166 results on '"Angelo B. Cefalù"'
Search Results
2. Withdrawal: Lipase maturation factor 1 is required for endothelial lipase activity
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Osnat Ben-Zeev, Maryam Hosseini, Ching-Mei Lai, Nicole Ehrhardt, Howard Wong, Angelo B. Cefalù, Davide Noto, Maurizio R. Averna, Mark H. Doolittle, and Miklós Péterfy
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Biochemistry ,QD415-436 - Published
- 2019
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3. Clinical characteristics and plasma lipids in subjects with familial combined hypolipidemia: a pooled analysis[S]
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Ilenia Minicocci, Sara Santini, Vito Cantisani, Nathan Stitziel, Sekar Kathiresan, Juan Antonio Arroyo, Gertrudis Martí, Livia Pisciotta, Davide Noto, Angelo B. Cefalù, Marianna Maranghi, Giancarlo Labbadia, Giovanni Pigna, Fabio Pannozzo, Fabrizio Ceci, Ester Ciociola, Stefano Bertolini, Sebastiano Calandra, Patrizia Tarugi, Maurizio Averna, and Marcello Arca
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ANGPTL3 mutations ,angiopoietin-like 3 ,cardiovascular disease ,fatty liver ,diabetes mellitus ,Biochemistry ,QD415-436 - Abstract
Angiopoietin-like 3 (ANGPTL3) regulates lipoprotein metabolism by modulating extracellular lipases. Loss-of function mutations in ANGPTL3 gene cause familial combined hypolipidemia (FHBL2). The mode of inheritance and hepatic and vascular consequences of FHBL2 have not been fully elucidated. To get further insights on these aspects, we reevaluated the clinical and the biochemical characteristics of all reported cases of FHBL2. One hundred fifteen FHBL2 individuals carrying 13 different mutations in the ANGPTL3 gene (14 homozygotes, 8 compound heterozygotes, and 93 heterozygotes) and 402 controls were considered. Carriers of two mutant alleles had undetectable plasma levels of ANGPTL3 protein, whereas heterozygotes showed a reduction ranging from 34% to 88%, according to genotype. Compared with controls, homozygotes as well as heterozygotes showed a significant reduction of all plasma lipoproteins, while no difference in lipoprotein(a) [Lp(a)] levels was detected between groups. The prevalence of fatty liver was not different in FHBL2 subjects compared with controls. Notably, diabetes mellitus and cardiovascular disease were absent among homozygotes. FHBL2 trait is inherited in a codominant manner, and the lipid-lowering effect of two ANGPTL3 mutant alleles was more than four times larger than that of one mutant allele. No changes in Lp(a) were detected in FHBL2. Furthermore, our analysis confirmed that FHBL2 is not associated with adverse clinical sequelae. The possibility that FHBL2 confers lower risk of diabetes and cardiovascular disease warrants more detailed investigation.
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- 2013
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4. Lipase maturation factor 1 is required for endothelial lipase activity[S]
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Osnat Ben-Zeev, Maryam Hosseini, Ching-Mei Lai, Nicole Ehrhardt, Howard Wong, Angelo B. Cefalù, Davide Noto, Maurizio R. Averna, Mark H. Doolittle, and Miklós Péterfy
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combined lipase deficiency ,endoplasmic reticulum ,hepatic ,metabolism ,phospholipases ,Biochemistry ,QD415-436 - Abstract
Lipase maturation factor 1 (Lmf1) is an endoplasmic reticulum (ER) membrane protein involved in the posttranslational folding and/or assembly of lipoprotein lipase (LPL) and hepatic lipase (HL) into active enzymes. Mutations in Lmf1 are associated with diminished LPL and HL activities (“combined lipase deficiency”) and result in severe hypertriglyceridemia in mice as well as in human subjects. Here, we investigate whether endothelial lipase (EL) also requires Lmf1 to attain enzymatic activity. We demonstrate that cells harboring a (cld) loss-of-function mutation in the Lmf1 gene are unable to generate active EL, but they regain this capacity after reconstitution with the Lmf1 wild type. Furthermore, we show that cellular EL copurifies with Lmf1, indicating their physical interaction in the ER. Finally, we determined that post-heparin phospholipase activity in a patient with the LMF1W464X mutation is reduced by more than 95% compared with that in controls. Thus, our study indicates that EL is critically dependent on Lmf1 for its maturation in the ER and demonstrates that Lmf1 is a required factor for all three vascular lipases, LPL, HL, and EL.
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- 2011
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5. Identification of a novel mutation of MTP gene in a patient with abetalipoproteinemia
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Mehri Najafi Sani, Mozhgan Sabbaghian, Fatemeh Mahjoob, Angelo B. Cefalù, Maurizio R. Averna, and Nima Rezaei
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Abetalipoproteinemia. ,ApoB-containing lipoproteins. ,Hypocholesterolemia. ,MTP gene mutations. ,Specialties of internal medicine ,RC581-951 - Abstract
Abetalipoproteinemia (ABL), or Bassen-Kornzweig syndrome, is a rare autosomal recessive disorder of lipoprotein metabolism, characterized by fat malabsorption, hypocholesterolemia retinitis pigmentosa, progressive neuropathy and acanthocytosis from early infancy. We describe the clinical and molecular characterization of a 6-month-old infant born of consanguineous, apparently healthy parents from Iran. The patient was hospitalized because of failure to thrive, greasy stool and vomiting. The patient's serum lipid profile, the clinical phenotype and the duodenal histology suggested the clinical diagnosis of ABL. The MTP gene analysis by direct sequencing revealed a novel homozygous mutation (c.1586 A > G-H529R). The parents were heterozygotes for the same mutation and interestingly the father showed a lipid profile characterized by a slight reduction of total and LDL-cholesterol plasma levels.
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- 2011
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6. Novel LDL-cholesterol lowering therapies: A step forward a personalized medicine
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Maurizio Averna, Angelo B. Cefalù, Averna, Maurizio, and Cefalu, Angelo Baldassare
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Internal Medicine ,LDL, personalized medicine - Published
- 2023
7. Lp(a): a genetic cause of clinical FH in children
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Maurizio R Averna, Angelo B Cefalù, Averna, Maurizio, and Cefalu', Angelo B
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Children ,Settore MED/09 - Medicina Interna ,Lp(a) ,Familial Hypercholesterolemia ,Cardiology and Cardiovascular Medicine - Abstract
No abstract available
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- 2022
8. Circulating Molecular Chaperones in Subjects with Amnestic Mild Cognitive Impairment and Alzheimer’s Disease: Data from the Zabùt Aging Project
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Giulia Accardi, Everly Conway de Macario, Alberto J.L. Macario, Antonella Marino Gammazza, Roberta Baschi, Angelo B. Cefalù, Vincenzo Restivo, Roberto Monastero, Francesco Cappello, Celeste Caruso Bavisotto, Marino Gammazza, Antonella, Restivo, Vincenzo, Baschi, Roberta, Caruso Bavisotto, Celeste, Cefalù, Angelo B, Accardi, Giulia, Conway de Macario, Everly, Macario, Alberto J L, Cappello, Francesco, and Monastero, Roberto
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0301 basic medicine ,Oncology ,Aging ,medicine.medical_specialty ,Settore MED/09 - Medicina Interna ,Hsp90 ,Disease ,Neuropsychological Tests ,medicine.disease_cause ,Hsp70 ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,Internal medicine ,Epidemiology ,oxidative stress ,Humans ,Medicine ,Dementia ,Cognitive Dysfunction ,Prospective Studies ,Pathological ,Tissue homeostasis ,cognitive impairment ,Settore MED/04 - Patologia Generale ,business.industry ,General Neuroscience ,Neurodegeneration ,neurodegeneration ,General Medicine ,molecular chaperone ,Hsp60 ,medicine.disease ,Psychiatry and Mental health ,Clinical Psychology ,030104 developmental biology ,Settore MED/26 - Neurologia ,Geriatrics and Gerontology ,business ,Alzheimer’s disease ,030217 neurology & neurosurgery ,Oxidative stress ,Molecular Chaperones ,Cohort study - Abstract
Molecular chaperones play essential roles in many processes such as cell differentiation, tissue homeostasis, and organ remodeling. Recent data indicate that chaperones can act as cytoprotectants for brain cells during the progression of neurodegenerative diseases, including Alzheimer’s disease (AD). However, very few data on the levels of chaperones in dementia, including its prodromal phases, have been reported. In this study, we used biological samples and epidemiological data collected during the Zabùt Aging Project (a prospective, community-based, cohort study of normal/pathological aging conducted in Sicily, Italy, with a follow-up of ten years) to determine if there is an association between plasma levels of the chaperones Hsp60, Hsp70, and Hsp90 with amnestic mild cognitive impairment (aMCI) and AD. Twenty-six aMCI individuals, 26 AD and 26 controls, matched for age and sex, were enrolled. After adjustment for education, subjects with AD showed significantly higher levels of Hsp60 than aMCI (OR = 1.16, 95% CI 1.04–1.30) and controls (OR = 1.12, 95% CI 1.03–1.22), while Hsp70 was significantly higher only in AD (OR = 1.84, 95% CI 1.09–3.10) than controls. In contrast, circulating levels of Hsp90 were significantly diminished in aMCI (OR = 0.69, 95% CI 0.52–0.91) and AD (OR = 0.51, 95% CI 0.35–0.75) compared to controls. However, these results were no longer significant after adjustment for multiple comparisons. Although the results lost significance after adjustment for multiple comparisons, they are encouraging despite the smallness of the sample and new studies should be carried out with larger populations to determine to what extent sequential measurement of serum chaperones in aMCI and AD can be trusted as indicators of disease status and progression.
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- 2022
9. Diagnosis of familial hypercholesterolemia in a large cohort of Italian genotyped hypercholesterolemic patients
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Davide Noto, Rossella Spina, Antonina Giammanco, Carlo M. Barbagallo, Antonina Ganci, Chiara Scrimali, Federica Brucato, Gabriella Misiano, Marcello Ciaccio, Rosalia Caldarella, Angelo B. Cefalù, Maurizio Averna, Noto, Davide, Spina, Rossella, Giammanco, Antonina, Barbagallo, Carlo M, Ganci, Antonina, Scrimali, Chiara, Brucato, Federica, Misiano, Gabriella, Ciaccio, Marcello, Caldarella, Rosalia, Cefalù, Angelo Baldassare, and Averna, Maurizio
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Cohort Studies ,Hyperlipoproteinemia Type II ,Heterozygote ,Settore MED/09 - Medicina Interna ,Settore BIO/12 - Biochimica Clinica E Biologia Molecolare Clinica ,Genetic ,Predictive scores ,Familial hypercholesterolemia ,Humans ,Cholesterol, LDL ,Lipid ,Cardiology and Cardiovascular Medicine ,Retrospective Studies - Abstract
Background and aims: Familial hypercholesterolemia (FH) is the most relevant genetic cause of early cardiovascular disease (CVD). FH is suspected when low density lipoprotein cholesterol (LDL-C) levels exceed the 95th percentile of the population distribution. Different diagnostic scoring systems have been developed, as the Dutch Lipid Clinic Network (DLCN) score, used worldwide. The aim of the study is to describe the characteristics of FH patients of a large cohort of more than eight hundred genotyped subjects enrolled in an Italian Lipid Clinic, and evaluate the DLCN score performance applied retrospectively to the case study. Methods: 836 hypercholesterolemic patients with LDL-C > 4.88mmol/L were genotyped for FH causative gene variants in the LDLR, PCSK and APOB genes. Relatives of mutated patients were also analyzed by cascade screening. Results: Gene variant carriers were younger, presented higher LDL-C and DLCN score and lower HDL-C levels in comparison with hypercholesterolemic (HC) non-carriers and presented a five-fold higher prevalence of previous CV events. Carotid US data available in 490 subjects showed that variant carriers had an odds ratio of 3.66 (1.43-10.24) for atherosclerotic plaques in comparison with non-carriers. Scoring system were evaluated by ROC analysis in 203 subjects without missing DLCN items and with available pre-therapy LDL-C levels, and LDL-C levels (A.U.C.=0.737) resulted to be more performing than the DLCN score (A.U.C.=0.662), even including carotid US data (A.U.C.=0.641) in a modified DLCN score version. Conclusions: the DLCN score failed to demonstrate a clear superiority in predicting FH gene variants in comparison with the measure of LDL-C levels in a retrospective case study.
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- 2022
10. APOC-III: a Gatekeeper in Controlling Triglyceride Metabolism
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Antonina Giammanco, Rossella Spina, Angelo B. Cefalù, Maurizio Averna, Giammanco, Antonina, Spina, Rossella, Cefalu', Angelo B, and Averna, Maurizio
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Cardiovascular disease burden ,Post prandial lipemia ,Triglyceride-rich lipoproteins (TRLs) ,Cardiology and Cardiovascular Medicine ,ApoC-III - Abstract
Purpose of Review Apolipoprotein C-III (ApoC-III) is a widely known player in triglyceride metabolism, and it has been recently recognized as a polyhedric factor which may regulate several pathways beyond lipid metabolism by influencing cardiovascular, metabolic, and neurological disease risk. This review summarizes the different functions of ApoC-III and underlines the recent findings related to its multifaceted pathophysiological role. Recent Findings The role of ApoC-III has been implicated in HDL metabolism and in the development of atherosclerosis, inflammation, and ER stress in endothelial cells. ApoC-III has been recently considered an important player in insulin resistance mechanisms, lipodystrophy, diabetic dyslipidemia, and postprandial hypertriglyceridemia (PPT). The emerging evidence of the involvement of ApoC-III in the in the pathogenesis of Alzheimer’s disease open the way to further study if modification of ApoC-III level slows disease progression. Furthermore, ApoC-III is clearly linked to cardiovascular disease (CVD) risk, and progression of coronary artery disease (CAD) as well as the calcification of aortic valve and recent clinical trials has pointed out the inhibition of ApoC-III as a promising approach to manage hypertriglyceridemia and prevent CVD. Summary Several evidences highlight the role of ApoC-III not only in triglyceride metabolism but also in several cardio-metabolic pathways. Results from recent clinical trials underline that the inhibition of ApoC-III is a promising therapeutical strategy for the management of severe hypertriglyceridemia and in CVD prevention.
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- 2023
11. Efficacy and safety of lomitapide in familial chylomicronaemia syndrome
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Angelo B. Cefalù, Laura D'Erasmo, Gabriella Iannuzzo, Davide Noto, Antonina Giammanco, Anna Montali, Alberto Zambon, Francesco Forte, Patrizia Suppressa, Stefano Giannini, Carlo M. Barbagallo, Antonina Ganci, Emilio Nardi, Federica Vernuccio, Rosalia Caldarella, Marcello Ciaccio, Marcello Arca, Maurizio Averna, Cefalu', Angelo Baldassare, D'Erasmo, Laura, Iannuzzo, Gabriella, Noto, Davide, Giammanco, Antonina, Montali, Anna, Zambon, Alberto, Forte, Francesco, Suppressa, Patrizia, Giannini, Stefano, Barbagallo, Carlo M, Ganci, Antonina, Nardi, Emilio, Vernuccio, Federica, Caldarella, Rosalia, Ciaccio, Marcello, Arca, Marcello, Averna, Maurizio, and Cefalù, Angelo B
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Adult ,Pancreatiti ,Settore MED/09 - Medicina Interna ,Triglyceride ,Benzimidazole ,Lomitapide ,Abdominal Pain ,Pancreatitis ,Hyperlipoproteinemia Type I ,Humans ,Benzimidazoles ,Cardiology and Cardiovascular Medicine ,Triglycerides ,Familial chylomicronaemia syndrome ,Human - Abstract
Familial chylomicronaemia syndrome (FCS) is a rare autosomal recessive disorder, resulting in elevated triglycerides (TGs), abdominal pain and pancreatitis. Treatment options are limited. Lomitapide, a microsomal triglyceride transfer protein inhibitor, is approved for the treatment of homozygous familial hypercholesterolaemia. Whether its therapeutic use may be extended to FCS remains unknown. The aim of this study was to evaluate the efficacy and safety of lomitapide in adult patients with FCS.The open-label, single-arm 'LOCHNES' study of lomitapide in FCS enrolled patients18 years with genetically confirmed FCS, elevated fasting TG ≥ 750 mg/dL and history of pancreatitis. Patients were administered lomitapide to the maximum tolerated dose for 26 weeks. The primary endpoint was the percent change in TGs from baseline to Week 26.Eighteen patients were enrolled with median baseline TG levels 1803.5 mg/dL (97.5% CI, 1452-2391 mg/dL). At Week 26, median fasting TGs were reduced to 305 mg/dL (97.5% CI 219-801 mg/dL; 70.5% reduction); median lomitapide dose was 35 mg/day; 13 patients achieved TGs ≤750 mg/dL. Adverse events were mild to moderate and mainly related to gastrointestinal tolerability. Liver imaging at baseline and Week 26 revealed hepatic fat increases from median 12.0%-32.5%, while median hepatic stiffness remained normal. No patient experienced acute pancreatitis or severe abdominal pain during lomitapide treatment.Lomitapide is effective and well tolerated in reducing TGs in FCS patients with a history of pancreatitis. Larger studies are warranted to determine lomitapide effectiveness in FCS.
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- 2022
12. rs629301 CELSR2 polymorphism confers a ten-year equivalent risk of critical stenosis assessed by coronary angiography
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G.I. Altieri, Marco Caruso, Oliviero Olivieri, Filippo M. Sarullo, V. Ingrassia, F. Brucato, Nicola Martinelli, Vincenzo Pernice, Rossella Spina, Carlo M. Barbagallo, C. Scrimali, Domenico Girelli, Francesca Fayer, Gabriella Misiano, Angelo B. Cefalù, Maurizio Averna, Antonina Giammanco, Davide Noto, Salvatore Novo, Noto D., Cefalu A.B., Martinelli N., Giammanco A., Spina R., Barbagallo C.M., Caruso M., Novo S., Sarullo F., Pernice V., Brucato F., Ingrassia V., Fayer F., Altieri G.I., Scrimali C., Misiano G., Olivieri O., Girelli D., and Averna M.
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Male ,Apolipoprotein E ,Time Factors ,Apolipoprotein B ,Coronary Stenosi ,Endocrinology, Diabetes and Metabolism ,Medicine (miscellaneous) ,Genome-wide association study ,030204 cardiovascular system & hematology ,Coronary Angiography ,Coronary artery disease ,Severity of Illness Index ,Gastroenterology ,0302 clinical medicine ,Risk Factors ,Genotype ,Age Factor ,Nutrition and Dietetics ,biology ,Gene polymorphism ,Age Factors ,Single Nucleotide ,Lipid ,Middle Aged ,Cadherins ,Prognosis ,Lipids ,Apolipoprotein ,Phenotype ,Italy ,Female ,lipids (amino acids, peptides, and proteins) ,Cardiology and Cardiovascular Medicine ,medicine.medical_specialty ,030209 endocrinology & metabolism ,Risk Assessment ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Predictive Value of Tests ,Intensive care ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Polymorphism ,Genetic Association Studies ,Aged ,business.industry ,Coronary Stenosis ,Biomarker ,Odds ratio ,medicine.disease ,Sortilin ,Apolipoproteins ,biology.protein ,business ,Biomarkers - Abstract
Background and aims Novel genetic determinants associated with coronary artery disease (CAD) have been discovered by genome wide association studies. Variants encompassing the CELSR2- PSRC1-SORT1 gene cluster have been associated with CAD. This study is aimed to investigate the rs629301 polymorphism association with the extent of CAD evaluated by coronary angiography (CAG), and to evaluate its associations with an extensive panel of lipid and lipoprotein measurements in a large Italian cohort of 2429 patients. Methods and results The patients were collected by four Intensive Care Units located in Palermo and Verona (Italy). Clinical Records were filed, blood samples were collected, lipids and apolipoproteins (apo) were measured in separate laboratories. CAD was defined by the presence of stenotic arteries (>50% lumen diameter) by CAG. The presence of CAD was associated with the rs629301 genotype. Patients with CAD were 78% and 73% (p = 0.007) of the T/T vs. T/G + G/G genotype carriers respectively. T/T genotype was also correlated with the number of stenotic arteries, with a 1.29 (1.04–1.61) risk to have a three-arteries disease. T/T genotype correlated with higher levels of LDL-, non-HDL cholesterol, apoB, apoE and apoCIII, and lower HDL-cholesterol. Logistic Regression confirmed that rs629301was associated with CAD independently from the common risk factors, with a risk similar to that conferred by ten years of age [odds ratios were 1.43 (1.04–1.96) and 1.39 (1.22–1.58) respectively]. Conclusions rs629301 risk allele was independently associated with the extension and severity of CAD and positively with apoE and apoB containing lipoproteins.
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- 2021
13. Worldwide experience of homozygous familial hypercholesterolaemia:retrospective cohort study
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Tycho R Tromp, Merel L Hartgers, G Kees Hovingh, Antonio J Vallejo-Vaz, Kausik K Ray, Handrean Soran, Tomas Freiberger, Stefano Bertolini, Mariko Harada-Shiba, Dirk J Blom, Frederick J Raal, Marina Cuchel, Tycho R. Tromp, Merel L. Hartgers, G. Kees Hovingh, Antonio J. Vallejo-Vaz, Kausik K. Ray, Stefano A. Bertolini, Jing Pang, Gerald F. Watts, Susanne Greber-Platzer, Martin Mäser, Thomas M. Stulnig, Christoph F. Ebenbichler, Khalid Bin Thani, David Cassiman, Olivier S. Descamps, Daisy Rymen, Peter Witters, Raul D. Santos, Liam R. Brunham, Gordon A. Francis, Jacques Genest, Robert A. Hegele, Brooke A. Kennedy, Isabelle Ruel, Mark H. Sherman, Long Jiang, Luya Wang, Željko Reiner, Vladimir Blaha, Richard Ceska, Jana Dvorakova, Lubomir Dlouhy, Pavel Horak, Vladimir Soska, Lukas Tichy, Robin Urbanek, Helena Vaverkova, Michal Vrablik, Stanislav Zemek, Lukas Zlatohlavek, Sameh Emil, Tarek Naguib, Ashraf Reda, Sophie Béliard, Eric Bruckert, Antonio Gallo, Moses S. Elisaf, Genovefa Kolovou, Hofit Cohen, Ronen Durst, Eldad J. Dann, Avishay Elis, Osama Hussein, Eran Leitersdorf, Daniel Schurr, Nitika Setia, Ishwar C. Verma, Mohammed D. Alareedh, Mutaz Al-Khnifsawi, Ali F. Abdalsahib Al-Zamili, Sabah H. Rhadi, Foaad K. Shaghee, Marcello Arca, Maurizio Averna, Andrea Bartuli, Marco Bucci, Paola S. Buonuomo, Paolo Calabrò, Sebastiano Calandra, Manuela Casula, Alberico L. Catapano, Angelo B. Cefalù, Arrigo F.G. Cicero, Sergio D'Addato, Laura D'Erasmo, Alessia Di Costanzo, Tommaso Fasano, Marta Gazzotti, Antonina Giammanco, Gabriella Iannuzzo, Anastasia Ibba, Emanuele A. Negri, Andrea Pasta, Chiara Pavanello, Livia Pisciotta, Claudio Rabacchi, Carlo Ripoli, Tiziana Sampietro, Francesco Sbrana, Fulvio Sileo, Patrizia Suppressa, Patrizia Tarugi, Chiara Trenti, Maria G. Zenti, Mika Hori, Mahmoud H. Ayesh, Sami T. Azar, Fadi F. Bitar, Akl C. Fahed, Elie M. Moubarak, Georges Nemer, Hapizah M. Nawawi, Ramón Madriz, Roopa Mehta, Arjen J. Cupido, Joep C. Defesche, M. Doortje Reijman, Jeanine E. Roeters-van Lennep, Erik S.G. Stroes, Albert Wiegman, Linda Zuurbier, Khalid Al-Waili, Fouzia Sadiq, Krzysztof Chlebus, Mafalda Bourbon, Isabel M. Gaspar, Katarina S. Lalic, Marat V. Ezhov, Andrey V. Susekov, Urh Groselj, Min-Ji Charng, Weerapan Khovidhunkit, Melih Aktan, Bulent B. Altunkeser, Sinan Demircioglu, Melis Kose, Cumali Gokce, Osman Ilhan, Meral Kayikcioglu, Leyla G. Kaynar, Irfan Kuku, Erdal Kurtoglu, Harika Okutan, Osman I. Ozcebe, Zafer Pekkolay, Saim Sag, Osman Z. Salcioglu, Ahmet Temizhan, Mustafa Yenercag, Mehmet Yilmaz, Hamiyet Yilmaz Yasar, Olena Mitchenko, Alexander R.M. Lyons, Christophe A.T. Stevens, Julie A. Brothers, Lisa C. Hudgins, Christina Nguyen, Rano Alieva, Aleksandr Shek, Doan-Loi Do, Ngoc-Thanh Kim, Hong-An Le, Thanh-Tung Le, Mai-Ngoc T. Nguyen, Thanh-Huong Truong, Dirk J. Blom, Frederick J. Raal, VU University medical center, Tromp T.R., Hartgers M.L., Hovingh G.K., Vallejo-Vaz A.J., Ray K.K., Soran H., Freiberger T., Bertolini S., Harada-Shiba M., Blom D.J., Raal F.J., Cuchel M., Bertolini S.A., Pang J., Watts G.F., Greber-Platzer S., Maser M., Stulnig T.M., Ebenbichler C.F., Bin Thani K., Cassiman D., Descamps O.S., Rymen D., Witters P., Santos R.D., Brunham L.R., Francis G.A., Genest J., Hegele R.A., Kennedy B.A., Ruel I., Sherman M.H., Jiang L., Wang L., Reiner Z., Blaha V., Ceska R., Dvorakova J., Dlouhy L., Horak P., Soska V., Tichy L., Urbanek R., Vaverkova H., Vrablik M., Zemek S., Zlatohlavek L., Emil S., Naguib T., Reda A., Beliard S., Bruckert E., Gallo A., Elisaf M.S., Kolovou G., Cohen H., Durst R., Dann E.J., Elis A., Hussein O., Leitersdorf E., Schurr D., Setia N., Verma I.C., Alareedh M.D., Al-Khnifsawi M., Abdalsahib Al-Zamili A.F., Rhadi S.H., Shaghee F.K., Arca M., Averna M., Bartuli A., Bucci M., Buonuomo P.S., Calabro P., Calandra S., Casula M., Catapano A.L., Cefalu A.B., Cicero A.F.G., D'Addato S., D'Erasmo L., Di Costanzo A., Fasano T., Gazzotti M., Giammanco A., Iannuzzo G., Ibba A., Negri E.A., Pasta A., Pavanello C., Pisciotta L., Rabacchi C., Ripoli C., Sampietro T., Sbrana F., Sileo F., Suppressa P., Tarugi P., Trenti C., Zenti M.G., Hori M., Ayesh M.H., Azar S.T., Bitar F.F., Fahed A.C., Moubarak E.M., Nemer G., Nawawi H.M., Madriz R., Mehta R., Cupido A.J., Defesche J.C., Reijman M.D., Roeters-van Lennep J.E., Stroes E.S.G., Wiegman A., Zuurbier L., Al-Waili K., Sadiq F., Chlebus K., Bourbon M., Gaspar I.M., Lalic K.S., Ezhov M.V., Susekov A.V., Groselj U., Charng M.-J., Khovidhunkit W., Aktan M., Altunkeser B.B., Demircioglu S., Kose M., Gokce C., Ilhan O., Kayikcioglu M., Kaynar L.G., Kuku I., Kurtoglu E., Okutan H., Ozcebe O.I., Pekkolay Z., Sag S., Salcioglu O.Z., Temizhan A., Yenercag M., Yilmaz M., Yilmaz Yasar H., Mitchenko O., Lyons A.R.M., Stevens C.A.T., Brothers J.A., Hudgins L.C., Nguyen C., Alieva R., Shek A., Do D.-L., Kim N.-T., Le H.-A., Le T.-T., Nguyen M.-N.T., Truong T.-H., University of Amsterdam, University of Pennsylvania, European Atherosclerosis Society, Experimental Vascular Medicine, Graduate School, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, Human Genetics, Paediatric Metabolic Diseases, ACS - Diabetes & metabolism, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ACS - Heart failure & arrhythmias, R Tromp, Tycho, L Hartgers, Merel, Kees Hovingh, G, J Vallejo-Vaz, Antonio, K Ray, Kausik, Soran, Handrean, Freiberger, Toma, A Bertolini, Stefano, Harada-Shiba, Mariko, Pang, Jing, F Watts, Gerald, Greber-Platzer, Susanne, Mäser, Martin, M Stulnig, Thoma, F Ebenbichler, Christoph, Bin Thani, Khalid, Cassiman, David, S Descamps, Olivier, Rymen, Daisy, Witters, Peter, D Santos, Raul, R Brunham, Liam, A Francis, Gordon, Genest, Jacque, A Hegele, Robert, A Kennedy, Brooke, Ruel, Isabelle, H Sherman, Mark, Jiang, Long, Wang, Luya, Reiner, Željko, Blaha, Vladimir, Ceska, Richard, Dvorakova, Jana, Dlouhy, Lubomir, Horak, Pavel, Soska, Vladimir, Tichy, Luka, Urbanek, Robin, Vaverkova, Helena, Vrablik, Michal, Zemek, Stanislav, Zlatohlavek, Luka, Emil, Sameh, Naguib, Tarek, Reda, Ashraf, Béliard, Sophie, Bruckert, Eric, Gallo, Antonio, S Elisaf, Mose, Kolovou, Genovefa, Cohen, Hofit, Durst, Ronen, J Dann, Eldad, Elis, Avishay, Hussein, Osama, Leitersdorf, Eran, Schurr, Daniel, Setia, Nitika, C Verma, Ishwar, D Alareedh, Mohammed, Al-Khnifsawi, Mutaz, F Abdalsahib Al-Zamili, Ali, H Rhadi, Sabah, K Shaghee, Foaad, Arca, Marcello, Averna, Maurizio, Bartuli, Andrea, Bucci, Marco, S Buonuomo, Paola, Calabrò, Paolo, Calandra, Sebastiano, Casula, Manuela, L Catapano, Alberico, B Cefalù, Angelo, G Cicero, Arrigo F, D'Addato, Sergio, D'Erasmo, Laura, Di Costanzo, Alessia, Fasano, Tommaso, Gazzotti, Marta, Giammanco, Antonina, Iannuzzo, Gabriella, Ibba, Anastasia, A Negri, Emanuele, Pasta, Andrea, Pavanello, Chiara, Pisciotta, Livia, Rabacchi, Claudio, Ripoli, Carlo, Sampietro, Tiziana, Sbrana, Francesco, Sileo, Fulvio, Suppressa, Patrizia, Tarugi, Patrizia, Trenti, Chiara, G Zenti, Maria, Hori, Mika, H Ayesh, Mahmoud, T Azar, Sami, F Bitar, Fadi, C Fahed, Akl, M Moubarak, Elie, Nemer, George, M Nawawi, Hapizah, Madriz, Ramón, Mehta, Roopa, J Cupido, Arjen, C Defesche, Joep, Doortje Reijman, M, E Roeters-van Lennep, Jeanine, G Stroes, Erik S, Wiegman, Albert, Zuurbier, Linda, Al-Waili, Khalid, Sadiq, Fouzia, Chlebus, Krzysztof, Bourbon, Mafalda, M Gaspar, Isabel, S Lalic, Katarina, V Ezhov, Marat, V Susekov, Andrey, Groselj, Urh, Charng, Min-Ji, Khovidhunkit, Weerapan, Aktan, Melih, B Altunkeser, Bulent, Demircioglu, Sinan, Kose, Meli, Gokce, Cumali, Ilhan, Osman, Kayikcioglu, Meral, G Kaynar, Leyla, Kuku, Irfan, Kurtoglu, Erdal, Okutan, Harika, I Ozcebe, Osman, Pekkolay, Zafer, Sag, Saim, Z Salcioglu, Osman, Temizhan, Ahmet, Yenercag, Mustafa, Yilmaz, Mehmet, Yilmaz Yasar, Hamiyet, Mitchenko, Olena, M Lyons, Alexander R, T Stevens, Christophe A, A Brothers, Julie, C Hudgins, Lisa, Nguyen, Christina, Alieva, Rano, Shek, Aleksandr, Do, Doan-Loi, Kim, Ngoc-Thanh, Le, Hong-An, Le, Thanh-Tung, T Nguyen, Mai-Ngoc, Truong, Thanh-Huong, J Blom, Dirk, J Raal, Frederick, and Cuchel, Marina
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Adult ,Male ,Homozygous Familial Hypercholesterolemia ,Adolescent ,retrospective study ,CHILDREN ,Doenças Cardio e Cérebro-vasculares ,Cohort Studies ,Young Adult ,Medicine, General & Internal ,General & Internal Medicine ,Cardiovascular Disease ,Humans ,Registries ,LIPOPROTEIN-APHERESIS ,Child ,11 Medical and Health Sciences ,Retrospective Studies ,Homozygous Familial Hypercholesterolaemia International Clinical Collaborators ,Science & Technology ,GUIDANCE ,clinical characteristic ,EVOLOCUMAB ,Homozygous familial hypercholesterolemia ,Worldwide ,Therapies ,Cardiovascular disease ,General Medicine ,CARE ,OPEN-LABEL ,EFFICACY ,INSIGHTS ,Child, Preschool ,outcome ,Female ,genetic ,Familial Hypercholesterolaemia ,Life Sciences & Biomedicine - Abstract
[Background]: Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally., [Methods]: The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005., [Findings]: Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12∙0 years (IQR 5∙5–27∙0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 (64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14∙7 mmol/L (IQR 11∙6–18∙4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3∙93 mmol/L, IQR 2∙6–5∙8) versus non-highincome countries (9∙3 mmol/L, 6∙7–12∙7), with greater use of three or more lipid-lowering therapies (LLT; highincome 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high-income 21% vs non-high-income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24∙5 years (IQR 17∙0–34∙5) versus 37∙0 years (29∙0–49∙0) in high-income countries (adjusted hazard ratio 1∙64, 95% CI 1∙13–2∙38)., [Interpretation]: Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH., Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; and European Atherosclerosis Society
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- 2022
14. NPC1L1 and ABCG5/8 induction explain synergistic fecal cholesterol excretion in ob/ob mice co-treated with PPAR-α and LXR agonists
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Maurizio Averna, Nishtha S Srivastava, Angelo B. Cefalù, Rai Ajit K. Srivastava, Srivastava R.A.K., Cefalu A.B., Srivastava N.S., and Averna M.
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Male ,0301 basic medicine ,medicine.medical_specialty ,Hydrocarbons, Fluorinated ,HDL ,Lipoproteins ,Clinical Biochemistry ,Mice, Obese ,ABCA1 ,NPC1L1 ,Cholesterol 7 alpha-hydroxylase ,Excretion ,Feces ,Mice ,ob/ob ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Fenofibrate ,Internal medicine ,medicine ,Animals ,PPAR alpha ,TICE ,ATP Binding Cassette Transporter, Subfamily G, Member 5 ,Liver X receptor ,Molecular Biology ,Liver X Receptors ,Sulfonamides ,biology ,Chemistry ,Cholesterol ,ATP Binding Cassette Transporter, Subfamily G, Member 8 ,Reverse cholesterol transport ,Membrane Transport Proteins ,Drug Synergism ,Cell Biology ,General Medicine ,030104 developmental biology ,Endocrinology ,030220 oncology & carcinogenesis ,ABCG5/G8 ,biology.protein ,Intestinal cholesterol absorption ,lipids (amino acids, peptides, and proteins) ,medicine.drug - Abstract
Reverse cholesterol transport (RCT) and transintestinal cholesterol efflux (TICE) are two important pathways for body cholesterol elimination. We studied these pathways in an animal model of diabetes and obesity (ob/ob) where HDL function is compromised as a result of hyperglycemia, low-grade inflammation and oxidative stress. Co-treatment of ob/ob mice with PPAR-α (fenofibrate) and LXR (T0901317) agonists increased fecal cholesterol by 12-fold; PPAR-α and LXR agonists individually showed 2.6- and 4.0-fold fecal cholesterol excretion, respectively. We investigated the mechanism of synergistic efficacy of PPAR-α and LXR agonists in fecal cholesterol excretion. LXR agonist and the combination of PPAR-α and LXR agonists had greater HDL-C elevation. Ex vivo cholesterol efflux showed correlation with the fecal cholesterol excretion but was not sufficient to explain 12-fold increases in the fecal cholesterol in the co-treated mice. Therefore, we examined TICE to explain the 12-fold increases in the fecal cholesterol. A strong positive correlation of fecal cholesterol with ATP binding cassette transporter G5 (ABCG5) and G8 and anegative correlation with NPC1L1 was observed. ABCG5, G8 and NPC1L1 are involved in intestinal cholesterol absorption. The extent of influence of PPAR-α and LXR agonists on RCT and TICE was distinctly different. PPAR-α agonist increased fecal cholesterol primarily by influencing TICE, while LXR agonist influenced fecal cholesterol excretion via both RCT and TICE mechanisms. Synergistic efficacy on fecal cholesterol excretion following co-treatment with PPAR-α and LXR agonists occurred through a combination of RCT, TICE, and the key enzyme in bile synthesis, cholesterol 7-α hydroxylase (cyp7a1). These results suggest that cholesterol efflux, biliary cholesterol excretion, and TICE collectively contributed to the 12-fold increases in the fecal cholesterol excretion in ob/ob mice co-treated with PPAR-α and LXR agonists.
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- 2020
15. Rapid degradation of ABCA1 protein following cAMP withdrawal and treatment with PKA inhibitor suggests ABCA1 is a short-lived protein primarily regulated at the transcriptional level
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Maurizio Averna, Rai Ajit K. Srivastava, Angelo B. Cefalù, Neelam Srivastava, Srivastava N., Cefalu A.B., Averna M., and Srivastava R.A.K.
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0301 basic medicine ,Endocrinology, Diabetes and Metabolism ,Response element ,ABCA1 ,030209 endocrinology & metabolism ,Diabete ,Protein kinase ,03 medical and health sciences ,0302 clinical medicine ,cAMP ,polycyclic compounds ,Internal Medicine ,ABCA1 Gene ,Medicine ,cardiovascular diseases ,Protein kinase A ,biology ,business.industry ,Reverse cholesterol transport ,HEK 293 cells ,nutritional and metabolic diseases ,hemic and immune systems ,Transfection ,Cell biology ,030104 developmental biology ,Cell culture ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Stably transfected ,business ,Regulation ,Research Article - Abstract
Objectives: ATP-binding cassette transporter A1 (ABCA1) is a key player in the reverse cholesterol transport (RCT) and HDL biogenesis. Since RCT is compromised as a result of ABCA1 dysfunction in diabetic state, the objective of this study was to investigate the regulation of ABCA1 in a stably transfected 293 cells expressing ABCA1 under the control of cAMP response element. Methods: To delineate transcriptional and posttranscriptional regulation of ABCA1, 293 cells were stably transfected with the full length ABCA1 cDNA under the control of CMV promoter harboring cAMP response element. cAMP-mediated regulation of ABCA1 and cholesterol efflux were studied in the presence of 8-Br-cAMP and after withdrawal of 8-Br-cAMP. The mechanism of cAMP-mediated transcriptional induction of the ABCA1 gene was studied in protein kinase A (PKA) inhibitors-treated cells. Results: The transfected 293 cells expressed high levels of ABCA1, while non-transfected wild-type 293 cells showed very low levels of ABCA1. Treatments of transfected cells with 8-Br-cAMP increased ABCA1 protein by 10-fold and mRNA by 20-fold. Cholesterol efflux also increased in parallel. Withdrawal of 8-Br-cAMP caused time-dependent rapid diminution of ABCA1 protein and mRNA, suggesting ABCA1 regulation at the transcriptional level. Treatment with PKA inhibitors abolished the cAMP-mediated induction of the ABCA1 mRNA and protein, resulting dampening of ABCA1-dependent cholesterol efflux. Conclusions: These results demonstrate that transfected cell line mimics cAMP response similar to normal cells with natural ABCA1 promoter and suggest that ABCA1 is a short-lived protein primarily regulated at the transcriptional level to maintain cellular cholesterol homeostasis.
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- 2020
16. Comparison of two polygenic risk scores to identify non-monogenic primary hypocholesterolemias in a large cohort of Italian hypocholesterolemic subjects
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Angelo B. Cefalù, Rossella Spina, Davide Noto, Claudio Rabacchi, Antonina Giammanco, Maria Luisa Simone, Federica Brucato, Chiara Scrimali, Maria Grazia Gueli-Alletti, Carlo M. Barbagallo, Patrizia Tarugi, and Maurizio R. Averna
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Multifactorial Inheritance ,Nutrition and Dietetics ,Endocrinology, Diabetes and Metabolism ,Lipid Metabolism Disorders ,Cholesterol, LDL ,Hypobetalipoproteinemia, Mutations, Polygenic risk score, Panel based NGS sequencing ,Hypobetalipoproteinemias ,Polygenic risk score ,Risk Factors ,Panel based NGS sequencing ,Mutation ,Internal Medicine ,Humans ,Proprotein Convertase 9 ,Cardiology and Cardiovascular Medicine ,Hypobetalipoproteinemia ,Mutations ,Angiopoietin-Like Protein 3 ,Apolipoproteins B ,Monomeric GTP-Binding Proteins - Abstract
Primary Hypobetalipoproteinemias (HBL) are a group of dominant and recessive monogenic genetic disorders caused by mutations in APOB, PCSK9, ANGPTL3, MTTP, Sar1b genes and characterized by plasma levels of total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (apoB) below the 5To explore the complex genetic architecture of HBL we compared two polygenic risk scores in order to assess the role of the polygenic burden and the differences in the clinical phenotype between monogenic and polygenic HBL; we studied a cohort of 170 subjects with primary HBL referred over a 25-year period to 2 Italian reference centers have been studied.The genetic analyses have been based on: Sanger sequencing, in-house NGS customized panel and two scores, PRS1 and PRS2 for the polygenic burden.Sixty 60 (35%) and 63 (37%) subjects had a monogenic and polygenic HBL respectively. LDL-C plasma levels were significantly lower in monogenic HBL (30.87 ± 3.12 mg/dl) compared with the non-monogenic HBL (42.80 ± 2.18 mg/dl) (p0.002) with no differences in the percentage of fatty liver.Only PRS1 is effective in detecting polygenic HBL while PRS2 does not improve the polygenic diagnosis.
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- 2022
17. Lifestyle versus ezetimibe plus lifestyle in patients with biopsy-proven non-alcoholic steatohepatitis (LISTEN): A double-blind randomised placebo-controlled trial
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Davide Noto, Salvatore Petta, Antonina Giammanco, Rossella Spina, Daniela Cabibbi, Rossana Porcasi, Rosalia Caldarella, Marcello Ciaccio, Roberto Muratore, Angelo B. Cefalù, Antonio Craxi, Maurizio Averna, Noto D., Petta S., Giammanco A., Spina R., Cabibi D., Porcasi R., Caldarella R., Ciaccio M., Muratore R., Cefalu A.B., Craxi A., and Averna M.
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Settore MED/12 - Gastroenterologia ,Nutrition and Dietetics ,Settore MED/09 - Medicina Interna ,Endocrinology, Diabetes and Metabolism ,Biopsy ,Medicine (miscellaneous) ,Liver biopsy ,Ezetimibe ,Treatment Outcome ,Double-Blind Method ,Randomized controlled trial ,Non-alcoholic Fatty Liver Disease ,Humans ,Cardiology and Cardiovascular Medicine ,Non-alcoholic steatohepatiti ,Life Style - Abstract
Background and aims: The LISTEN trial (ClinicalTrial.gov accession: NCT01950884) is a phase IV 52 weeks double blind parallel randomized controlled trial that evaluated the effect of ezetimibe plus lifestyle and dietary intervention (eze) vs. lifestyle and dietary intervention alone (placebo) on progression and complications of non-alcoholic steatohepatitis (NASH) evaluated by liver histology. Methods and results: Forty patients with NASH ascertained by histology were randomly allocated on the two study groups and subjected to a follow-up of 52 weeks, when they underwent a second liver biopsy. Main composite end point (EP) was based on the histological improvement in the severity of NASH. Thirty patients completed the study, Eze treatment was not able to improve the primary EP in comparison with placebo, with and odds ratio of 1.029 (0.18–6.38), p = 0.974. Treatment emergent adverse events registered during the study were not more prevalent in the treatment arm. Conclusions: ezetimibe administered on top of lifestyle and dietary modification failed to improve the histology of NASH in comparison with lifestyle and dietary modification alone. Trial accession number: ClinicalTrial.gov: NCT01950884.
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- 2021
18. A subgroup analysis of the ODYSSEY APPRISE study: Safety and efficacy of alirocumab in the Italian cohort
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Angelo B. Cefalù, Raffaella Garbelotto, Giuliana Mombelli, Matteo Pirro, Paolo Rubba, Marcello Arca, Claudio Borghi, Katia Bonomo, Stefano Gonnelli, Katia Massaroni, Giampaolo Tirone, Maurizio Averna, Francesco Angelico, Francesco Cipollone, Enzo Corghi, Pompilio Faggiano, Cesare Greco, Luigina Guasti, Tiziano Lucchi, Carlo Sabba, Riccardo Sarzani, Pierfranco Terrosu, Alberto Zambon, Cefalu', Angelo B, Garbelotto, Raffaella, Mombelli, Giuliana, Pirro, Matteo, Rubba, Paolo, Arca, Marcello, Borghi, Claudio, Bonomo, Katia, Gonnelli, Stefano, Massaroni, Katia, Tirone, Giampaolo, and Averna, Maurizio
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Settore MED/09 - Medicina Interna ,Nutrition and Dietetics ,LDL-C ,Endocrinology, Diabetes and Metabolism ,Anticholesteremic Agents ,Medicine (miscellaneous) ,alirocumab ,Cholesterol, LDL ,Antibodies, Monoclonal, Humanized ,Hyperlipoproteinemia Type II ,heterozygous familial hypercholesterolemia ,Treatment Outcome ,Italy ,Humans ,high cardiovascular risk ,Cardiology and Cardiovascular Medicine - Abstract
ODYSSEY APPRISE trial evaluated efficacy and safety of alirocumab in 994 patients with hypercholesterolemia and high CV risk in a real-life setting. The aim of the present report is to detail on the Italian cohort enrolled and treated in the trial.The methodology of the of the multinational, single-arm, Phase 3b open-label ODYSSEY APPRISE (Clinicaltrials.gov: NCT02476006) has been previously reported. 255 Italian patients were enrolled and treated according to the trial protocol. Overall mean exposure to alirocumab was 83.3 ± 27.7 weeks. At week 12, LDL-C decreased by 51.3 ± 23.1% and this reduction was overall maintained for the duration of the study. A similar reduction was observed in patients with and without heterozygous familial hypercholesterolemia (HeFH 50.7% ± 23.9 vs. non-FH, 53.6% ± 19.6). LDL-C was reduced below 1.8 mmol/L and/or by ≥ 50% reduction from baseline in 62% of patients overall (61% in HeFH and 67% in non-FH). Alirocumab was similarly well tolerated in the Italian cohort as in the entire study population and the more common treatment emergent adverse events (TEAEs) were influenza, myalgia and nasopharyngitis. The incidence LDL-C levels25 mg/dl and15 mg/dl, was 8.2% and 2.9% respectively.The efficacy and safety of alirocumab in a real-life setting, in the Italian subgroup of patients are consistent with findings in the entire study population and confirm that alirocumab is a beneficial approach to further reduce LDL-C levels in patients at high CV risk on maximally tolerated conventional lipid lowering treatment.NCT02476006.
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- 2021
19. Long-term efficacy of lipoprotein apheresis and lomitapide in the treatment of homozygous familial hypercholesterolemia (HoFH): a cross-national retrospective survey
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Tiziana Sampietro, Marcello Arca, Paolo Calabrò, Olga Kalmykova, Livia Pisciotta, Stefano Bertolini, Gabriella Iannuzzo, Francesco Sbrana, Fabio Nota, Antonio Gallo, Carlo Sabbà, Patrizia Suppressa, Arturo Cesaro, Giuliana Fortunato, Randa Bittar, Arturo Puja, Marco Bucci, Katia Bonomo, Angelo B. Cefalù, Samir Saheb, Maurizio Averna, Tiziana Montalcini, Alessio Buonaiuto, Sergio D'Addato, Alain Carrié, Chiara Pavanello, Sophie Béliard, Alessia Di Costanzo, S. Palmisano, Eric Bruckert, Giovanni Battista Vigna, Antonina Giammanco, Laura Calabresi, Fabio Fimiani, Laura D'Erasmo, D'Erasmo L., Gallo A., Cefalu A.B., Di Costanzo A., Saheb S., Giammanco A., Averna M., Buonaiuto A., Iannuzzo G., Fortunato G., Puja A., Montalcini T., Pavanello C., Calabresi L., Vigna G.B., Bucci M., Bonomo K., Nota F., Sampietro T., Sbrana F., Suppressa P., Sabba C., Fimiani F., Cesaro A., Calabro P., Palmisano S., D'Addato S., Pisciotta L., Bertolini S., Bittar R., Kalmykova O., Beliard S., Carrie A., Arca M., Bruckert E., D'Erasmo, L., Gallo, A., Cefalu, A. B., Di Costanzo, A., Saheb, S., Giammanco, A., Averna, M., Buonaiuto, A., Iannuzzo, G., Fortunato, G., Puja, A., Montalcini, T., Pavanello, C., Calabresi, L., Vigna, G. B., Bucci, M., Bonomo, K., Nota, F., Sampietro, T., Sbrana, F., Suppressa, P., Sabba, C., Fimiani, F., Cesaro, A., Calabro, Paolo, Palmisano, S., D'Addato, S., Pisciotta, L., Bertolini, S., Bittar, R., Kalmykova, O., Beliard, S., Carrie, A., Arca, M., Bruckert, E., Calabro, P., Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Palermo - University of Palermo, University of Naples Federico II = Università degli studi di Napoli Federico II, CEINGE - Biotecnologie Avanzate, Università degli Studi 'Magna Graecia' di Catanzaro = University of Catanzaro (UMG), Università degli Studi di Milano = University of Milan (UNIMI), Università degli Studi di Ferrara = University of Ferrara (UniFE), Università degli studi 'G. d'Annunzio' Chieti-Pescara [Chieti-Pescara] (Ud'A), Ospedale San Luigi Gonzaga, Fondazione Toscana Gabriele Monasterio, University of the Study of Campania Luigi Vanvitelli, Policlinico S. Orsola-malpighi, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO)-Servizio sanitario regionale Emilia-Romagna, Università degli studi di Genova = University of Genoa (UniGe), Ospedale Policlinico San Martino [Genoa], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)
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medicine.medical_specialty ,Settore MED/09 - Medicina Interna ,[SDV]Life Sciences [q-bio] ,Lipoproteins ,Genetic disease ,Therapeutics ,Familial hypercholesterolemia ,Disease ,Lipoprotein apheresi ,LDL ,Hyperlipoproteinemia Type II ,chemistry.chemical_compound ,Lipoprotein apheresis ,Retrospective survey ,Internal medicine ,Cholesterol burden ,Homozygous hypercholesterolemia ,Lomitapide ,Benzimidazoles ,Homozygote ,Humans ,Retrospective Studies ,Anticholesteremic Agents ,Blood Component Removal ,medicine ,Pharmacology (medical) ,Genetics (clinical) ,medicine.diagnostic_test ,business.industry ,Research ,General Medicine ,medicine.disease ,cholesterol burden ,genetic disease ,homozygous hypercholesterolemia ,lipoprotein apheresis ,lomitapide ,therapeutics ,chemistry ,Cohort ,Medicine ,Lipid profile ,business ,Cross national - Abstract
Abstract Background Homozygous familial hypercholesterolemia (HoFH) is a rare life-threatening condition that represents a therapeutic challenge. The vast majority of HoFH patients fail to achieve LDL-C targets when treated with the standard protocol, which associates maximally tolerated dose of lipid-lowering medications with lipoprotein apheresis (LA). Lomitapide is an emerging therapy in HoFH, but its place in the treatment algorithm is disputed because a comparison of its long-term efficacy versus LA in reducing LDL-C burden is not available. We assessed changes in long-term LDL-C burden and goals achievement in two independent HoFH patients’ cohorts, one treated with lomitapide in Italy (n = 30) and the other with LA in France (n = 29). Results The two cohorts differed significantly for genotype (p = 0.004), baseline lipid profile (p padj = 0.004). Yearly on-treatment LDL-C padj = 0.002). A trend towards fewer total cardiovascular events was observed in the Lomitapide than in the LA cohort. Conclusions In comparison with LA, lomitapide appears to provide a better control of LDL-C in HoFH. Further studies are needed to confirm this data and establish whether this translates into a reduction of cardiovascular risk.
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- 2021
20. Hyperalphalipoproteinemia and Beyond: The Role of HDL in Cardiovascular Diseases
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Emilio Nardi, Maurizio Averna, Davide Noto, Marcello Ciaccio, Angelo B. Cefalù, Carlo M. Barbagallo, Antonina Giammanco, Rosalia Caldarella, Giammanco, Antonina, Noto, Davide, Barbagallo, Carlo Maria, Nardi, Emilio, Caldarella, Rosalia, Ciaccio, Marcello, Averna, Maurizio, and Cefalù, Angelo Baldassare
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0301 basic medicine ,Endothelial lipase ,medicine.medical_specialty ,Apolipoprotein B ,HDL ,Science ,Population ,Genome-wide association study ,Review ,030204 cardiovascular system & hematology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,cardiovascular disease ,Internal medicine ,Cholesterylester transfer protein ,Mendelian randomization ,CETP ,Medicine ,Scavenger receptor ,education ,Ecology, Evolution, Behavior and Systematics ,education.field_of_study ,biology ,business.industry ,Paleontology ,030104 developmental biology ,Endocrinology ,Space and Planetary Science ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Hepatic lipase ,hyperalphalipoproteinemia ,business ,polymorphisms - Abstract
Hyperalphalipoproteinemia (HALP) is a lipid disorder characterized by elevated plasma high-density lipoprotein cholesterol (HDL-C) levels above the 90th percentile of the distribution of HDL-C values in the general population. Secondary non-genetic factors such as drugs, pregnancy, alcohol intake, and liver diseases might induce HDL increases. Primary forms of HALP are caused by mutations in the genes coding for cholesteryl ester transfer protein (CETP), hepatic lipase (HL), apolipoprotein C-III (apo C-III), scavenger receptor class B type I (SR-BI) and endothelial lipase (EL). However, in the last decades, genome-wide association studies (GWAS) have also suggested a polygenic inheritance of hyperalphalipoproteinemia. Epidemiological studies have suggested that HDL-C is inversely correlated with cardiovascular (CV) risk, but recent Mendelian randomization data have shown a lack of atheroprotective causal effects of HDL-C. This review will focus on primary forms of HALP, the role of polygenic inheritance on HDL-C, associated risk for cardiovascular diseases and possible treatment options.
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- 2021
21. Lipoprotein abnormalities in chronic kidney disease and renal transplantation
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Maurizio Averna, Davide Noto, Rosalia Caldarella, Emilio Nardi, Carlo M. Barbagallo, Antonina Giammanco, Marcello Ciaccio, Angelo B. Cefalù, Barbagallo C.M., Cefalu A.B., Giammanco A., Noto D., Caldarella R., Ciaccio M., Averna M., and Nardi E.
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medicine.medical_specialty ,Lipoproteins ,030232 urology & nephrology ,Disease ,Review ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,Gastroenterology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Chronic kidney disease ,medicine ,lcsh:Science ,Ecology, Evolution, Behavior and Systematics ,Kidney ,business.industry ,Hypertriglyceridemia ,Paleontology ,medicine.disease ,Cardiovascular disease ,Lipids ,Uremia ,female genital diseases and pregnancy complications ,Transplantation ,medicine.anatomical_structure ,Space and Planetary Science ,lipids (amino acids, peptides, and proteins) ,lcsh:Q ,business ,Dyslipidemia ,Kidney disease ,Lipoprotein - Abstract
Chronic kidney disease (CKD) is one of the most important risk factors for cardiovascular disease (CVD). Despite the kidney having no direct implications for lipoproteins metabolism, advanced CKD dyslipidemia is usually present in patients with CKD, and the frequent lipid and lipoprotein alterations occurring in these patients play a role of primary importance in the development of CVD. Although hypertriglyceridemia is the main disorder, a number of lipoprotein abnormalities occur in these patients. Different enzymes pathways and proteins involved in lipoprotein metabolism are impaired in CKD. In addition, treatment of uremia may modify the expression of lipoprotein pattern as well as determine acute changes. In renal transplantation recipients, the main lipid alteration is hypercholesterolemia, while hypertriglyceridemia is less pronounced. In this review we have analyzed lipid and lipoprotein disturbances in CKD and also their relationship with progression of renal disease. Hypolipidemic treatments may also change the natural history of CVD in CKD patients and may represent important strategies in the management of CKD patients.
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- 2021
22. DeepSRE: Identification of sterol responsive elements and nuclear transcription factors Y proximity in human DNA by Convolutional Neural Network analysis
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Rossella Spina, Maurizio Averna, Francesca Fayer, Angelo B. Cefalù, Davide Noto, Antonina Giammanco, Noto D., Giammanco A., Spina R., Fayer F., Cefalu A.B., and Averna M.
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Metabolic Processes ,Settore MED/09 - Medicina Interna ,Conservation Biology ,Gene Expression ,Biochemistry ,Conservation Science ,Data Management ,Regulation of gene expression ,Multidisciplinary ,Gene Ontologies ,Genomics ,Lipids ,Phylogenetics ,Cholesterol ,Conservation Genetics ,Medicine ,Settore MED/46 - Scienze Tecniche Di Medicina Di Laboratorio ,Research Article ,Computer and Information Sciences ,Sp1 Transcription Factor ,Sequence analysis ,Science ,DNA transcription ,Computational biology ,Biology ,Data mining, Deep Learning, Genetics, Transcription factor ,DNA-binding proteins ,Genetics ,Humans ,Gene Regulation ,Evolutionary Systematics ,Binding site ,Gene ,Transcription factor ,Taxonomy ,Evolutionary Biology ,Models, Genetic ,Ecology and Environmental Sciences ,Biology and Life Sciences ,Computational Biology ,Proteins ,Promoter ,DNA Patterns ,DNA ,Sequence Analysis, DNA ,Genome Analysis ,Regulatory Proteins ,Sterol regulatory element-binding protein ,Metabolism ,Serum Response Element ,CCAAT-Binding Factor ,Transcription Factors - Abstract
SREBP1 and 2, are cholesterol sensors able to modulate cholesterol-related gene expression responses. SREBPs binding sites are characterized by the presence of multiple target sequences as SRE, NFY and SP1, that can be arranged differently in different genes, so that it is not easy to identify the binding site on the basis of direct DNA sequence analysis. This paper presents a complete workflow based on a one-dimensional Convolutional Neural Network (CNN) model able to detect putative SREBPs binding sites irrespective of target elements arrangements. The strategy is based on the recognition of SRE linked (less than 250 bp) to NFY sequences according to chromosomal localization derived from TF Immunoprecipitation (TF ChIP) experiments. The CNN is trained with several 100 bp sequences containing both SRE and NF-Y. Once trained, the model is used to predict the presence of SRE-NFY in the first 500 bp of all the known gene promoters. Finally, genes are grouped according to biological process and the processes enriched in genes containing SRE-NFY in their promoters are analyzed in details. This workflow allowed to identify biological processes enriched in SRE containing genes not directly linked to cholesterol metabolism and possible novel DNA patterns able to fill in for missing classical SRE sequences.
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- 2021
23. Lomitapide does not alter PCSK9 and Lp(a) levels in homozygous familial hypercholesterolemia patients: analysis on cytokines and lipid profile
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Diletta Arcidiacono, Laura D'Erasmo, Sara De Martin, Nicola Ferri, Fabio Fimiani, Alice Zaramella, Angelo B. Cefalù, Maria Giovanna Lupo, Paolo Calabrò, Alberto Zambon, Maurizio Averna, Marcello Arca, Lupo, M. G., Arcidiacono, D., Zaramella, A., Fimiani, F., Calabro', P., Cefalu, A. B., Averna, M., D'Erasmo, L., Arca, M., De Martin, S., Zambon, A., Ferri, N., Lupo M.G., Arcidiacono D., Zaramella A., Fimiani F., Calabro P., Cefalu AB, Averna M, D'Erasmo L., Arca M., De Martin S., Zambon A., and Ferri N.
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Drug ,medicine.medical_specialty ,media_common.quotation_subject ,Familial hypercholesterolemia ,PCSK9 ,chemistry.chemical_compound ,Internal medicine ,Lomitapide, Lipoprotein (a), PCSK9, Familial Hypercholesterolemia ,Lipoprotein (a) ,Internal Medicine ,medicine ,Diseases of the circulatory (Cardiovascular) system ,Familial Hypercholesterolemia ,skin and connective tissue diseases ,media_common ,Ldl cholesterol ,medicine.diagnostic_test ,business.industry ,nutritional and metabolic diseases ,Plasma levels ,medicine.disease ,Lomitapide ,lp(a) ,Endocrinology ,chemistry ,RC666-701 ,pcsk9 ,lipids (amino acids, peptides, and proteins) ,sense organs ,Cardiology and Cardiovascular Medicine ,Lipid profile ,business - Abstract
Lomitapide, a drug for the treatment of homozygous familial hypercholesterolemia patients, reduced total and LDL cholesterol but no significant changes were observed on PCSK9 and Lp(a) plasma levels. Some changes of inflammatory mediators were also observed, including hsCRP, which may suggest an anti-inflammatory effect.
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- 2021
24. Lack of phenotypic additive effect of familial defective apolipoprotein B3531 in familial hypercholesterolaemia
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Angelo B. Cefalù, Maurizio Averna, Davide Noto, Carlo M. Barbagallo, Francesca Fayer, Rossella Spina, Antonina Giammanco, Giammanco A., Spina R., Fayer F., Barbagallo C.M., Noto D., Cefalu A.B., and Averna M
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Proband ,Male ,medicine.medical_specialty ,Apolipoprotein B ,030204 cardiovascular system & hematology ,Compound heterozygosity ,Hyperlipoproteinemia Type II ,03 medical and health sciences ,chemistry.chemical_compound ,FDB3531 ,0302 clinical medicine ,Internal medicine ,Internal Medicine ,medicine ,Humans ,030212 general & internal medicine ,Apolipoproteins B ,double heterozygote ,biology ,business.industry ,Cholesterol ,LDL receptor ,nutritional and metabolic diseases ,Heterozygote advantage ,Middle Aged ,Endocrinology ,chemistry ,Italy ,Receptors, LDL ,Mutation (genetic algorithm) ,Mutation ,familial hypercholesterolaemia ,biology.protein ,lipids (amino acids, peptides, and proteins) ,business ,Lipoprotein - Abstract
Familial defective apolipoprotein (apo) B (FDB) and familial hypercholesterolaemia (FH) are the two common genetic conditions that cause hypercholesterolaemia. R3531C mutation of the APOB gene is a rare cause of FDB. Individuals with both FDB and FH are rare. A 51-year-old man with hypercholesterolaemia (11.4 mmol/L) and his family were studied. Low-density lipoprotein (LDL) receptor (LDLR) and APOB genes were analysed by direct sequencing. LDL of four subjects were studied in a fibroblast LDL receptor-binding displacement assay. We found a mutation of the LDLR gene (p.Y398X) in the proband and in four other family members: the p.R3531C APOB gene mutation was also found in the proband, his father and his children. The proband and his son were thus compound heterozygotes for both FH and FDB. Double heterozygotes did not show higher cholesterol levels compared to carriers of LDLR gene mutation alone. LDL from one of the carriers of the p.R3531C alone exhibited a binding ability, which was similar to a normal subject. This is the first report in Italy of the p.R3531C mutation, and our results show that this mutation has no effect in LDLR p.Y398X/APOB p.R3531C double heterozygotes.
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- 2020
25. MOLECULAR CHARACTERIZATION OF PATIENTS WITH AND WITHOUT CORONARY ARTERY DISEASE WITH 'EXTREME LDL-C PHENOTYPES'
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Oliviero Olivieri, V. Ingrassia, Angelo B. Cefalù, F. Brucato, C. Scrimali, C.M. Barbagallo, Gabriella Misiano, Domenico Girelli, F. Busti, Nicola Martinelli, Francesca Fayer, Maurizio Averna, A. Giammanco, Davide Noto, Rossella Spina, G.I. Altieri, Brucato, F, Martinelli, N, Spina, R, Busti, F, Ingrassia, V, Scrimali, C, Altieri, GI, Noto, D, Misiano, G, Giammanco, A, Barbagallo, CM, Fayer, F, Cefalu, AB, Olivieri, O, Girelli, D, and Averna, M
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Coronary artery disease ,medicine.medical_specialty ,genotyping ,business.industry ,Internal medicine ,Cardiology ,Medicine ,Cardiology and Cardiovascular Medicine ,business ,medicine.disease ,Phenotype ,LDL - Published
- 2020
26. Therapeutic options for homozygous familial hypercholesterolemia: the role of Lomitapide
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Maurizio Averna, Angelo B. Cefalù, Davide Noto, Antonina Giammanco, Giammanco, Antonina, Cefalù, Angelo B, Noto, Davide, and Averna, Maurizio
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Drug ,medicine.medical_specialty ,media_common.quotation_subject ,Familial hypercholesterolemia ,030204 cardiovascular system & hematology ,Biochemistry ,Microsomal triglyceride transfer protein ,Hyperlipoproteinemia Type II ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Drug Discovery ,Medicine ,Humans ,030212 general & internal medicine ,media_common ,Pharmacology ,biology ,business.industry ,Anticholesteremic Agents ,Organic Chemistry ,Hypertriglyceridemia ,Plasma levels ,medicine.disease ,Lomitapide ,Europe ,Tolerability ,chemistry ,biology.protein ,Molecular Medicine ,Pancreatitis ,Benzimidazoles ,HoFH – Lomitapide – LOWER Registry – MTP inhibition – MTP SNPs ,business - Abstract
Background:Lomitapide (Juxtapid® in US and Lojuxta® in Europe) is the first developed inhibitor of the Microsomal Triglyceride Transfer Protein (MTP) approved as a novel drug for the management of Homozygous Familial Hypercholesterolemia (HoFH). It acts by binding directly and selectively to MTP thus decreasing the assembly and secretion of the apo-B containing lipoproteins both in the liver and in the intestine.Aims:The present review aims at summarizing the recent knowledge on lomitapide in the management of HoFH.Results:The efficacy and safety of lomitapide have been evaluated in several trials and it has been shown a reduction of the plasma levels of Low-Density Lipoprotein Cholesterol (LDL-C) by an average of more than 50%. Although the most common side effects are gastrointestinal and liver events, lomitapide presents generally with a good tolerability and satisfactory patients compliance. Recently, in Europe, to evaluate the long-term safety and efficacy of lomitapide, the LOWER registry (ClinicalTrials.gov Identifier: NCT02135705) has been established in order to acquire informations on HoFH lomitapidetreated patients from “real life” clinical practice.:Furthermore, the observation that lomitapide decreases triglyceride levels may be considered for patients affected by severe forms of hypertriglyceridemia who undergo recurrent episodes of pancreatitis and are poor responders to conventional treatment.Conclusion:Lomitapide represents an innovative and efficacious drug for the treatment of HoFH. Longterm safety data, treatment of pediatric and pregnant HoFH patients and management of severe hypertriglyceridemia still require further investigations.
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- 2020
27. Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features
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Maurizio Averna, Gabriella Iannuzzo, Andrea Bartuli, Carlo Ripoli, Stefano Bertolini, Sebastiano Calandra, Patrizia Suppressa, Francesco Sbrana, Anastasia Ibba, Chiara Trenti, Alberico L. Catapano, Tommaso Fasano, Manuela Casula, Livia Pisciotta, Angelo B. Cefalù, Patrizia Tarugi, Tiziana Sampietro, Paolo Calabrò, Andrea Pasta, Paola Sabrina Buonuomo, Fulvio Sileo, M. G. Zenti, Chiara Pavanello, Sergio D'Addato, Marco Bucci, Marcello Arca, Arrigo F G Cicero, Emanuele A. Negri, Claudio Rabacchi, Laura D'Erasmo, Bertolini S., Calandra S., Arca M., Averna M., Catapano A.L., Tarugi P., Bartuli A., Bucci M., Buonuomo P.S., Calabro P., Casula M., Cefalu A.B., Cicero A., D'Addato S., D'Erasmo L., Fasano T., Iannuzzo G., Ibba A., Negri E.A., Pasta A., Pavanello C., Pisciotta L., Rabacchi C., Ripoli C., Sampietro T., Sbrana F., Sileo F., Suppressa P., Trenti C., Zenti M.G., Bertolini, S., Calandra, S., Arca, M., Averna, M., Catapano, A. L., Tarugi, P., Bartuli, A., Bucci, M., Buonuomo, P. S., Calabro', P., Casula, M., Cefalu, A. B., Cicero, A., D'Addato, S., D'Erasmo, L., Fasano, T., Iannuzzo, G., Ibba, A., Negri, E. A., Pasta, A., Pavanello, C., Pisciotta, L., Rabacchi, C., Ripoli, C., Sampietro, T., Sbrana, F., Sileo, F., Suppressa, P., Trenti, C., Zenti, M. G., Bertolini, S, Calandra, S, Arca, M, Averna, M, Catapano, Al, Tarugi, P, IAndrea Bartuli, 7, Marco, Bucci, Paola Sabrina Buonuomo, Calabro', Paolo, Manuela, Casula, Angelo Baldassare Cefalù, Arrigo, Cicero, Sergio, D'Addato, Laura, D'Erasmo, Tommaso, Fasano, Iannuzzo, Gabriella, Anastasia, Ibba, Emanuele, A Negri Andrea Pasta, Chiara, Pavanello, Livia, Pisciotta, Claudio, Rabacchi, Carlo, Ripoli, Tiziana, Sampietro, Francesco, Sbrana, Fulvio, Sileo, Patrizia, Suppressa, Chiara, Trenti, and Maria Grazia Zenti
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Adult ,0301 basic medicine ,medicine.medical_specialty ,Candidate gene ,Genotype-phenotype correlation ,Apolipoprotein B ,Candidate genes ,Genotype-phenotype correlations ,Homozygous familial hypercholesterolemia ,Pathogenic variants ,Familial hypercholesterolemia ,030204 cardiovascular system & hematology ,Compound heterozygosity ,Hyperlipoproteinemia Type II ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,biology ,business.industry ,PCSK9 ,Homozygote ,Genetic disorder ,medicine.disease ,Phenotype ,030104 developmental biology ,Endocrinology ,Italy ,Receptors, LDL ,Autosomal Recessive Hypercholesterolemia ,Mutation ,LDL receptor ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Proprotein Convertase 9 ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background and aims Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extremely elevated plasma levels of low density lipoprotein cholesterol (LDL-C) and high risk of premature atherosclerotic cardiovascular disease (ASCVD). HoFH is caused by pathogenic variants in several genes, such as LDLR, APOB and PCSK9, responsible for autosomal dominant hypercholesterolemia (ADH), and LDLRAP1 responsible for autosomal recessive hypercholesterolemia (ARH). Aim of this study was the review of the clinical and molecular features of patients with HoFH identified in Italy from 1989 to 2019. Methods Data were collected from lipid clinics and laboratories, which had performed molecular diagnosis in suspected HoFH. Clinical data included baseline lipid levels and ASCVD events. Results A total of 125 subjects with ADH were identified, of whom 60 were true homozygotes, 58 compound heterozygotes and 7 double heterozygotes for LDLR (likely) pathogenic variants. Compared with compound heterozygotes, true homozygotes showed a more severe lipid phenotype and more ASCVD events. ADH carriers of LDLR negative variants (R-NEG) presented with a more aggressive phenotype, as compared to carriers of LDLR defective variants (R-DEF). Kaplan-Meier analysis showed that the median age of ASCVD event-free survival was 25 years of age in R-NEG as opposed to 50 years of age in R-DEF patients. A total of 66 patients with ARH were also identified, of whom 46 were homozygotes and 20 compound heterozygotes. The phenotypic features of ARH patients were similar to those of R-DEF/ADH patients. Overall, 45% ADH patients and 33% ARH patients did not meet the classic diagnostic criteria for HoFH. Conclusions In our cohort, the phenotypic variability of HoFH was dependent on the candidate gene involved and the functional impact of its variants on the LDL receptor pathway.
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- 2020
28. Autosomal Recessive Hypercholesterolemia
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Sandro Muntoni, Maurizio Averna, Juan F. Ascaso, Antonio Nicolucci, Marco Scardapane, Cesare Sirtori, Marcello Arca, Pablo Prieto-Matos, Davide Noto, José T. Real, Anja Vogt, Francisco Fuentes, Chiara Pavanello, Pedro Mata, Sabina Zambon, Angelo B. Cefalù, Luis Masana, Alberto Zambon, Adolfo Pacifico, Paolo Pintus, Giovanni Mario Pes, Ilenia Minicocci, Miguel Pocovi, Laura D'Erasmo, Mariko Harada-Shiba, Stefano Bertolini, Enzo Manzato, Eduardo Esteve Lafuente, Laura Calabresi, Renato Fellin, Rosa M. Sánchez-Hernández, Barbara Sjouke, and Janine E. Roeters Van Lennep
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0301 basic medicine ,medicine.medical_specialty ,Statin ,Atherosclerotic cardiovascular disease ,business.industry ,medicine.drug_class ,030204 cardiovascular system & hematology ,Lomitapide ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Ezetimibe ,chemistry ,Autosomal Recessive Hypercholesterolemia ,Internal medicine ,medicine ,Effective treatment ,lipids (amino acids, peptides, and proteins) ,In patient ,Cardiology and Cardiovascular Medicine ,business ,Cardiovascular outcomes ,medicine.drug - Abstract
Background Autosomal recessive hypercholesterolemia (ARH) is a rare lipid disorder characterized by premature atherosclerotic cardiovascular disease (ASCVD). There are sparse data for clinical management and cardiovascular outcomes in ARH. Objectives Evaluation of changes in lipid management, achievement of low-density lipoprotein cholesterol (LDL-C) goals and cardiovascular outcomes in ARH. Methods Published ARH cases were identified by electronic search. All corresponding authors and physicians known to treat these patients were asked to provide follow-up information, using a standardized protocol. Results We collected data for 52 patients (28 females, 24 males; 31.1 ± 17.1 years of age; baseline LDL-C: 571.9 ± 171.7 mg/dl). During a mean follow-up of 14.1 ± 7.3 years, there was a significant increase in the use of high-intensity statin and ezetimibe in combination with lipoprotein apheresis; in 6 patients, lomitapide was also added. Mean LDL-C achieved at nadir was 164.0 ± 85.1 mg/dl (−69.6% from baseline), with a better response in patients taking lomitapide (−88.3%). Overall, 23.1% of ARH patients reached LDL-C of Conclusions Despite intensive treatment, LDL-C in ARH patients remains far from targets, and this translates into a poor long-term cardiovascular prognosis. Our data highlight the importance of an early diagnosis and treatment and confirm the fact that an effective treatment protocol for ARH is still lacking.
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- 2018
29. Characterisation of patients with familial chylomicronaemia syndrome (FCS) and multifactorial chylomicronaemia syndrome (MCS): Establishment of an FCS clinical diagnostic score
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Ioanna Gouni-Berthold, Handrean Soran, Laura D'Erasmo, Erik S.G. Stroes, Željko Reiner, Robert Cramb, Luis Antonio Alvarez-Sala Walther, Marcello Arca, Xavier Pintó, Claudia Stefanutti, Maurizio Averna, Robert Dufour, Colin D. Johnson, Jan Borén, Davide Noto, Philippe Moulin, Alessia Di Costanzo, Elizabeth Hughes, Eric Bruckert, C. Marcais, Angelo B. Cefalù, Maciej Banach, Jeanine E. Roeters van Lennep, Moulin, Philippe, Dufour, Robert, Averna, Maurizio, Arca, Marcello, Cefalù, Angelo B., Noto, Davide, D'Erasmo, Laura, Di Costanzo, Alessia, Marçais, Christophe, Walther, Luis Antonio Alvarez-Sala, Banach, Maciej, Borén, Jan, Cramb, Robert, Gouni-Berthold, Ioanna, Hughes, Elizabeth, Johnson, Colin, Pintó, Xavier, Reiner, Željko, van Lennep, Jeanine Roeter, Soran, Handrean, Stefanutti, Claudia, Stroes, Erik, Bruckert, Eric, Internal Medicine, ACS - Atherosclerosis & ischemic syndromes, and Vascular Medicine
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Settore MED/09 - Medicina Interna ,diagnosis ,MEDLINE ,030209 endocrinology & metabolism ,030204 cardiovascular system & hematology ,Bioinformatics ,lcsh:Computer applications to medicine. Medical informatics ,03 medical and health sciences ,familial chylomicronaemia syndrome, diagnostic score ,0302 clinical medicine ,Diagnòstic ,Diagnosis ,Malalties hereditàries ,score ,Medicine ,lcsh:Science (General) ,Genetics, Genomics and Molecular Biology ,Multidisciplinary ,business.industry ,familial chylomicronaemia syndrome (FCS), multifactorial chylomicronaemia syndrome (MCS), diagnosis, score ,familial chylomicronaemia syndrome (FCS) ,Rare diseases ,lcsh:R858-859.7 ,lipids (amino acids, peptides, and proteins) ,Malalties rares ,chylomicronaemia syndrome ,multifactorial chylomicronaemia syndrome ,business ,multifactorial chylomicronaemia syndrome (MCS) ,Genetic diseases ,lcsh:Q1-390 - Abstract
Data presented in this article are supplementary material to our article entitled "Identification and diagnosis of patients with familial chylomicronaemia syndrome (FCS): expert panel recom mendations and proposal of an "FCS Score" (Moulin et al., 2018, in press). The data describe the genotypes of patients with familial chylomicronaemia syndrome (FCS) and multifactorial chylomicro naemia syndrome (MCS), from the validation and replication cohorts.
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- 2018
30. Effectiveness and safety of lomitapide in a patient with familial chylomicronemia syndrome
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Maurizio Averna, Davide Noto, Rossella Spina, Antonina Giammanco, Angelo B. Cefalù, Daniela Cabibi, Carlo M. Barbagallo, Cefalu AB, Giammanco A, Noto D, Spina R, Cabibi D, Barbagallo CM, Averna M., Giammanco, A, Cefalu, AB, Noto, D, Spina, R, Cabibi, D, Barbagallo, CM, and Averna, M
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Abdominal pain ,Pediatrics ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Recurrent pancreatitis ,Internal medicine ,Fatty liver ,Humans ,Medicine ,Prospective Studies ,medicine.diagnostic_test ,business.industry ,Hypertriglyceridemia ,FCS ,Familial Chylomicronemia ,medicine.disease ,Lomitapide ,Acute pancreatitis ,Pancreatitis ,chemistry ,030220 oncology & carcinogenesis ,Liver biopsy ,Acute Disease ,Benzimidazoles ,Hyperlipoproteinemia Type I ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Familial chylomicronaemia syndrome - Abstract
Background: Familial chylomicronemia syndrome (FCS) is characterized by severe fasting hypertriglyceridemia, abdominal pain, and recurrent acute pancreatitis. Available triglyceride-lowering drugs are insufficient to avoid pancreatitis. Therefore, there is a significant unmet medical need for effective triglyceride-lowering drugs for patients with FCS. Case report: We report the second case of a patient with FCS and recurrent pancreatitis treated with lomitapide. Lomitapide treatment resulted in a reduction of fasting TG levels from 2897 mg/dL (32.71 mmol/L) to an average of 954 mg/dL (10.77 mmol/L) on the 30 mg lomitapide equating to a 67% reduction from baseline. After 26 months of lomitapide treatment, histological activity score for hepatic fibrosis was stable although liver biopsy showed a marked increase of liver steatosis and mild perivenular and perisinusoidal fibrosis. Conclusions: Lomitapide is effective in reducing triglycerides in FCS and preventing the recurrence of acute pancreatitis. A longer follow-up is necessary to evaluate long-term risk of progression toward severe stages of liver fibrosis. A prospective clinical trial may identify which subgroup of FCS patients would benefit from lomitapide treatment in the absence of significant liver adverse effects.
- Published
- 2021
31. PCSK9-D374Y mediated LDL-R degradation can be functionally inhibited by EGF-A and truncated EGF-A peptides: An in vitro study
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Francesca Fayer, Maurizio Averna, Carlo M. Barbagallo, G.I. Altieri, Gabriella Misiano, Vincenza Valenti, C. Scrimali, Davide Noto, Rossella Spina, Angelo B. Cefalù, Antonina Giammanco, V. Ingrassia, F. Brucato, Valenti V, Noto D, Giammanco A, Fayer F, Spina R, Altieri GI, Ingrassia V, Scrimali C, Barbagallo CM, Brucato F, Misiano G, Cefalu AB, and Averna M.
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0301 basic medicine ,Small peptides ,media_common.quotation_subject ,030204 cardiovascular system & hematology ,Decoy strategy ,PCSK9 ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Internalization ,Cells, Cultured ,media_common ,Expression vector ,Epidermal Growth Factor ,Chemistry ,PCSK9 Inhibitors ,Transfection ,Proprotein convertase ,PCSK9 inhibition ,In vitro ,Cell biology ,EGF-A domain ,030104 developmental biology ,LDLR ,Receptors, LDL ,LDL receptor ,Mutation ,Kexin ,lipids (amino acids, peptides, and proteins) ,Proprotein Convertase 9 ,Cardiology and Cardiovascular Medicine - Abstract
Background and aims Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low density lipoprotein receptor (LDLR) through the LDLR epidermal growth factor-like repeat A (EGF-A) domain and induces receptor internalization and degradation. PCSK9 has emerged as a novel therapeutic target for hypercholesterolemia. Clinical studies with PCSK9 inhibiting antibodies have demonstrated strong LDL-c lowering effects, but other therapeutic approaches using small molecule inhibitors for targeting PCSK9 functions may offer supplementary therapeutic options. The aim of our study was to evaluate the effect of synthetic EGF-A analogs on mutated (D374Y) PCSK9-D374Y mediated LDLR degradation in vitro. Methods Huh7 human hepatoma cells were transiently transfected to overexpress the gain-of-function D374Y PCSK9 mutation, which has been associated with severe hypercholesterolemia in humans. Results Transient transfection of cells with PCSK9-D374Y expression vector very effectively enhanced degradation of mature LDLR in Huh7. Treatment with both EGF-A and EGF-A truncated peptides inhibited this effect and showed increased LDLR protein in Huh7 cells transfected with PCSK9-D374Y in a clear concentration dependent manner. Huh7 transfected cells treated with increasing concentration of EGF-A analogs also showed an increase internalization of labeled Dil-LDL. Conclusions The result of our study shows that EGF-A analogs are able to effectively hamper the enhanced degradation of LDLR in liver cells expressing PCSK9-D374Y.
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- 2019
32. Mutation in candidate genes account for a small minority of hypobetalipoproteinemias and NGS analysis support polygenicity in mutation-negative patients
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Gabriella Misiano, G.I. Altieri, Maurizio Averna, Rossella Spina, A. Giammanco, C.M. Barbagallo, Vincenza Valenti, Davide Noto, A. Ganci, V. Ingrassia, F. Brucato, Francesca Fayer, C. Scrimali, Angelo B. Cefalù, Giammanco, Antonina, Scrimali, C, Spina, R, Ingrassia, V, Brucato, F, Valenti, V, Cefalu, AB, Misiano, G, Altieri, GI, Noto, D, Barbagallo, CM, Ganci, A, Fayer, F, and Averna, M
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Genetics ,POLYGENIC ,Candidate gene ,Mutation (genetic algorithm) ,Biology ,Cardiology and Cardiovascular Medicine ,HYPOBETALIPOPROTEINEMIAS ,NGS ANALYSIS - Published
- 2020
33. Proprotein Convertase Subtilisin Kexin Type 9 Inhibition for Autosomal Recessive Hypercholesterolemia—Brief Report
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Frederick J. Raal, Geesje Dallinga-Thie, Livia Pisciotta, Maurizio Averna, Jorge Peter, Maxime Passard, Dirk J. Blom, Barbara Sjouke, Kees Hovingh, Alexis Guedon, Maria Laura Cossu, Aurélie Thedrez, Milco Ciccarese, Raul D. Santos, Mickael Croyal, Angelo B. Cefalù, Simon Prampart-Fauvet, Gilles Lambert, Paolo Pintus, Physiologie des Adaptations Nutritionnelles [UMR_A1280] (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Department of Vascular Medicine, Emma Children’s Hospital Academic Medical Centre, Lipidology Division of Internal Medicine, University of Cape Town, Dipartimiento di Nefrologia Dialisi e Trapianto, SS Annunziata Hospital, School of Medicine, University of Patras [Greece], University of Genoa (UNIGE), Lipid Clinic Heart Institute (InCor), University of São Paulo, Sao Paolo Medica School Hospital, Faculty of Health Sciences, Aarhus University [Aarhus], Dipartimento di Medicina Interna, Brotzu Hospital, Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de La Réunion (UR), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Investigator Initiated Study Concept Research Grant from Sanofi-Regeneron, Agence Nationale de la Recherche (Programme blanc BCNCT), Thedrez, A., Sjouke, B., Passard, M., Prampart-Fauvet, S., Guédon, A., Croyal, M., Dallinga-Thie, G., Peter, J., Blom, D., Ciccarese, M., Cefalù, A., Pisciotta, L., Santos, R., Averna, M., Raal, F., Pintus, P., Cossu, M., Hovingh, K., Lambert, G., Physiologie des Adaptations Nutritionnelles (PhAN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Vascular Medicine, and Experimental Vascular Medicine
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Male ,0301 basic medicine ,Settore MED/09 - Medicina Interna ,[SDV]Life Sciences [q-bio] ,receptors ,alirocumab ,Familial hypercholesterolemia ,030204 cardiovascular system & hematology ,proprotein convertase subtilisin kexin type 9 ,0302 clinical medicine ,therapeutics ,Lymphocytes ,Cells, Cultured ,hypercholesterolemia ,Anticholesteremic Agents ,PCSK9 Inhibitors ,Antibodies, Monoclonal ,Middle Aged ,3. Good health ,Phenotype ,Autosomal Recessive Hypercholesterolemia ,Kexin ,Drug Therapy, Combination ,Female ,lipids (amino acids, peptides, and proteins) ,Lovastatin ,Proprotein Convertase 9 ,Cardiology and Cardiovascular Medicine ,medicine.drug ,Adult ,medicine.medical_specialty ,Serine Proteinase Inhibitors ,Adolescent ,Biology ,Antibodies, Monoclonal, Humanized ,LDL ,Young Adult ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Adaptor Proteins, Signal Transducing ,Alirocumab ,PCSK9 ,receptors, LDL ,Cholesterol, LDL ,medicine.disease ,Proprotein convertase ,therapeutic ,030104 developmental biology ,Endocrinology ,Case-Control Studies ,Mutation ,LDL receptor ,Hydroxymethylglutaryl-CoA Reductase Inhibitors - Abstract
Objective— Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors lower low-density lipoprotein (LDL) cholesterol in the vast majority of patients with autosomal dominant familial hypercholesterolemia. Will PCSK9 inhibition with monoclonal antibodies, in particular alirocumab, be of therapeutic value for patients with autosomal recessive hypercholesterolemia (ARH)? Approach and Results— Primary lymphocytes were obtained from 28 genetically characterized ARH patients and 11 controls. ARH lymphocytes treated with mevastatin were incubated with increasing doses of recombinant PCSK9 with or without saturating concentrations of alirocumab. Cell surface LDL receptor expression measured by flow cytometry and confocal microscopy was higher in ARH than in control lymphocytes. PCSK9 significantly reduced LDL receptor expression in ARH lymphocytes albeit to a lower extent than in control lymphocytes (25% versus 76%, respectively), an effect reversed by alirocumab. Fluorescent LDL cellular uptake, also measured by flow cytometry, was reduced in ARH lymphocytes compared with control lymphocytes. PCSK9 significantly lowered LDL cellular uptake in ARH lymphocytes, on average by 18%, compared with a 46% reduction observed in control lymphocytes, an effect also reversed by alirocumab. Overall, the effects of recombinant PCSK9, and hence of alirocumab, on LDL receptor expression and function were significantly less pronounced in ARH than in control cells. Conclusions— PCSK9 inhibition with alirocumab on top of statin treatment has the potential to lower LDL cholesterol in some autosomal recessive hypercholesterolemia patients.
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- 2016
34. Lomitapide affects HDL composition and function
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J.E. Roeters van Lennep, Monique T. Mulder, Maria Pia Adorni, Laura Calabresi, Angelo B. Cefalù, Franco Bernini, R. Yahya, Eric J.G. Sijbrands, Elda Favari, Monica Gomaraschi, Maurizio Averna, Adrie J.M. Verhoeven, Francesca Zimetti, Yahya, R., Favari, E., Calabresi, L., Verhoeven, A., Zimetti, F., Adorni, M., Gomaraschi, M., Averna, M., Cefalù, A., Bernini, F., Sijbrands, E., Mulder, M., Roeters van Lennep, J., and Internal Medicine
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Settore MED/09 - Medicina Interna ,HDL ,Homozygous familial hypercholesterolemia ,Familial hypercholesterolemia ,030204 cardiovascular system & hematology ,Hyperlipoproteinemia Type II ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Humans ,Medicine ,In patient ,Clinical efficacy ,Cholesterol ,business.industry ,Cholesterol, HDL ,Homozygote ,nutritional and metabolic diseases ,Cholesterol, LDL ,Cholesterol efflux capacity ,Atherosclerosis ,medicine.disease ,Cholesterol lowering drugs ,Lomitapide ,Phenotype ,Treatment Outcome ,030104 developmental biology ,Endocrinology ,chemistry ,Benzimidazoles ,Female ,lipids (amino acids, peptides, and proteins) ,Composition (visual arts) ,Cholesterol lowering drug ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Lipoproteins, HDL ,Cardiology and Cardiovascular Medicine ,business ,ATP Binding Cassette Transporter 1 - Abstract
Background Lomitapide reduces low-density lipoprotein-cholesterol (LDL-C) but also high-density lipoprotein-cholesterol (HDL-C) levels. The latter may reduce the clinical efficacy of lomitapide. We investigated the effect of lomitapide on HDL-C levels and on cholesterol efflux capacity (CEC) of HDL in patients with homozygous familial hypercholesterolemia (HoFH). Methods and results Four HoFH patients were treated with increasing dosages of lomitapide. Lomitapide decreased LDL-C (range −34 to −89%). Total HDL-C levels decreased (range −16 to −34%) with a shift to buoyant HDL. ABCA1-mediated CEC decreased in all patients (range −39 to −99%). The changes of total, ABCG1- and SR-BI-mediated CEC were less consistent. Conclusion Lomitapide decreased LDL-C and HDL-C levels. Our report raises the hypothesis that the anti-atherogenic potential of HDL seems to be unaffected as total CEC did not seem to change consistently. Combined with the reduction of atherogenic lipoproteins, the net effect of lomitapide appears to be beneficial in HoFH patients.
- Published
- 2016
35. Albumin versus solvent/detergent-treated pooled plasma as replacement fluid for long-term plasma exchange therapy in a patient with primary hypertriglyceridemia and recurrent hyperlipidemic pancreatitis
- Author
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Antonina Giammanco, Maurizio Averna, Calogero Caruso, Danilo Di Bona, Sergio Rizzo, Carlo M. Barbagallo, Elisabetta Scirè, Claudia Rizzo, Giacomo M. Lima, and Angelo B. Cefalù
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medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,Serum albumin ,030204 cardiovascular system & hematology ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Recurrent pancreatitis ,Internal medicine ,medicine ,Immunology and Allergy ,Lipoprotein lipase ,Triglyceride ,biology ,business.industry ,Albumin ,Hematology ,medicine.disease ,Endocrinology ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,Pancreatitis ,Acute pancreatitis ,Plasmapheresis ,business - Abstract
BACKGROUND Chylomicronemia syndrome is a metabolic condition characterized by severe fasting hypertrigliceridemia (≥1000 mg/dL) and other clinical features including chronic abdominal pain and recurrent acute pancreatitis. In patients with acute or recurrent pancreatitis, plasma exchange (PEx) is indicated for the treatment of acute disease and prevention of recurrence. The use of plasma instead of albumin as replacement fluid has been suggested for its putative ability to replace the deficient enzyme possibly leading to better clinical improvement. CASE REPORT A 40-year-old man with chylomicronemia syndrome due to a newly identified loss-of-function mutation in the lipoprotein lipase (LPL) gene (IVS2, c.250-1G/C) has been treated at our hospital since the age of 13. From age 18 to age 34, the patient had five episodes of acute pancreatitis while his triglyceride (TG) levels were extremely high (2500–4000 mg/dL). As the TG levels remained stable over 4000 mg/dL despite the maximum medical treatment, the patient started long-term PEx treatment on a weekly basIs. Both albumin and plasma have been used as replacement solution. Thirty months from the beginning of this treatment, no episode of acute pancreatitis has been reported, and the chronic abdominal pain fully disappeared. No differences were observed between the use of albumin or plasma as replacement solution. CONCLUSION Long-term PEx is effective in preventing the recurrence of acute pancreatitis and in treatment of chronic abdominal pain in this patient with chylomicronemia syndrome. Plasma is not more effective than albumin in lipid reduction, likely because of its extremely low enzyme content. Therefore, in patients with LPL deficiency serum albumin should be preferred to plasma as replacement fluid because of the low rate of side effects and reduced costs.
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- 2015
36. Automated untargeted stable isotope assisted lipidomics of liver cells on high glucose shows alteration of sphingolipid kinetics
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C. Scrimali, Serena Indelicato, Massimiliano Greco, Rossella Spina, Maurizio Averna, Ida Altieri, Antonina Giammanco, Francesca Di Gaudio, Davide Noto, Angelo B. Cefalù, David Bongiorno, Francesca Fayer, Sergio Indelicato, Alessandro Mattina, Noto D., Di Gaudio F., Altieri I.G., Cefalu A.B., Indelicato S., Fayer F., Spina R., Scrimali C., Giammanco A., Mattina A., Greco M., Bongiorno D., and Averna M.
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Kinetics ,Palmitic Acid ,Hep G2 Cell ,Fatty Acids, Nonesterified ,Orbitrap ,High resolution mass spectrometry ,01 natural sciences ,Gas Chromatography-Mass Spectrometry ,Workflow ,law.invention ,Palmitic acid ,Automation ,03 medical and health sciences ,chemistry.chemical_compound ,Insulin resistance ,law ,Lipidomics ,medicine ,Humans ,Molecular Biology ,030304 developmental biology ,Kinetic ,Sphingolipids ,0303 health sciences ,Chromatography ,Chemistry ,Lipidomic ,010401 analytical chemistry ,Lipid metabolism ,Hep G2 Cells ,Cell Biology ,Deuterium ,Lipid Metabolism ,medicine.disease ,Culture Media ,0104 chemical sciences ,Glucose ,Isotope Labeling ,Cell model ,Hepatocytes ,Monoisotopic mass ,Sphingomyelin ,Algorithms ,Software - Abstract
Untargeted lipidomics is a powerful tool to discover new biomarkers and to understand the physiology and pathology of lipids. The use of stable isotopes as tracers to investigate the kinetics of lipids is another tool able to supply dynamic information on lipid synthesis and catabolism. Coupling the two methodology is then very appealing in the study of lipid metabolism. The main issue to face is to perform thousands of calculations in order to obtain kinetic parameters starting from the MS raw data. An automated computerized routine able to do accomplish such task is presented in this paper. We analyzed the lipid kinetics of palmitic acid (PA) in hepatoma liver cells cultured in vitro in which insulin resistance has been induced by high glucose supplementation. The deuterated palmitate tracer (d5PA) was administered as a bolus and the cells were harvested daily for 48 h. 5dPA was incorporated into 326 monoisotopic compounds and in 84 of their [M + 1] isotopologues detected by high resolution orbitrap MS. The differences between the kinetics curves showed that at least four long chain triglycerides (TG) species incorporated more PA in glucose treated cells, while phosphocholines, sphingomyelins, mono- and di-glycerides and ceramides (Cer) incorporated less tracer under glucose treatment. Nevertheless, Cer amount was increased by glucose treatment. In conclusion we developed an automated powerful algorithm able to model simultaneously hundreds of kinetic curves obtained in a cell culture spiked with a stable isotope tracer, and to analyze the difference between the two different cell models.
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- 2020
37. Identification and diagnosis of patients with familial chylomicronaemia syndrome (FCS): Expert panel recommendations and proposal of an 'FCS score'
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Handrean Soran, Maurizio Averna, Davide Noto, Elizabeth A. Hughes, Luis Antonio Alvarez-Sala Walther, Angelo B. Cefalù, Željko Reiner, Alessia Di Costanzo, Laura D'Erasmo, Robert Dufour, Ioanna Gouni-Berthold, Erik S.G. Stroes, Jan Borén, C. Marcais, Philippe Moulin, Marcello Arca, Eric Bruckert, Xavier Pintó, Colin D. Johnson, Jeanine E. Roeters van Lennep, Maciej Banach, Robert Cramb, Claudia Stefanutti, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Department of Bioinformatics and Telemedicine, Jagiellonian University - Medical College, Jagiellonian University [Krakow] (UJ)-Jagiellonian University [Krakow] (UJ), Service d' Endocrinologie, Centre Hospitalier Universitaire de Grenoble, Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ)-Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Internal Medicine, Moulin, Philippe, Dufour, Robert, Averna, Maurizio, Arca, Marcello, Cefalù, Angelo B., Noto, Davide, D'Erasmo, Laura, Di Costanzo, Alessia, Marçais, Christophe, Alvarez-Sala Walther, Luis Antonio, Banach, Maciej, Borén, Jan, Cramb, Robert, Gouni-Berthold, Ioanna, Hughes, Elizabeth, Johnson, Colin, Pintó, Xavier, Reiner, Željko, van Lennep, Jeanine Roeter, Soran, Handrean, Stefanutti, Claudia, Stroes, Erik, and Bruckert, Eric
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[SDV]Life Sciences [q-bio] ,Diagnosis tool ,population ,030204 cardiovascular system & hematology ,burden ,apoa5 ,0302 clinical medicine ,Loss of Function Mutation ,Risk Factors ,Chylomicrons ,030212 general & internal medicine ,Age of Onset ,Hypolipidemic Agents ,BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti. Interna medicina ,Lipoprotein lipase ,plasma triglycerides ,hyperlipoproteinemia ,Prognosis ,3. Good health ,Up-Regulation ,Phenotype ,Acute pancreatitis ,lipids (amino acids, peptides, and proteins) ,Hyperlipoproteinemia Type I ,Familial chylomicronaemia syndrome ,Major hypertriglyceridaemia ,Multifactorial chylomicronaemia ,Cardiology and Cardiovascular Medicine ,Algorithms ,acute-pancreatitis ,medicine.medical_specialty ,Consensus ,hypertriglyceridemia ,etiology ,Decision Support Techniques ,Diagnosis, Differential ,03 medical and health sciences ,Predictive Value of Tests ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Acute pancreatiti ,BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences. Internal Medicine ,Genotyping ,Triglycerides ,Pregnancy ,Receiver operating characteristic ,business.industry ,severe ,Reproducibility of Results ,mutations ,lipoprotein-lipase gene ,medicine.disease ,Confidence interval ,Lipoprotein Lipase ,Pancreatitis ,Cardiovascular System & Cardiology ,business ,Biomarkers - Abstract
Familial chylomicronaemia syndrome (FCS) is a rare, inherited disorder characterised by impaired clearance of triglyceride (TG)-rich lipoproteins from plasma, leading to severe hypertriglyceridaemia (HTG) and a markedly increased risk of acute pancreatitis. It is due to the lack of lipoprotein lipase (LPL) function, resulting from recessive loss of function mutations in the genes coding LPL or its modulators. A large overlap in the phenotype between FCS and multifactorial chylomicronaemia syndrome (MCS) contributes to the inconsistency in how patients are diagnosed and managed worldwide, whereas the incidence of acute hypertriglyceridaemic pancreatitis is more frequent in FCS. A panel of European experts provided guidance on the diagnostic strategy surrounding FCS and proposed an algorithm-based diagnosis tool for identification of these patients, which can be readily translated into practice. Features included in this FCS score comprise: severe elevation of plasma TGs (fasting TG levels \textgreater 10 mmol/L [885 mg/dL] on multiple occasions), refractory to standard TG-lowering therapies, a young age at onset, the lack of secondary factors (except for pregnancy and oral oestrogens) and a history of episodes of acute pancreatitis. Considering 53 FCS patients from three cohorts and 52 MCS patients from three cohorts, the overall sensitivity of the FCS score (\textgreater= 10) was 88% (95% confidence interval [CI]: 0.76, 0.97) with an overall specificity of 85% (95% CI: 0.75, 0.94). Receiver operating characteristic curve area was 0.91. Pragmatic clinical scoring, by standardising diagnosis, may help differentiate FCS from MCS, may alleviate the need for systematic genotyping in patients with severe HTG and may help identify high-priority candidates for genotyping. (c) 2018 The Authors. Published by Elsevier B.V.
- Published
- 2018
38. Anti-PCSK9 treatment: is ultra-low low-density lipoprotein cholesterol always good?
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Angelo B. Cefalù, Maurizio Averna, Davide Noto, Carlo M. Barbagallo, and Antonina Giammanco
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0301 basic medicine ,Serine Proteinase Inhibitors ,Time Factors ,Physiology ,medicine.drug_class ,030204 cardiovascular system & hematology ,Pharmacology ,Monoclonal antibody ,Risk Assessment ,03 medical and health sciences ,PCSK9 Gene ,chemistry.chemical_compound ,0302 clinical medicine ,Risk Factors ,Physiology (medical) ,Diabetes mellitus ,medicine ,Animals ,Humans ,Dyslipidemias ,medicine.diagnostic_test ,business.industry ,Cholesterol ,PCSK9 ,Anticholesteremic Agents ,PCSK9 Inhibitors ,Antibodies, Monoclonal ,Cholesterol, LDL ,medicine.disease ,Fatty Liver ,Hypocholesterolemia ,030104 developmental biology ,Treatment Outcome ,chemistry ,Diabetes Mellitus, Type 2 ,lipids (amino acids, peptides, and proteins) ,Proprotein Convertase 9 ,Cardiology and Cardiovascular Medicine ,Lipid profile ,business ,Cognition Disorders ,Biomarkers ,Lipoprotein - Abstract
Anti-PCSK9 (proprotein convertase subtilisin kexin 9) monoclonal antibodies (Mab) are novel, potent lipid-lowering drugs. They demonstrated to improve the lipid profile in high cardiovascular risk patients. Anti-PCSK9 Mab inhibit the targeted low-density lipoprotein (LDL)-receptor degradation induced by PCSK9 protein and are able to reduce LDL cholesterol (LDL-C) levels on top of conventional lipid-lowering therapy. Though these drugs proved to be very safe in the short-term, little is known about the possible long-term effects, due to the short period of their marketing. The genetic low cholesterol syndromes (LCS) represent the natural models of the lipid-lowering anti-PCSK9 therapy, and a valuable opportunity to predict the long-term effects of these drugs. By looking at the clinical features of such models, we could be able to foresee possible drug-induced side effects. In the present review, the correspondences and discordances between the side effects of anti-PCSK9 therapy and the corresponding LCS models will be examined in the attempt to forecast possible long-term consequences of these novel lipid-lowering agents.
- Published
- 2018
39. Lack of Correlation of Plasma HDL With Fecal Cholesterol and Plasma Cholesterol Efflux Capacity Suggests Importance of HDL Functionality in Attenuation of Atherosclerosis
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Angelo B. Cefalù, Maurizio Averna, Neelam Srivastava, Rai Ajit K. Srivastava, Srivastava, Neelam, Cefalu, Angelo B., Averna, Maurizio, and Srivastava, Rai A. K.
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Settore MED/09 - Medicina Interna ,HDL ,Apolipoprotein B ,Physiology ,030204 cardiovascular system & hematology ,lcsh:Physiology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,Cholesterylester transfer protein ,medicine ,HDL, mouse, PPAR-α, LXR, reverse cholesterol transport, cholesterol efflux, ABCA1, atherosclerosis ,Liver X receptor ,mouse ,Fenofibrate ,lcsh:QP1-981 ,biology ,Cholesterol ,Reverse cholesterol transport ,nutritional and metabolic diseases ,reverse cholesterol transport ,030104 developmental biology ,Endocrinology ,chemistry ,ABCA1 ,biology.protein ,Cholesteryl ester ,LXR ,lipids (amino acids, peptides, and proteins) ,cholesterol efflux ,PPAR-α ,medicine.drug - Abstract
A number of clinical findings suggested HDL-raising as a plausible approach to treat residual risk of CVD. However, lack of CVD risk reduction by elevated HDL cholesterol (HDL-C) through cholesterol ester transfer protein (CETP) inhibition and enhanced risk reduction in apolipoprotein A-I Milano (apoAI-M) individuals with low HDL-C shifted the focus from HDL-C level to HDL function. In the present study, we investigated correlations between HDL-C, HDL function, fecal cholesterol excretion, and ex vivo plasma cholesterol efflux capacity (CEC) in animal models using two HDL modulators, LXR and PPAR-α agonists. In C57Bl mice, LXR agonist, T1317, raised HDL-C by 30%, while PPAR-α agonist, fenofibrate, reduced HDL-C by 30%, but fecal cholesterol showed twofold increase in both cases. CEC showed a 30–40% increase. Combination of LXR and PPAR-α agonists showed no changes in HDL-C, but, interestingly, fecal cholesterol increased by 4.5-fold, and CEC by 40%, suggesting existence of additional pathway for fecal cholesterol excretion. Regression analysis showed a lack of correlation between HDL-C and fecal cholesterol and CEC, while fecal cholesterol showed significant correlation with CEC, a measure of HDL function. ABCA1 and G1, the two important players in RCT showed greater induction with LXR agonist than PPAR-α agonist. HDL-C increased by 40 and 80% in LXR and PPAR-α treated apoA-I transgenic mice, respectively, with 80% increase in fecal cholesterol. A fivefold increase in fecal cholesterol with no correlation with either plasma HDL-C or CEC following co-treatment with LXR and PPAR-α agonists suggested existence of an HDL-independent pathway for body cholesterol elimination. In hyperlipidemic diabetic ob/ob mice also combination of LXR and PPAR-α agonists showed marked increases in fecal cholesterol content (10–20-fold), while HDL-C rise was only 40%, further suggesting HDL-independent elimination of body cholesterol in mice treated with combination of LXR and PPAR-α agonists. Atherosclerosis attenuation by LXR and PPAR-α agonists in LDLr-deficient mice was associated with increased fecal cholesterol, but not HDL-C. However, fecal cholesterol counts showed inverse correlation with aortic cholesteryl ester content. These data suggest: (a) lack of correlation between HDL-C and fecal or aortic cholesterol content; (b) HDL function (CEC) correlated with fecal cholesterol content; (c) association of reduced aortic lipids in LDLr−/− mice with increased fecal cholesterol, but not with HDL-C, and (d) existence of an HDL-independent pathway for fecal cholesterol excretion following co-treatment with LXR and PPAR-α agonists.
- Published
- 2018
40. Heparin induces an accumulation of atherogenic lipoproteins during hemodialysis in normolipidemic end-stage renal disease patients
- Author
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Maurizio Averna, Davide Noto, Angelo B. Cefalù, Antonia Ganci, Gaspare Cusumano, Francesca Di Gaudio, Massimiliano Greco, Carlo M. Barbagallo, Carlo Giammarresi, and Donata Panno
- Subjects
Apolipoprotein E ,medicine.medical_specialty ,Triglyceride ,business.industry ,medicine.medical_treatment ,Hematology ,Heparin ,End stage renal disease ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Nephrology ,Concomitant ,Internal medicine ,Medicine ,lipids (amino acids, peptides, and proteins) ,Hemodialysis ,business ,Dialysis ,medicine.drug ,Lipoprotein - Abstract
Dyslipidemias may account for the excess of cardiovascular mortality in end-stage renal disease (ESRD). Lipoprotein studies in ESRD patients are usually relative to prehemodialysis samples even if significative changes may occur after dialysis. In this study, we aimed to investigate the effects of ESRD on triglyceride-rich lipoproteins (TRL) subpopulations distribution and acute change following hemodialytic procedures, including the relative contribution of heparin administration. We selected a group of normolipidemic male middle-aged ESRD patients free of any concomitant disease affecting lipoprotein remnant metabolism compared with controls. We separated TRL subfractions according to density and apoE content and evaluated the changes of these particles after hemodialytic procedures with or without heparin. ESRD subjects had higher TRL subfractions, with the exception of apoE-rich particles, lower high-density lipoprotein (HDL) largest subclasses, and a smaller low-density lipoprotein peak particle size than controls. After a hemodialytic standard procedure with heparin, we demonstrated a significant reduction of triglyceride, an increase of HDL-cholesterol levels, and a raise of small very-low-density lipoprotein, intermediate-density lipoproteins (IDL), apoE-rich particles, and non-HDL-cholesterol levels. When hemodialysis was performed without heparin, no significant changes were observed. In the absence of concomitant hyperlipidemic triggers, ESRD patients show significant lipoprotein abnormalities before dialysis, but without any increased remnant particles concentrations. We speculate that hemodialysis, in particular heparin administration during this procedure, leads to a massive atherogenic TRLs production because of the acute stimulation of the dysfunctional lipolytic system not followed by an efficient removal, determining a recurrent lipoprotein remnant accumulation.
- Published
- 2014
41. Genetic epidemiology of autosomal recessive hypercholesterolemia in Sicily: Identification by next-generation sequencing of a new kindred
- Author
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Roberto Monastero, Gabriella Misiano, Maurizio Averna, Davide Noto, V. Ingrassia, Antonina Pipitone, Vincenza Valenti, Angelo B. Cefalù, Rossella Spina, C. Scrimali, Carlo M. Barbagallo, Antonina Giammanco, Maria P. La Spada, Roberta Baschi, Spina, R., Noto, D., Barbagallo, C., Monastero, R., Ingrassia, V., Valenti, V., Baschi, R., Pipitone, A., Giammanco, A., La Spada, M., Misiano, G., Scrimali, C., Cefalu', A., and Averna, M.
- Subjects
0301 basic medicine ,Male ,Settore MED/09 - Medicina Interna ,Endocrinology, Diabetes and Metabolism ,Familial hypercholesterolemia ,030204 cardiovascular system & hematology ,0302 clinical medicine ,Child ,N-Glycosyl Hydrolases ,Sicily ,Genetics ,Aged, 80 and over ,education.field_of_study ,Nutrition and Dietetics ,Allele frequency ,Homozygote ,High-Throughput Nucleotide Sequencing ,Autosomal recessive hypercholesterolemia ,Middle Aged ,Autosomal Recessive Hypercholesterolemia ,Settore MED/26 - Neurologia ,Female ,Cardiology and Cardiovascular Medicine ,Adult ,Adolescent ,Genotype ,Population ,Hypercholesterolemia ,Biology ,DNA sequencing ,03 medical and health sciences ,Young Adult ,ARH1 ,Internal Medicine ,medicine ,Humans ,Allele ,education ,Genotyping ,Alleles ,Adaptor Proteins, Signal Transducing ,Aged ,Heterozygous carrier ,Sequence Analysis, DNA ,medicine.disease ,NGS-based gene panel ,030104 developmental biology ,Genetic epidemiology ,Receptors, LDL - Abstract
Background Autosomal recessive hypercholesterolemia (ARH) is a rare inherited lipid disorder. In Sardinia, differently from other world regions, the mutated allele frequency is high. It is caused by mutations in the low-density lipoprotein receptor adaptor protein 1 gene. Fourteen different mutations have been reported so far; in Sardinia, 2 alleles (ARH1 and ARH2) explain most of the cases. Four ARH patients, all carriers of the ARH1 mutation, have been identified in mainland Italy and 2 in Sicily. Objective The objectives of the study were to improve the molecular diagnosis of familial hypercholesterolemia (FH) and to estimate the frequency of the ARH1 allele in 2 free-living Sicilian populations. Methods We sequenced by targeted next-generation sequencing 20 genes related to low-density lipoprotein metabolism in 50 hypercholesterolemic subjects. Subjects from 2 free-living populations from Northern (Ventimiglia Heart Study, 848 individuals) and Southern Sicily (Zabut Zabut Aging Project, 1717 individuals) were genotyped for ARH1 allele. Results We identified 1 homozygous carrier of the ARH1 mutation among the 50 hypercholesterolemic outpatients. Population-based genotyping of ARH1 in 2565 subjects allowed the identification of 1 heterozygous carrier. The overall estimated allele frequency of ARH1 in Sicily was 0.0002 (0.02%). Conclusions The identification of a new case of ARH in Sicily among 50 clinically diagnosed FH highlights the importance of next-generation sequencing analysis as tool to improve the FH diagnosis. Our results also indicate that ARH1 carrier status is present in ∼1:2500 of Sicilian inhabitants, confirming that ARH is extremely rare outside Sardinia.
- Published
- 2017
42. Efficacy of Lomitapide in the Treatment of Familial Homozygous Hypercholesterolemia: Results of a Real-World Clinical Experience in Italy
- Author
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Marco Bucci, Tiziana Sampietro, Maurizio Averna, Fulvio Sileo, Paolo Pintus, Antonina Giammanco, Patrizia Suppressa, Francesco Natale, Davide Noto, Cesare Sirtori, Carlo Sabbà, Paolo Medde, Paolo Calabrò, Giovanni Battista Vigna, Laura Calabresi, Angelo B. Cefalù, Laura D'Erasmo, Francesco Sbrana, Marcello Arca, Katia Bonomo, Federico Bigazzi, Chiara Pavanello, D'Erasmo, Laura, Cefalù, Angelo Baldassare, Noto, Davide, Giammanco, Antonina, Averna, Maurizio, Pintus, Paolo, Medde, Paolo, Vigna, Giovanni Battista, Sirtori, Cesare, Calabresi, Laura, Pavanello, Chiara, Bucci, Marco, Sabbà, Carlo, Suppressa, Patrizia, Natale, Francesco, Calabro', Paolo, Sampietro, Tiziana, Bigazzi, Federico, Sbrana, Francesco, Bonomo, Katia, Sileo, Fulvio, Arca, Marcello, D'Erasmo, L., Cefalu', A., Noto, D., Giammanco, A., Averna, M., Pintus, P., Medde, P., Vigna, G., Sirtori, C., Calabresi, L., Pavanello, C., Bucci, M., Sabbã , C., Suppressa, P., Natale, F., Calabrã², P., Sampietro, T., Bigazzi, F., Sbrana, F., Bonomo, K., Sileo, F., and Arca, M.
- Subjects
Male ,Settore MED/09 - Medicina Interna ,Hyperlipidemia, Familial Combined ,030204 cardiovascular system & hematology ,Pharmacology ,Benzimidazole ,cholesterol-lowering effect ,clinical practice ,genetics ,lomitapide ,severe hypercholesterolemia ,medicine (all) ,pharmacology (medical) ,chemistry.chemical_compound ,0302 clinical medicine ,Retrospective Studie ,Anticholesteremic Agent ,030212 general & internal medicine ,Aged, 80 and over ,Anticholesteremic Agents ,Homozygote ,General Medicine ,Middle Aged ,Safety profile ,Italy ,lipids (amino acids, peptides, and proteins) ,Female ,Human ,Adult ,medicine.medical_specialty ,Socio-culturale ,Liver ultrasound ,LDLRAP1 gene ,Hyperlipoproteinemia Type II ,03 medical and health sciences ,Genetic ,Internal medicine ,medicine ,Humans ,Liver damage ,Familial homozygous hypercholesterolemia ,Aged ,Retrospective Studies ,business.industry ,medicine.disease ,Rheumatology ,Lomitapide ,chemistry ,Benzimidazoles ,business ,Dyslipidemia - Abstract
Homozygous familial hypercholesterolaemia (HoFH) is a rare form of inherited dyslipidemia resistant to conventional cholesterol-lowering medications so that lipoprotein apheresis (LA) is usually required. Lomitapide has been approved for the treatment of HoFH. The aim of this study was to evaluate the benefits of lomitapide in HoFH patients followed with the usual clinical care. Homozygous familial hypercholesterolaemia (HoFH) is a rare form of inherited dyslipidemia resistant to conventional cholesterol-lowering medications so that lipoprotein apheresis (LA) is usually required. Lomitapide has been approved for the treatment of HoFH. The aim of this study was to evaluate the benefits of lomitapide in HoFH patients followed with the usual clinical care.Clinical and biochemical data were retrospectively collected in 15 HoFH patients (10 with mutations in the LDLR gene and 5 in the LDLRAP1 gene) treated for at least 6 months with lomitapide in addition to lipid-lowering therapies (LLT) in different Lipid Clinics across Italy.The mean follow-up period was 32.3 +/- 29.7 months. During background therapies, HoFH patients showed a mean LDL-C level of 426.0 +/- 204.0 mg/dl. The addition of lomitapide at the average dosage of 19 mg/day lowered LDL-C levels by 68.2 +/- 24.8%. At their last visit, 60% of patients showed LDL-C < 100 mg/dl and 46.6% < 70 mg/dl. During follow-up, 8 of 10 patients receiving LA (80%) stopped this treatment due to marked LDL-C reduction. A wide range (13-95%) of individual LDL-C reduction was observed, but this was not related to genotype. During follow-up, 53.3% of patients reported at least one episode of diarrhea, but none was referred as severe; none had liver transaminase > 5x ULN or had to stop treatment due to side effects. A subset of patients was evaluated by liver ultrasound and fibroscan (n = 5) or nuclear magnetic resonance with spectroscopy (MRS) (n = 1) not showing clinical evidence of liver damage.In this real-world experience, lomitapide was confirmed to be a very powerful cholesterol-lowering agent in HoFH showing a good safety profile.
- Published
- 2017
43. Clinical and biochemical characteristics of individuals with low cholesterol syndromes: A comparison between familial hypobetalipoproteinemia and familial combined hypolipidemia
- Author
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Alessia Di Costanzo, Angelo B. Cefalù, Laura D'Erasmo, Patrizia Tarugi, Maurizio Averna, Enza Di Leo, Vito Cantisani, Davide Noto, Rossella Spina, Luca Polito, Ilenia Minicocci, Marcello Arca, Di Costanzo, A., Di Leo, E., Noto, D., Cefalu', A., Minicocci, I., Polito, L., D'Erasmo, L., Cantisani, V., Spina, R., Tarugi, P., Averna, M., and Arca, M.
- Subjects
0301 basic medicine ,Male ,Hepatic steatosis ,Settore MED/09 - Medicina Interna ,Apolipoprotein B ,Endocrinology, Diabetes and Metabolism ,030204 cardiovascular system & hematology ,medicine.disease_cause ,ANGPTL3 gene ,APOB gene ,Familial combined hypolipidemia ,Familial hypobetalipoproteinemia ,HDL cholesterol ,Low cholesterol syndromes ,Hypobetalipoproteinemias ,Exon ,0302 clinical medicine ,ANGPTL3 ,Nutrition and Dietetic ,Genetics ,Mutation ,Nutrition and Dietetics ,biology ,hepatic steatosis ,Homozygote ,Middle Aged ,Phenotype ,lipids (amino acids, peptides, and proteins) ,Female ,Cardiology and Cardiovascular Medicine ,familial combined hypolipidemia ,familial hypobetalipoproteinemia ,low cholesterol syndromes ,medicine.medical_specialty ,Heterozygote ,Low cholesterol syndrome ,Hepatic steatosi ,03 medical and health sciences ,Internal medicine ,Internal Medicine ,medicine ,Humans ,Gene ,Aged ,Angiopoietin-Like Protein 3 ,Apolipoproteins B ,business.industry ,Heterozygote advantage ,medicine.disease ,030104 developmental biology ,Endocrinology ,Angiopoietin-like Proteins ,biology.protein ,Steatosis ,business - Abstract
Background The most frequent monogenic causes of low plasma cholesterol are familial hypobetalipoproteinemia (FHBL1) because of truncating mutations in apolipoprotein B coding gene (APOB) and familial combined hypolipidemia (FHBL2) due to loss-of-function mutations in ANGPTL3 gene. Objective A direct comparison of lipid phenotypes of these 2 conditions has never been carried out. In addition, although an increased prevalence of liver steatosis in FHBL1 has been consistently reported, the hepatic consequences of FHBL2 are not well established. Methods We investigated 350 subjects, 67 heterozygous carriers of APOB mutations, 63 carriers of the p.S17* mutation in ANGPTL3 (57 heterozygotes and 6 homozygotes), and 220 noncarrier normolipemic controls. Prevalence and degree of hepatic steatosis were assessed by ultrasonography. Results A steady decrease of low-density lipoprotein cholesterol levels were observed from heterozygous to homozygous FHBL2 and to FHBL1 individuals, with the lowest levels in heterozygous FHBL1 carrying truncating mutations in exons 1 to 25 of APOB (P for trend
- Published
- 2017
44. Genotypic and phenotypic characterization of patients with autosomal dominant hypercholesterolemia in sicily
- Author
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Francesca Fayer, Rossella Spina, Angelo B. Cefalù, Maurizio Averna, G.I. Altieri, Gabriella Misiano, Carlo M. Barbagallo, Davide Noto, V. Ingrassia, Antonina Giammanco, C. Scrimali, A. Ganci, Vincenza Valenti, Giammanco, Antonina, Spina, Rossella, Ingrassia, Valeria, Valenti, Vincenza, Scrimali, Chiara, Misiano, Gabriella, Altieri, Grazia I., Fayer, Francesca, Barbagallo, Carlo M., Ganci, Antonina, Noto, Davide, Cefalu', Angelo B., and Averna, Maurizio
- Subjects
Genetics ,Genotype ,medicine ,Familial hypercholesterolemia ,Biology ,Familial Hypercholesterolemia ,Cardiology and Cardiovascular Medicine ,medicine.disease ,Phenotype - Abstract
Aim: Autosomal dominant hypercholesterolemia (ADH) is an autosomal dominant disorder characterized by high serum low density lipoproteincholesterol (LDL-C) levels. The clinical manifestations of ADH might vary among affected subjects and the phenotype correlates with the severity of mutation and the specific gene involved. The aim of this study was to evaluate the clinical expression and clinical outcomes in a cohort of ADH subjects. Methods: 300 ADH probands with a DUTCH score > 6 were enrolled in this study and the analysis was extended to the family members of these index cases. Anthropometric measures, clinical and biochemical parameters, life style (smoker and/or alcohol habits) and cardiovascular outcomes were evaluated. A total of 407 relatives were identified and characterized as well. Results: Molecular diagnosis was defined in 62.6 % of probands; 97 % were carriers of pathogenic mutations in LDLR gene (55 different mutations). The phenotypic characterization of LDLR mutation carriers (ADH-1) and revealed that in both sexes independent predictors of the presence of tendon xanthomas were LDL cholesterol, the presence of coronary heart disease (CHD) and of receptor negative mutations. Independent predictors of CHD were male gender, tendon xanthomas. Conclusions: This study confirms the genetic heterogeneity of ADH and underscores that the variability in phenotypic expression of ADH-1 is greatly affected by the type of LDLR mutation.
- Published
- 2017
45. Lomitapide: a novel drug for homozygous familial hypercholesterolemia
- Author
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Maurizio Averna, Maria D. Panno, Angelo B. Cefalù, Panno, MD, Cefalu', AB, and Averna, M
- Subjects
Drug ,Settore MED/09 - Medicina Interna ,Endocrinology, Diabetes and Metabolism ,media_common.quotation_subject ,HoFH ,apheresi ,Familial hypercholesterolemia ,Pharmacology ,Microsomal triglyceride transfer protein ,chemistry.chemical_compound ,Medicine ,media_common ,Ldl cholesterol ,biology ,business.industry ,Plasma levels ,medicine.disease ,Lomitapide ,Treatment period ,apheresis ,Apheresis ,chemistry ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Cardiology and Cardiovascular Medicine ,business - Abstract
Lomitapide (Juxtapid® and Lojuxta®; Aegerion Pharmaceuticals, Inc., MA, USA), an orally administered inhibitor of the microsomal triglyceride transfer protein, inhibits the synthesis and secretion of ApoB-containing lipoproteins and, thus, reduces plasma levels of LDL cholesterol (LDL-C). Lomitapide has been approved for the therapy of homozygous familial hypercholesterolemia patients. After a proof-of-concept Phase II trial, lomitapide has been tested in a multinational single-arm, open-label, 78-week, Phase III trial. Lomitapide effectively reduced mean plasma LDL-C levels by 50% from baseline in 23 adults with homozygous familial hypercholesterolemia over a 26-week treatment period and this reduction was sustained for an additional 52 weeks of lomitapide treatment. The Phase III trial also demonstrated that 46% of patients (six out of 13) interrupted or reduced the frequency of apheresis treatments because of an important and stable reduction of LDL-C. Lomitapide was generally well tolerated and the most common adverse events in the Phase III trial were gastrointestinal and hepatic events.
- Published
- 2014
46. Coronary artery calcium is independently associated to pulse wave velocity and LDL cholesterol burden in patients with familial hypercholesterolemia
- Author
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Alessandro Mattina, Maurizio Averna, Davide Noto, T. Smeraldi, Francesca Fayer, C. Di Benedetto, Ludovico La Grutta, Rossella Spina, Massimo Midiri, F. D'Ignoto, A. Giammanco, Angelo B. Cefalù, Giulio Geraci, C.M. Barbagallo, and A. Cardella
- Subjects
Ldl cholesterol ,Coronary artery calcium ,medicine.medical_specialty ,business.industry ,Internal medicine ,Cardiology ,Medicine ,In patient ,Familial hypercholesterolemia ,Cardiology and Cardiovascular Medicine ,business ,medicine.disease ,Pulse wave velocity - Published
- 2018
47. Withdrawal: Lipase maturation factor 1 is required for endothelial lipase activity
- Author
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Nicole Ehrhardt, Howard Wong, Angelo B. Cefalù, Maryam Hosseini, Maurizio Averna, Davide Noto, Mark H. Doolittle, Ching-Mei Lai, Miklós Péterfy, and Osnat Ben-Zeev
- Subjects
Endothelial lipase ,medicine.medical_specialty ,biology ,Chemistry ,Maturation Factor 1 ,QD415-436 ,Cell Biology ,Biochemistry ,Endocrinology ,Internal medicine ,medicine ,biology.protein ,Lipase - Published
- 2019
48. Prevalence Of Statin Intolerance In A Cohort Of Outpatients In A Lipid Clinic
- Author
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Vincenza Valenti, Alessandro Mattina, C.M. Barbagallo, A. Giammanco, Gabriella Misiano, Maurizio Averna, A. Ganci, Davide Noto, Angelo B. Cefalù, V. Ingrassia, F. Brucato, M. Trevisin, A. Cardella, C. Scrimali, Rossella Spina, Giammanco, A, Noto, D, Trevisin, M, Mattina, A, Cardella, A, Spina, R, Scrimali, C, Brucato, F, Ingrassia, V, Valenti, V, Misiano, G, Barbagallo, CM, Ganci, A, Cefalu, AB, and Averna, M
- Subjects
medicine.medical_specialty ,Statin ,business.industry ,medicine.drug_class ,Internal medicine ,Cohort ,lipid clinic ,Medicine ,Cardiology and Cardiovascular Medicine ,business ,Lipid clinic ,statin intolerance - Published
- 2019
49. Identification Of P.Leu167Del Apoe Gene Mutation By Next Generation Sequencing In A Large Hypercholesterolemic Family
- Author
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V. Ingrassia, Maurizio Averna, G.I. Altieri, F. Brucato, Francesca Fayer, C. Scrimali, Davide Noto, C.M. Barbagallo, A. Giammanco, Vincenza Valenti, Rossella Spina, Angelo B. Cefalù, Gabriella Misiano, Scrimali, C, Spina, R, Ingrassia, V, Cefalu, AB, Brucato, F, Misiano, G, Valenti, V, Noto, D, Altieri, GI, Fayer, F, Giammanco, A, Barbagallo, C, and Averna, M
- Subjects
Apolipoprotein E ,Genetics ,Settore MED/09 - Medicina Interna ,NEXT GENERATION SEQUENCING HYPERCHOLESTEROLEMIA ,Mutation (genetic algorithm) ,APOE GENE ,Identification (biology) ,Biology ,Cardiology and Cardiovascular Medicine ,MUTATION ,DNA sequencing - Published
- 2019
50. The Atrial Natriuretic Peptide Genetic Variant rs5068 Is Associated With a Favorable Cardiometabolic Phenotype in a Mediterranean Population
- Author
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John C. Burnett, G. Cavera, Michele Pagano, M. Sapienza, Valentina Cannone, Kent R. Bailey, Maurizio Averna, Christopher G. Scott, Davide Noto, Angelo B. Cefalù, Cannone, V, Cefalu', AB, Noto, D, Scott, CG, Bailey, KR, Cavera, G, Pagano, M, Sapienza, M, Averna, M, and Burnett, JCJr
- Subjects
Adult ,Male ,genetic variant ,Cardiovascular and Metabolic Risk ,medicine.medical_specialty ,Settore MED/09 - Medicina Interna ,Genotype ,Endocrinology, Diabetes and Metabolism ,Population ,Blood Pressure ,Gene Frequency ,cardiometabolic phenotype ,Atrial natriuretic peptide ,Internal medicine ,Natriuretic Peptide, Brain ,atrial natriuretic peptide ,Internal Medicine ,medicine ,Humans ,Allele ,education ,Allele frequency ,Aged ,Original Research ,Advanced and Specialized Nursing ,education.field_of_study ,business.industry ,Odds ratio ,Middle Aged ,medicine.disease ,Genotype frequency ,Minor allele frequency ,Phenotype ,Endocrinology ,Female ,Metabolic syndrome ,business ,Atrial Natriuretic Factor - Abstract
OBJECTIVE We hypothesized that the minor allele of the atrial natriuretic peptide (ANP) genetic variant rs5068 is associated with a favorable cardiometabolic phenotype in a general Mediterranean population. RESEARCH DESIGN AND METHODS We genotyped a random sample of the residents of Ventimiglia di Sicilia, Sicily, for rs5068. RESULTS Genotype frequencies of rs5068 are AA, 93.5%; AG, 6.4%; and GG, 0.1%. All subsequent analyses are AA versus AG+GG. After adjusting for age and sex, the minor G allele is associated with lower BMI (estimate [SE]: −1.7 kg/m2 [0.8], P = 0.04). In the AG+GG group, males with HDL cholesterol levels CONCLUSIONS The association between the minor allele of rs5068 and a favorable cardiometabolic phenotype that we previously reported in a U.S. population is now replicated in a Mediterranean population in which the G allele of rs5068 is associated with lower blood pressure, BMI, and prevalence of hypertension and metabolic syndrome. These findings may lead to a diagnostic strategy to assess cardiometabolic risk and lay the foundation for the future development of an ANP or ANP-like therapy for metabolic syndrome.
- Published
- 2013
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