Complex beta Subunits, Internalization, Extracellular Signal-Regulated MAP Kinases, beta-Arrestins, media_common, G protein-coupled receptor, Multidisciplinary, biology, Chemistry, Beta-Arrestins, Cell Membrane, Clathrin-Coated Vesicles, General Chemistry, eye diseases, 3. Good health, Cell biology, Rats, Enzyme Activation, 030104 developmental biology, HEK293 Cells, biology.protein, sense organs, Signal transduction, 030217 neurology & neurosurgery, Protein Binding, Signal Transduction
Abstract: In addition to G protein-coupled receptor (GPCR) desensitization and endocytosis, β-arrestin recruitment to ligand-stimulated GPCRs promotes non-canonical signalling cascades. Distinguishing the respective contributions of β-arrestin recruitment to the receptor and β-arrestin-promoted endocytosis in propagating receptor signalling has been limited by the lack of selective analytical tools. Here, using a combination of virtual screening and cell-based assays, we have identified a small molecule that selectively inhibits the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP2 without interfering with the formation of receptor/β-arrestin complexes. This selective β-arrestin/β2-adaptin inhibitor (Barbadin) blocks agonist-promoted endocytosis of the prototypical β2-adrenergic (β2AR), V2-vasopressin (V2R) and angiotensin-II type-1 (AT1R) receptors, but does not affect β-arrestin-independent (transferrin) or AP2-independent (endothelin-A) receptor internalization. Interestingly, Barbadin fully blocks V2R-stimulated ERK1/2 activation and blunts cAMP accumulation promoted by both V2R and β2AR, supporting the concept of β-arrestin/AP2-dependent signalling for both G protein-dependent and -independent pathways., Beta-arrestins play central roles in the mechanisms regulating GPCR signalling and trafficking. Here the authors identify a selective inhibitor of the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP-2, which they use to dissect the role of the β-arrestin/β2-adaptin interaction in GPCR signalling.
Published: 2017

24. Free glycerol correlate with post-heparin lipoprotein lipase activity and contribute to differentiate familial vs. multifactorial chylomicronemia

Author: Daniel Gaudet, Diane Brisson, and Etienne Khoury
Subjects: medicine.medical_specialty, Free Glycerol, Nutrition and Dietetics, business.industry, Endocrinology, Diabetes and Metabolism, Heparin, Endocrinology, Internal medicine, Internal Medicine, medicine, Cardiology and Cardiovascular Medicine, business, Lipoprotein lipase activity, medicine.drug
Published: 2019

25. ANGPTL3 Inhibition in Homozygous Familial Hypercholesterolemia

Author: Zahid Ahmad, Jesper Gromada, Daniel Gaudet, Kuang Yuh Chyu, Poulabi Banerjee, Neil Stahl, Etienne Khoury, Viktoria Gusarova, Prediman K. Shah, Kuo Chen Chan, Daniel A. Gipe, Marina Cuchel, Diane Brisson, William J. Sasiela, G. Kees Hovingh, George D. Yancopoulos, and Robert Pordy
Subjects: 0301 basic medicine, medicine.medical_specialty, medicine.drug_class, Evinacumab, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Monoclonal antibody, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, ANGPTL3, Internal medicine, medicine, Receptor, biology, business.industry, Cholesterol, General Medicine, medicine.disease, 030104 developmental biology, Endocrinology, chemistry, biology.protein, lipids (amino acids, peptides, and proteins), Absolute Change, Antibody, business
Abstract: Evinacumab, a monoclonal antibody that blocks ANGPTL3, was administered to nine adults with homozygous familial hypercholesterolemia. At 4 weeks, LDL cholesterol was reduced by a mean of 49%, with a mean absolute change from baseline of −157 mg per deciliter.
Published: 2017

26. Safety and Efficacy of Evinacumab, A Monoclonal Antibody to ANGPTL3, In Homozygous Familial Hypercholesterolemia

Author: Etienne Khoury, Zahid Ahmad, William J. Sasiela, Kees Hovingh, Marina Cuchel, Kuang-Yuh Chyu, Daniel A. Gipe, Daniel Gaudet, Robert Pordy, Kuo-Chen Chan, and Prediman K. Shah
Subjects: Nutrition and Dietetics, business.industry, medicine.drug_class, Endocrinology, Diabetes and Metabolism, Evinacumab, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Monoclonal antibody, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, ANGPTL3, Immunology, Internal Medicine, Medicine, 030212 general & internal medicine, Cardiology and Cardiovascular Medicine, business
Published: 2017

27. Surviving Familial Hypercholesterolemia without Coronary Artery Disease: A Unique Phenomenon Associated with Newly Identified Biological and Genetic Markers

Author: Daniel Gaudet, Gérald Tremblay, Etienne Khoury, Nathalie Roy, and Diane Brisson
Subjects: Coronary artery disease, medicine.medical_specialty, Genetic marker, business.industry, Internal medicine, Internal Medicine, Cardiology, medicine, General Medicine, Familial hypercholesterolemia, Cardiology and Cardiovascular Medicine, medicine.disease, business
Published: 2018

28. Abstract 19911: Markers of Survival in Septuagenarians and Octogenarians With Heterozygous or Homozygous Familial Hypercholesterolemia

Author: Etienne Khoury, Karine Tremblay, Diane Brisson, Daniel Gaudet, and Gérald Tremblay
Subjects: medicine.medical_specialty, Cholesterol, business.industry, Autosomal dominant trait, Familial hypercholesterolemia, medicine.disease, chemistry.chemical_compound, Endocrinology, chemistry, Physiology (medical), Internal medicine, medicine, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, business, Lipoprotein
Abstract: Objective: Familial hypercholesterolemia (FH) is an autosomal dominant trait characterized by elevated low-density lipoprotein-cholesterol (LDL-C) concentrations appearing at birth and is associated with an increased risk of premature atherosclerotic cardiovascular disease (CAD). Some homozygous (Ho) FH subjects survive over 80 years of age and a proportion of heterozygous (He) FH subjects aged over 70 years have never experienced CAD symptoms. The objective of this study consists in identifying genetic, clinical and/or environmental factors associated with survival over 70 years in FH. Methods and Results: The familial analysis of 1,860 French-Canadian FH individuals carrying either the French-canadian Type 1 (15KB deletion) or the French-canadian Type 2, (W66G), which are both FH-causing mutations in the LDLR gene, was performed to identify HoFH and HeFH subjects over 70 years of age. Out of this number, we were able to list a total of 112 subjects (among which 2 HoFH aged 72 and 84 years with baseline cholesterol 18 and 21 mmol/L respectively). Multivariate regression analyses revealed that the gender, high-density lipoprotein-cholesterol (HDL-C) level, the proportion of LDL-C decrease under therapy and the type of mutation in the LDLR gene were significant contributory factors of survival over 80 years or of CAD-free survival over 70 years (p-value under 0.001). In these models, the contribution of HDL-C was independent from that of LDL-C reduction. Notably, HDL-C and gender were shown to be significant covariates of survival among HoFH relatives. Fine phenotyping and exome sequencing analyses are ongoing. Conclusion: Based on a monogenic model of high LDL-C and premature CAD, these results demonstrated that despite the reduction of LDL-C, several other covariates would probably constitute major targets for cardiovascular disease (CVD) risk management.
Published: 2015

29. Safety and efficacy of evinacumab, a monoclonal antibody to ANGPTL3, in patients with homozygous familial hypercholesterolemia: A single-arm, open-label, proof-of-concept study

Author: Kuo-Chen Chan, Daniel A. Gipe, Robert Pordy, William J. Sasiela, Daniel Gaudet, and Etienne Khoury
Subjects: Oncology, medicine.medical_specialty, medicine.drug_class, business.industry, Evinacumab, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, medicine.disease, Monoclonal antibody, 03 medical and health sciences, 0302 clinical medicine, Proof of concept, ANGPTL3, Internal medicine, medicine, In patient, 030212 general & internal medicine, Open label, Cardiology and Cardiovascular Medicine, business
Published: 2016

30. Safety and efficacy of evinacumab, a monoclonal antibody to ANGPTL3, in patients with homozygous familial hypercholesterolemia: a single-arm, open-label, proof-of-concept study

Author: Daniel Gaudet, Daniel Gipe, Kees Hovingh, Zahid Ahmad, Marina Cuchel, Prediman Shah, Kuang -Yuh Chyu, Robert Pordy, William Sasiela, Kuo -Chen Chan, and Etienne Khoury
Subjects: Cardiology and Cardiovascular Medicine
Published: 2017

31. Differential regulation of endosomal GPCR/β-arrestin complexes and trafficking by MAPK

Author: Stéphane A. Laporte, May Simaan, Etienne Khoury, Yoon Namkung, and Ljiljana Nikolajev
Subjects: Receptor recycling, Cell signaling, genetic structures, Endosome, Arrestins, Molecular Sequence Data, Endosomes, Biology, Biochemistry, Beta-Arrestin-2, Receptors, G-Protein-Coupled, Chlorocebus aethiops, Arrestin, Animals, Humans, Amino Acid Sequence, Molecular Biology, beta-Arrestins, G protein-coupled receptor, Sequence Homology, Amino Acid, Beta-Arrestins, Cell Biology, beta-Arrestin 2, eye diseases, Endocytosis, Cell biology, Rats, Protein Transport, HEK293 Cells, beta-Arrestin 1, COS Cells, sense organs, Signal transduction, Mitogen-Activated Protein Kinases, hormones, hormone substitutes, and hormone antagonists, Signal Transduction
Abstract: β-Arrestins are signaling adaptors that bind to agonist-occupied G protein-coupled receptors (GPCRs) and target them for endocytosis; however, the mechanisms regulating receptor/β-arrestin complexes and trafficking in endosomes, remain ill defined. Here we show, in live cells, differential dynamic regulation of endosomal bradykinin B2 receptor (B2R) complexes with either β-arrestin-1 or -2. We find a novel role for MAPK in the B2R/β-arrestin-2 complex formation, receptor trafficking and signaling mediated by an ERK1/2 regulatory motif in the hinge domain of the rat β-arrestin-2 (PET(178)P), but not rat β-arrestin-1 (PER(177)P). While the ERK1/2 regulatory motif is conserved between rat and mouse β-arrestin-2, it is surprisingly not conserved in human β-arrestin-2 (PEK(178)P). However, mutation of lysine 178 to threonine is sufficient to confer MAPK sensitivity to the human β-arrestin-2. Furthermore, substitution for a phosphomimetic residue in both the rat and the human β-arrestin-2 (T/K178D) significantly stabilizes B2R/β-arrestin complexes in endosomes, delays receptor recycling to the plasma membrane and maintains intracellular MAPK signaling. Similarly, the endosomal trafficking of β2-adrenergic, angiotensin II type 1 and vasopressin V2 receptors was altered by the β-arrestin-2 T178D mutant. Our findings unveil a novel subtype specific mode of MAPK-dependent regulation of β-arrestins in intracellular trafficking and signaling of GPCRs, and suggest differential endosomal receptor/β-arrestin-2 signaling roles among species.
Published: 2014

32. Allosteric and Biased G Protein-Coupled Receptor Signaling Regulation: Potentials for New Therapeutics

Author: Stéphane A. Laporte, Etienne Khoury, and Stéphanie Clément
Subjects: GTPase-activating protein, G protein, Endocrinology, Diabetes and Metabolism, Allosteric regulation, Review Article, Pharmacology, Biology, lcsh:Diseases of the endocrine glands. Clinical endocrinology, 03 medical and health sciences, Endocrinology, 0302 clinical medicine, G protein-coupled receptors, Functional selectivity, Receptor domains, Binding site, Receptor, biased signaling, 030304 developmental biology, G protein-coupled receptor, allosterism, 0303 health sciences, lcsh:RC648-665, G Protein-Coupled Receptor Signaling, Cell biology, functional selectivity, 030217 neurology & neurosurgery
Abstract: G protein-coupled receptors (GPCRs) are seven plasma membrane (PM)-spanning proteins that participate in many aspects of the endocrine function and are important targets for drug development. They transduce signals mainly, but not exclusively, via hetero-trimeric G proteins, leading to a diversity of intracellular signaling cascades. Ligands binding at the hormone orthosteric sites of receptors have been classified as agonists, antagonists and/or inverse agonists based on their ability to mainly modulate G protein signaling. Accumulating evidence also indicates that such ligands, alone or in combination with other ones such as those acting outside of the orthosteric hormone binding sites (e.g. allosteric modulators), have the ability to selectively engage subsets of signaling responses as compared to the natural endogenous ligands. Such modes of functioning have been variously referred to as “functional selectivity” or “ligand-biased signaling”. In this review, we provide an overview of the current knowledge regarding GPCR biased signaling and their functional regulation with a focus on the evolving concept that receptor domains can also be targeted to allosterically bias signaling, and discuss the usefulness of such modes of regulation for the design of more efficient therapeutics.
Published: 2014

33. Environmental and Biological Markers of Survival in Septuagenarians and Octogenarians Carrying FH-Causing LDLR Gene Mutations*

Author: Daniel Gaudet, Diane Brisson, Gérald Tremblay, Karine Tremblay, Etienne Khoury, and Nathalie Roy
Subjects: Genetics, Nutrition and Dietetics, Endocrinology, Diabetes and Metabolism, Ldlr gene, Internal Medicine, Biology, Cardiology and Cardiovascular Medicine
Published: 2016

34. Biasing the prostaglandin F2α receptor responses toward EGFR-dependent transactivation of MAPK

Author: Brandon Zimmerman, Terence E. Hébert, Sahar M. Jaffal, Veronica Wisehart, Eugénie Goupil, Stéphane A. Laporte, and Etienne Khoury
Subjects: MAPK/ERK pathway, medicine.medical_specialty, Arrestins, MAP Kinase Signaling System, Receptors, Prostaglandin, Biology, Dinoprost, Tropomyosin receptor kinase C, Transactivation, Endocrinology, Growth factor receptor, Internal medicine, medicine, Enzyme-linked receptor, Humans, 5-HT5A receptor, Extracellular Signal-Regulated MAP Kinases, Molecular Biology, Protein Kinase C, beta-Arrestins, Insulin-like growth factor 1 receptor, Cell Proliferation, Original Research, Beta-Arrestins, General Medicine, Cell biology, ErbB Receptors, HEK293 Cells, Inositol, Protein Binding
Abstract: The G protein-coupled prostaglandin F2α (PGF2α) receptor [F prostanoid (FP) receptor] has been implicated in many physiological events including cardiovascular, respiratory, immune, reproductive, and endocrine responses. Binding of PGF2α to FP receptor elicits inositol production and protein kinase C-dependent MAPK activation through Gαq coupling. Here we report that AL-8810, previously characterized as an orthosteric antagonist of PGF2α-dependent, Gαq-mediated signaling, potently activates ERK1/2 in a protein kinase C-independent manner. Rather, AL-8810 promoted ERK1/2 activation via an epidermal growth factor receptor transactivation mechanism in both human embryonic kidney 293 cells and in the MG-63 osteoblast-like cells, which express endogenous FP receptors. Neither AL-8810- nor PGF2α-mediated stimulation of FP receptor promoted association with β-arrestins, suggesting that MAPK activation induced by these ligands is independent of β-arrestin's signaling scaffold functions. Interestingly, the spatiotemporal activation of ERK1/2 promoted by AL-8810 and PGF2α showed almost completely opposite responses in the nucleus and the cytosol. Finally, using [3H]thymidine incorporation, we noted differential regulation of PGF2α- and AL-8810-induced cell proliferation in MG-63 cells. This study reveals, for the first time, the signaling biased nature of FP receptor orthosteric ligands toward MAPK signaling. Our findings on the specific patterns of ERK1/2 activation promoted by FP receptor ligands may help dissect the distinct roles of MAPK in FP receptor-dependent physiological responses.
Published: 2012

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources

Refine your results

34 results on '"Etienne Khoury"'

1. Discovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen

2. A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling

3. Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing.

4. Monitoring G protein-coupled receptor and β-arrestin trafficking in live cells using enhanced bystander BRET

5. Correlation between chylomicronemia diagnosis scores and post-heparin lipoprotein lipase activity

6. Lessons learned from the evinacumab trials in the treatment of homozygous familial hypercholesterolemia

7. Atherosclerotic plaque regression in homozygous familial hypercholesterolaemia: a case report of a long-term lipid-lowering therapy involving LDL-receptor-independent mechanisms

8. Lomitapide for treatment of homozygous familial hypercholesterolemia: The Québec experience

9. Identifying Markers of Cardiovascular Event-Free Survival in Familial Hypercholesterolemia

10. Influence of the LDL-Receptor Genotype on Statin Response in Heterozygous Familial Hypercholesterolemia: Insights From the Canadian FH Registry

11. Coronary Atheroma Regression From Infusions of Autologous Selectively Delipidated Preβ-HDL-Enriched Plasma in Homozygous Familial Hypercholesterolemia

12. Discovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen

13. Review of the long-term safety of lomitapide: a microsomal triglycerides transfer protein inhibitor for treating homozygous familial hypercholesterolemia

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

15. Discovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen

16. Dissection of Clinical and Gene Expression Signatures of Familial versus Multifactorial Chylomicronemia

17. Preclinical discovery and development of evolocumab for the treatment of hypercholesterolemia

18. Familial hypercholesterolemia in Canada: Initial results from the FH Canada national registry

19. 4944The contribution of familial hypercholesterolemia (FH) to premature coronary artery disease decreased by 2-fold between 1998 and 2018 in a founder population with high prevalence of FH

20. Palmar striated xanthomas expression beyond type III dysbetalipoproteinemia

21. Correlation between chylomicronemia diagnosis scores and post-heparin lipoprotein lipase activity

22. 5938Efficacy of evinacumab in homozygous familial hypercholesterolemia patients with null or non-null LDL-receptor mutations and on various background therapies

23. A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling

24. Free glycerol correlate with post-heparin lipoprotein lipase activity and contribute to differentiate familial vs. multifactorial chylomicronemia

25. ANGPTL3 Inhibition in Homozygous Familial Hypercholesterolemia

26. Safety and Efficacy of Evinacumab, A Monoclonal Antibody to ANGPTL3, In Homozygous Familial Hypercholesterolemia

27. Surviving Familial Hypercholesterolemia without Coronary Artery Disease: A Unique Phenomenon Associated with Newly Identified Biological and Genetic Markers

28. Abstract 19911: Markers of Survival in Septuagenarians and Octogenarians With Heterozygous or Homozygous Familial Hypercholesterolemia

29. Safety and efficacy of evinacumab, a monoclonal antibody to ANGPTL3, in patients with homozygous familial hypercholesterolemia: A single-arm, open-label, proof-of-concept study

30. Safety and efficacy of evinacumab, a monoclonal antibody to ANGPTL3, in patients with homozygous familial hypercholesterolemia: a single-arm, open-label, proof-of-concept study

31. Differential regulation of endosomal GPCR/β-arrestin complexes and trafficking by MAPK

32. Allosteric and Biased G Protein-Coupled Receptor Signaling Regulation: Potentials for New Therapeutics

33. Environmental and Biological Markers of Survival in Septuagenarians and Octogenarians Carrying FH-Causing LDLR Gene Mutations*

34. Biasing the prostaglandin F2α receptor responses toward EGFR-dependent transactivation of MAPK

Catalog

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Database

Publisher

34 results on '"Etienne Khoury"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources