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1. Sphingolipid and Trimethylamine-N-Oxide (TMAO) Levels in Women with Obesity after Combined Physical Training

Author: Camila Fernanda Cunha Brandao, Michel Krempf, Flávia Giolo de Carvalho, Audrey Aguesse, Márcia Varella Morandi Junqueira-Franco, Gabriela Batitucci, Ellen Cristini de Freitas, Natalia Yumi Noronha, Guilherme da Silva Rodrigues, Gizela Pedroso Junqueira, Diego Alcantara Borba, Stéphanie Billon-Crossouard, Mikael Croyal, and Julio Sergio Marchini
Subjects: physical fitness, body composition, lipids, cardiovascular risk, weight loss, Microbiology, QR1-502
Abstract: Obesity causes metabolic changes, such as the development of cardiovascular diseases. Moreover, physical exercise promotes protection against these diseases. Thus, the objective of the present study was to evaluate whether combined physical training can improve the metabolic system of women with obesity, reducing plasma concentrations of trimethylamine N-oxide (TMAO) and sphingolipids, regardless of weight loss. Fourteen obese women (BMI 30–40 kg/m2), aged 20–40 years, sedentary, were submitted to 8 weeks of combined physical training (strength and aerobic exercises). The training was performed three times/week, 55 min/session, at 75–90% maximum heart rate. All participants were evaluated pre- and post-exercise intervention, and their body composition, plasma TMAO, creatinine, lipid profile, and sphingolipid concentrations were recorded. Maximum oxygen consumption (VO2max), Speed lactate threshold 1 (SpeedLT1), and Speed lactate threshold 2 (SpeedLT2) evaluated physical performance. Results: After combined exercise, it did not change body composition, but TMAO, total cholesterol, and sphingolipid concentrations significantly decreased (p < 0.05). There was an increase in physical performance by improving VO2max, SpeedLT1, and SpeedLT2 (p < 0.05). The combined physical exercise could induce cardiovascular risk protection by decreasing TMAO in obese women, parallel to physical performance improvement, independent of weight loss.
Published: 2024
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2. Burden of cardiovascular disease in a large contemporary cohort of patients with heterozygous familial hypercholesterolemia

Author: Jean Ferrières, Michel Farnier, Eric Bruckert, Alexandre Vimont, Vincent Durlach, Emile Ferrari, Antonio Gallo, Franck Boccara, Dorota Ferrières, Sophie Béliard, Denis Angoulvant, Karine Aouchiche, Sophie Beliard, Bertrand Cariou, Valérie Carreau, Alain Carrie, Sybil Charrieres, Yves Cottin, Mathilde Di Filippo, Caroline Dourmap, Pierre-Henri Ducluzeau, Dorota Ferrieres, Jean Ferrieres, Regis Hankard, Jocelyn Inamo, Olga Kalmykova, Michel Krempf, Julie Lemale, Philippe Moulin, François Paillard, Noel Peretti, Agnes Perrin, Alain Pradignac, Yann Pucheu, Jean Pierre Rabes, Rachel Reynaud, Vincent Rigalleau, François Schiele, Ariane Sultan, Patrick Tounian, René Valero, Bruno Verges, Cecile Yelnik, and Olivier Ziegler
Subjects: Heterozygous familial hypercholesterolemia, Registry, Incidence, Recurrence, Lipid-lowering treatment, Prognosis, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background and aims: Heterozygous familial hypercholesterolemia (HeFH) is increasingly better diagnosed and treatments can improve the cardiovascular prognosis. We evaluated the long-term cardiovascular risk of HeFH using the French REgistry of Familial hypERCHOLesterolemia (REFERCHOL). Methods: We studied HeFH patients diagnosed genetically and clinically by the Dutch Lipid Clinic Network (DLCN) criteria in all lipid clinics across the country and their 5-year risk of cardiovascular events (all fatal and non-fatal acute coronary, cerebral and peripheral arterial disease events, aortic valve replacement surgery) using the French national health data system. Results: The database comprised 3202 individuals, 2010 (62.8%) with genetically verified HeFH and 1192 (37.2%) a DLCN score ≥6. Of these individuals, 2485 (77.6%) were in primary prevention and 717 (22.4%) in secondary prevention. The incidence of cardiovascular events was 24.58 per 1000 person-years for the overall sample, 19.15 in primary prevention and 43.40 in secondary prevention. The incidence of myocardial infarction, cerebral infarction and death was 16.32 per 1000 person-years for the overall sample, 12.93 in primary prevention and 28.08 in secondary prevention. The incidence of aortic valve replacement was 1.78 per 1000 person-years. In the overall sample, at inclusion, 41% were not treated for LDL cholesterol, 48% of these in primary prevention and 20% in secondary prevention and high-dose statins were used by only 24% of individuals, 15% of these in primary prevention and 45% in secondary prevention. Conclusions: The incidence of cardiovascular events in HeFH is high and lipid-lowering treatment is far from optimal. The cardiovascular risk of HeFH is underestimated and patients are inadequately treated.
Published: 2022
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3. Untargeted lipidomic analysis of plasma from obese women submitted to combined physical exercise

Author: Rocio San Martin, Camila Fernanda Cunha Brandao, Márcia Varella Morandi Junqueira-Franco, Gizela Pedroso Junqueira, Ellen Cristini de Freitas, Flavia Giolo de Carvalho, Caio Henrique Pinke Rodrigues, Audrey Aguesse, Stéphanie Billon-Crossouard, Michel Krempf, Mikaël Croyal, and Julio Sergio Marchini
Subjects: Medicine, Science
Abstract: Abstract This study aimed to determine the changes of lipidome in obese women undergoing combined physical exercise training. Fourteen adult women with obesity (mean BMI and age, 33 kg/m2 and 34 ± 5 years), were submitted to combined physical training (aerobic and strength exercises, alternately, 55 min at 75–90% of the maximum heart rate, 3 times a week) for 8 weeks. All participants were evaluated before and after the training intervention for lipidome, anthropometric measurements, muscle strength, and maximum oxygen consumption (VO2max). Untargeted liquid chromatography-mass spectrometry analyses allowed the identification of 1252 variables, of which 160 were significant (p
Published: 2022
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4. Evaluation of hypercholesterolemia management in at-risk patients by cardiologists in France: a case vignette-based study

Author: Jean Ferrieres, Eric Bruckert, Michel Farnier, Michel Krempf, Jean-Jacques Mourad, Baptiste Roux, and Francois Schiele
Subjects: cardiologists, cardiovascular risk, case-vignette, ezetimibe, france, hypercholesterolemia, lipid-lowering, online interactive survey, statin, treatment, Public aspects of medicine, RA1-1270
Abstract: Aim: This online interactive survey investigated lipid-lowering approaches of French cardiologists in highand very high-cardiovascular risk patients with hypercholesterolemia. Materials & methods: Physicians assessed three hypothetical patients at three clinic visits, and selected the patients’ cardiovascular risk category, target low-density lipoprotein cholesterol (LDL-C) and treatment. Results: A total of 162 physicians completed 480 risk assessments; 58% of assessments correctly categorized the hypothetical patients. Most physicians chose the correct LDL-C target for one of the very high-risk patients, but higherthan- recommended targets were selected for the other very high-risk patient and the high-risk patient. Statins were the most commonly chosen treatment. Conclusion: French cardiologists often underestimate cardiovascular risk in patients with hypercholesterolemia, select a higher-than-recommended LDL-C target and prescribe less intensive treatment than that recommended by guidelines.
Published: 2023
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5. A high-throughput mass spectrometry-based assay for large-scale profiling of circulating human apolipoproteins[S]

Author: Valentin Blanchard, Damien Garçon, Catherine Jaunet, Kevin Chemello, Stéphanie Billon-Crossouard, Audrey Aguesse, Aya Garfa, Gilles Famchon, Amada Torres, Cédric Le May, Matthieu Pichelin, Edith Bigot-Corbel, Gilles Lambert, Bertrand Cariou, Samy Hadjadj, Michel Krempf, Kalyane Bach-Ngohou, and Mikaël Croyal
Subjects: proteomics, lipoprotein metabolism, metabolic disease, assay development, isotopic labeling, lipid metabolism, Biochemistry, QD415-436
Abstract: Apolipoproteins govern lipoprotein metabolism and are promising biomarkers of metabolic and cardiovascular diseases. Unlike immunoassays, MS enables the quantification and phenotyping of multiple apolipoproteins. Hence, here, we aimed to develop a LC-MS/MS assay that can simultaneously quantitate 18 human apolipoproteins [A-I, A-II, A-IV, A-V, B48, B100, C-I, C-II, C-III, C-IV, D, E, F, H, J, L1, M, and (a)] and determined apoE, apoL1, and apo(a) phenotypes in human plasma and serum samples. The plasma and serum apolipoproteins were trypsin digested through an optimized procedure and peptides were extracted and analyzed by LC-MS/MS. The method was validated according to standard guidelines in samples spiked with known peptide amounts. The LC-MS/MS results were compared with those obtained with other techniques, and reproducibility, dilution effects, and stabilities were also assessed. Peptide markers were successfully selected for targeted apolipoprotein quantification and phenotyping. After optimization, the assay was validated for linearity, lower limits of quantification, accuracy (biases: –14.8% to 12.1%), intra-assay variability [coefficients of variation (CVs): 1.5–14.2%], and inter-assay repeatability (CVs: 4.1–14.3%). Bland-Altman plots indicated no major statistically significant differences between LC-MS/MS and other techniques. The LC-MS/MS results were reproducible over five repeated experiments (CVs: 1.8–13.7%), and we identified marked differences among the plasma and serum samples. The LC-MS/MS assay developed here is rapid, requires only small sampling volumes, and incurs reasonable costs, thus making it amenable for a wide range of studies of apolipoprotein metabolism. We also highlight how this assay can be implemented in laboratories.
Published: 2020
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6. The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential

Author: Jean-Charles Fruchart, Raul D. Santos, Carlos Aguilar-Salinas, Masanori Aikawa, Khalid Al Rasadi, Pierre Amarenco, Philip J. Barter, Richard Ceska, Alberto Corsini, Jean-Pierre Després, Patrick Duriez, Robert H. Eckel, Marat V. Ezhov, Michel Farnier, Henry N. Ginsberg, Michel P. Hermans, Shun Ishibashi, Fredrik Karpe, Tatsuhiko Kodama, Wolfgang Koenig, Michel Krempf, Soo Lim, Alberto J. Lorenzatti, Ruth McPherson, Jesus Millan Nuñez-Cortes, Børge G. Nordestgaard, Hisao Ogawa, Chris J. Packard, Jorge Plutzky, Carlos I. Ponte-Negretti, Aruna Pradhan, Kausik K. Ray, Željko Reiner, Paul M. Ridker, Massimiliano Ruscica, Shaukat Sadikot, Hitoshi Shimano, Piyamitr Sritara, Jane K. Stock, Ta-Chen Su, Andrey V. Susekov, André Tartar, Marja-Riitta Taskinen, Alexander Tenenbaum, Lale S. Tokgözoğlu, Brian Tomlinson, Anne Tybjærg-Hansen, Paul Valensi, Michal Vrablík, Walter Wahli, Gerald F. Watts, Shizuya Yamashita, Koutaro Yokote, Alberto Zambon, and Peter Libby
Subjects: Residual cardiovascular risk, Visceral obesity, Diabetes, Atherogenic dyslipidemia, Triglycerides, Remnant cholesterol, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Abstract In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARMα agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARMα agonist safely reduces residual cardiovascular risk.
Published: 2019
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7. Plasma lipidomic analysis reveals strong similarities between lipid fingerprints in human, hamster and mouse compared to other animal species

Author: Zied Kaabia, Julie Poirier, Michelle Moughaizel, Audrey Aguesse, Stéphanie Billon-Crossouard, Fanta Fall, Manon Durand, Elie Dagher, Michel Krempf, and Mikaël Croyal
Subjects: Lipid Fingerprint, Liquid Chromatography High-resolution Mass Spectrometry (LC-HRMS), Animal Model Selection, Lipoprotein Profile, Atherothrombotic Cardiovascular Disease (ACVD), Medicine, Science
Abstract: Abstract Cardiovascular diseases are often associated with impaired lipid metabolism. Animal models are useful for deciphering the physiological mechanisms underlying these pathologies. However, lipid metabolism is contrasted between species limiting the transposition of findings from animals to human. Hence, we aimed to compare extended lipid profiles of several animal species to bring new insights in animal model selections. Human lipid phenotype was compared with those of 10 animal species. Standard plasma lipids and lipoprotein profiles were obtained by usual methods and lipidomic analysis was conducted by liquid chromatography-high-resolution mass spectrometry (LC-HRMS). As anticipated, we found contrasted lipid profiles between species. Some of them exhibited similar plasma lipids to human (non-human primate, rat, hamster, pig), but only usual lipid profiles of pigs were superimposable with human. LC-HRMS analyses allowed the identification of 106 other molecular species of lipids, common to all samples and belonging to major lipid families. Multivariate analyses clearly showed that hamster and, in a lower extent mouse, exhibited close lipid fingerprints to that of human. Besides, several lipid candidates that were previously reported to study cardiovascular diseases ranged similarly in human and hamster. Hence, hamster appeared to be the best option to study physiological disturbances related to cardiovascular diseases.
Published: 2018
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8. Kinetics of plasma apolipoprotein E isoforms by LC-MS/MS: a pilot study

Author: Valentin Blanchard, Stéphane Ramin-Mangata, Stéphanie Billon-Crossouard, Audrey Aguesse, Manon Durand, Kevin Chemello, Brice Nativel, Laurent Flet, Maud Chétiveaux, David Jacobi, Jean-Marie Bard, Khadija Ouguerram, Gilles Lambert, Michel Krempf, and Mikaël Croyal
Subjects: peptide, liquid chromatography, tandem mass spectrometry, stable isotope tracers, lipoprotein/kinetics, lipoprotein/metabolism, Biochemistry, QD415-436
Abstract: Human apoE exhibits three major isoforms (apoE2, apoE3, and apoE4) corresponding to polymorphism in the APOE gene. Total plasma apoE concentrations are closely related to these isoforms, but the underlying mechanisms are unknown. We aimed to describe the kinetics of apoE individual isoforms to explore the mechanisms for variable total apoE plasma concentrations. We used LC-MS/MS to discriminate between isoforms by identifying specific peptide sequences in subjects (three E2/E3, three E3/E3, and three E3/E4 phenotypes) who received a primed constant infusion of 2H3-leucine for 14 h. apoE concentrations and leucine enrichments were measured hourly in plasma. Concentrations of apoE2 were higher than apoE3, and concentrations of apoE4 were lower than apoE3. There was no difference between apoE3 and apoE4 catabolic rates and between apoE2 and apoE3 production rates (PRs), but apoE2 catabolic rates and apoE4 PRs were lower. The mechanisms leading to the difference in total plasma apoE concentrations are therefore related to contrasted kinetics of the isoforms. Production or catabolic rates are differently affected according to the specific isoforms. On these grounds, studies on the regulation of the involved biochemical pathways and the impact of pathological environments are now warranted.
Published: 2018
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9. Bariatric Surgery Improves the Atherogenic Profile of Circulating Methylarginines in Obese Patients: Results from a Pilot Study

Author: Julie Poirier, Chloé Cloteau, Audrey Aguesse, Xavier Billot, Etienne Thévenot, Michel Krempf, René Valéro, Marie Maraninchi, and Mikaël Croyal
Subjects: bariatric surgery, ADMA, SDMA, NMMA, DMGV, methylarginines, Microbiology, QR1-502
Abstract: Bariatric surgery improves obesity-related comorbidities. Methylarginines are biomarkers of cardiometabolic risk, liver steatosis, and insulin resistance. Here, we aimed to investigate methylarginines in obese patients undergoing bariatric surgery and compared them to age- and sex-matched healthy subjects. Thirty-one obese patients who underwent bariatric surgery and 31 healthy individuals were used for this retrospective study. The basal serum methylarginine levels were determined in the healthy individuals and the obese patients, before surgery and 6 and 12 months after surgery, by mass spectrometry. Compared with the healthy individuals, the obese patients displayed elevated monomethylarginine (mean change: +95%, p < 0.001), asymmetric-dimethylarginine (+105%, p < 0.001), symmetric-dimethylarginine (+25%, p = 0.003), and dimethylguanidino valerate (+32%, p = 0.008) concentrations. Bariatric surgery durably reduced the body mass index by 28% (12 months, 95%CI: 24–33, p = 0.002) and improved plasma lipids, insulin resistance, and liver function. Bariatric surgery reduced the serum levels of monomethylarginine and asymmetric-dimethylarginine by 12% (95%CI: 6–17) and 36% (95%CI: 27–45) (12 months, p = 0.003), respectively, but not symmetric-dimethylarginine or dimethylguanidino valerate. The monomethylarginine and asymmetric-dimethylarginine concentrations were strongly correlated with markers of dyslipidemia, insulin resistance, and a fatty liver. Serum dimethylguanidino valerate was primarily correlated with glycemia and renal function, whereas serum symmetric-dimethylarginine was almost exclusively associated with renal function. In conclusion, the monomethylarginine and asymmetric-dimethylarginine levels are efficiently decreased by bariatric surgery, leading to a reduced atherogenic profile in obese patients. Methylarginines follow different metabolic patterns, which could help for the stratification of cardiometabolic disorders in obese patients.
Published: 2021
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10. Stable Isotope Abundance and Fractionation in Human Diseases

Author: Illa Tea, Arnaud De Luca, Anne-Marie Schiphorst, Mathilde Grand, Sophie Barillé-Nion, Eric Mirallié, Delphine Drui, Michel Krempf, Régis Hankard, and Guillaume Tcherkez
Subjects: isotope effect, fractionation, metabolic partitioning, diabetes, cancer, metal homeostasis, Microbiology, QR1-502
Abstract: The natural abundance of heavy stable isotopes (13C, 15N, 18O, etc.) is now of considerable importance in many research fields, including human physiology. In fact, it varies between tissues and metabolites due to isotope effects in biological processes, that is, isotope discriminations between heavy and light isotopic forms during enzyme or transporter activity. The metabolic deregulation associated with many diseases leads to alterations in metabolic fluxes, resulting in changes in isotope abundance that can be identified easily with current isotope ratio technologies. In this review, we summarize the current knowledge on changes in natural isotope composition in samples (including various tissues, hair, plasma, saliva) found in patients compared to controls, caused by human diseases. We discuss the metabolic origin of such isotope fractionations and highlight the potential of using isotopes at natural abundance for medical diagnosis and/or prognostic.
Published: 2021
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11. PCSK9 Modulates the Secretion But Not the Cellular Uptake of Lipoprotein(a) Ex Vivo

Author: Elise F. Villard, PhD, Aurélie Thedrez, PhD, Jorg Blankenstein, PhD, Mikaël Croyal, BSc, Thi-Thu-Trang Tran, PhD, Bruno Poirier, PhD, Jean-Christophe Le Bail, PhD, Stéphane Illiano, PhD, Estelle Nobécourt, MD, PhD, Michel Krempf, MD, PhD, Dirk J. Blom, MD, PhD, A. David Marais, MD, Philip Janiak, PhD, Anthony J. Muslin, MD, PhD, Etienne Guillot, PhD, and Gilles Lambert, PhD
Subjects: familial hypercholesterolemia, LDL receptor, lipoprotein(a), PCSK9, primary human hepatocytes, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: To elucidate how the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor alirocumab modulates lipoprotein(a) [Lp(a)] plasma levels, the authors performed a series of Lp(a) uptake studies in primary human hepatocytes and dermal fibroblasts and measured Lp(a) secretion from human hepatocytes. They found that Lp(a) cellular uptake occurred in a low-density lipoprotein receptor–independent manner. Neither PCSK9 nor alirocumab altered Lp(a) internalization. By contrast, the secretion of apolipoprotein (a) from human hepatocytes was sharply increased by PCSK9, an effect that was reversed by alirocumab. They propose that PCSK9 does not significantly modulate Lp(a) catabolism, but rather enhances the secretion of Lp(a) from liver cells.
Published: 2016
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12. Multiplexed peptide analysis for kinetic measurements of major human apolipoproteins by LC/MS/MS[S]

Author: Mikaël Croyal, Fanta Fall, Véronique Ferchaud-Roucher, Maud Chétiveaux, Yassine Zaïr, Khadija Ouguerram, Michel Krempf, and Estelle Nobécourt
Subjects: lipoproteins/metabolism, lipoproteins/kinetics, nutrition protein, multiplexed assay, stable isotope, liquid chromatography-tandem mass spectrometry, Biochemistry, QD415-436
Abstract: A multiplexed assay was developed by MS to analyze, in a single run, six major human Apos involved in lipoprotein metabolism: ApoA-I, ApoA-II, ApoB100, ApoC-II, ApoC-III, and ApoE. This method was validated in vivo in six subjects who received a 14 h constant infusion of [5,5,5-2H3]L-leucine at 10 μM/kg/h. Plasma lipoprotein fractions were isolated from collected blood samples and were digested with trypsin. Proteotypic peptides were subsequently analyzed by LC/MS/MS. Enrichment measurement data were compared with those obtained by the standard method using GC/MS. The required time to obtain the LC/MS/MS data was less than that needed for GC/MS. The enrichments from both methods were correlated for ApoA-I (r = 0.994; P < 0.0001) and ApoB100 (r = 0.999; P < 0.0001), and the Bland-Altman plot confirmed the similarity of the two methods. Intra- and inter-assay variability calculated for the six Apos of interest did not exceed 10.7 and 12.5%, respectively, and kinetic parameters were similar and/or in agreement with previously reported data. Therefore, LC/MS/MS can be considered as a useful tool for human Apo kinetic studies using stable isotopes.
Published: 2016
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13. Apple Supplementation Improves Hemodynamic Parameter and Attenuates Atherosclerosis in High-Fat Diet-Fed Apolipoprotein E-Knockout Mice

Author: Raffaella Soleti, Charlotte Trenteseaux, Lionel Fizanne, Marine Coué, Gregory Hilairet, Fatima Kasbi-Chadli, Patricia Mallegol, Julien Chaigneau, Jerome Boursier, Michel Krempf, Mathilde Orsel, Khadija Ouguerram, and Ramaroson Andriantsitohaina
Subjects: apple supplementation, hemodynamic parameter, atherosclerosis, high fat diet, ApoE deficient mice, Biology (General), QH301-705.5
Abstract: Epidemiological studies describe the association between apple consumption and improved cardiovascular and metabolic dysfunction. Our recent multiparametric screening on cellular model studies has shown that apples exhibit vascular tropism including Granny Smith (GS) variety independently of the storage condition. The present study aimed to evaluate the cardiovascular and metabolic protection of supplementation of GS variety after storage in classic cold (GSCC) and extreme ultra-low oxygen conditions (GSXO) in the apolipoprotein E-deficient 8-week-old mice fed with high fat diet for 14 weeks. Supplementation with GSCC and GXO decreases circulating triglycerides, the expression of genes involved in lipogenesis, without change in cholesterol and glucose concentrations and HOMA-IR. Only GSXO supplementation ameliorates body weight gain, insulin level, and HDL/LDL ratio. GSXO supplementation does not modify cardiac parameters; while supplementation with GSCC decreases heart rate and improves cardiac output. Interestingly, GSCC and GSXO reduce systolic and diastolic blood pressure with a differential time course of action. These effects are associated with substantial decrease of atherosclerotic lesions. These data reinforce the knowledge about the vascular tropism of apple supplementation and underscore their ability to improve both cardiovascular and metabolic alterations in a mouse model of atherosclerosis.
Published: 2020
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14. Elevation of Trimethylamine-N-Oxide in Chronic Kidney Disease: Contribution of Decreased Glomerular Filtration Rate

Author: Caroline C. Pelletier, Mikael Croyal, Lavinia Ene, Audrey Aguesse, Stephanie Billon-Crossouard, Michel Krempf, Sandrine Lemoine, Fitsum Guebre-Egziabher, Laurent Juillard, and Christophe O. Soulage
Subjects: uremic toxin, trimethylamine-n-oxide, renal clearance, chronic kidney disease, hemodialysis, Medicine
Abstract: Gut microbiota-dependent Trimethylamine-N-oxide (TMAO) has been reported to be strongly linked to renal function and to increased cardiovascular events in the general population and in Chronic Kidney Disease (CKD) patients. Considering the lack of data assessing renal handling of TMAO, we conducted this study to explore renal excretion and mechanisms of accumulation of TMAO during CKD. We prospectively measured glomerular filtration rate (mGFR) with gold standard methods and plasma concentrations of trimethylamine (TMA), TMAO, choline, betaine, and carnitine by LC-MS/MS in 124 controls, CKD, and hemodialysis (HD) patients. Renal clearance of each metabolite was assessed in a sub-group of 32 patients. Plasma TMAO was inversely correlated with mGFR (r2 = 0.388, p < 0.001), confirming elevation of TMAO plasma levels in CKD. TMAO clearances were not significantly different from mGFR, with a mean ± SD TMAO fractional excretion of 105% ± 32%. This suggests a complete renal excretion of TMAO by glomerular filtration with a negligible participation of tubular secretion or reabsorption, during all stages of CKD. Moreover, TMAO was effectively removed within 4 h of hemodiafiltration, showing a higher fractional reduction value than that of urea (84.9% ± 6.5% vs. 79.2% ± 5.7%, p = 0.04). This study reports a strong correlation between plasma TMAO levels and mGFR, in CKD, that can be mainly related to a decrease in TMAO glomerular filtration. Clearance data did not support a significant role for tubular secretion in TMAO renal elimination.
Published: 2019
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15. Nicotinic Acid Accelerates HDL Cholesteryl Ester Turnover in Obese Insulin-Resistant Dogs.

Author: Jérôme Le Bloc'h, Véronique Leray, Hassan Nazih, Olivier Gauthier, Samuel Serisier, Thierry Magot, Michel Krempf, Patrick Nguyen, and Khadija Ouguerram
Subjects: Medicine, Science
Abstract: Nicotinic acid (NA) treatment decreases plasma triglycerides and increases HDL cholesterol, but the mechanisms involved in these change are not fully understood. A reduction in cholesteryl ester transfer protein (CETP) activity has been advanced to explain most lipid-modulating effects of NA. However, due to the central role of CETP in reverse cholesterol transport in humans, other effects of NA may have been hidden. As dogs have no CETP activity, we conducted this study to examine the specific effects of extended-release niacin (NA) on lipids and high-density lipoprotein (HDL) cholesteryl ester (CE) turnover in obese Insulin-Resistant dogs with increase plasma triglycerides.HDL kinetics were assessed in fasting dogs before and four weeks after NA treatment through endogenous labeling of cholesterol and apolipoprotein AI by simultaneous infusion of [1,2 13C2] acetate and [5,5,5 2H3] leucine for 8 h. Kinetic data were analyzed by compartmental modeling. In vitro cell cholesterol efflux of serum from NA-treated dogs was also measured.NA reduced plasma total cholesterol, low-density lipoprotein cholesterol, HDL cholesterol, triglycerides (TG), and very-low-density lipoprotein TG concentrations (p < 0.05). The kinetic study also showed a higher cholesterol esterification rate (p < 0.05). HDL-CE turnover was accelerated (p < 0.05) via HDL removal through endocytosis and selective CE uptake (p < 0.05). We measured an elevated in vitro cell cholesterol efflux (p < 0.05) with NA treatment in accordance with a higher cholesterol esterification.NA decreased HDL cholesterol but promoted cholesterol efflux and esterification, leading to improved reverse cholesterol transport. These results highlight the CETP-independent effects of NA in changes of plasma lipid profile.
Published: 2015
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16. Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells

Author: Florent Lalanne, Gilles Lambert, Marcelo J.A. Amar, Maud Chétiveaux, Yassine Zaïr, Anne-Laure Jarnoux, Khadija Ouguerram, José Friburg, Nabil G. Seidah, H. Bryan Brewer, Jr., Michel Krempf, and Philippe Costet
Subjects: Proprotein Convertase Subtilisin Kexin 9, low density lipoprotein, apolipoprotein B, Biochemistry, QD415-436
Abstract: Mutations in Proprotein Convertase Subtilisin Kexin 9 (PCSK9) have been associated with autosomal dominant hypercholesterolemia. In vivo kinetic studies indicate that LDL catabolism was impaired and apolipoprotein B (apoB)-containing lipoprotein synthesis was enhanced in two patients presenting with the S127R mutation on PCSK9. To understand the physiological role of PCSK9, we overexpressed human PCSK9 in mouse and cellular models as well as attenuated the endogenous expression of PCSK9 in HuH7 hepatoma cells using RNA interference. Here, we show that PCSK9 dramatically impairs the expression of the low density lipoprotein receptor (LDLr) and, in turn, LDL cellular binding as well as LDL clearance from the plasma compartment in C57BL6/J mice but not in LDLr-deficient mice, establishing a definitive role for PCSK9 in the modulation of the LDLr metabolic pathway. In contrast to data obtained in S127R-PCSK9 patients presenting with increased apoB production, our study indicates that wild-type PCSK9 does not significantly alter the production and/or secretion of VLDL apoB in either cultured cells or mice.Finally, we show that unlike PCSK9 overexpression in mice, the S127R mutation in patients led to increased VLDL apoB levels, suggesting a potential gain of function for S127R-PCSK9 in humans.
Published: 2005
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17. The differential apoA-I enrichment of preβ1 and αHDL is detectable by gel filtration separation

Author: Maud Chétiveaux, Hassan Nazih, Veronique Ferchaud-Roucher, Gilles Lambert, Yassine Zaïr, Martial Masson, Khadija Ouguerram, Daniele Bouhours, and Michel Krempf
Subjects: fast protein liquid chromatography, apolipoprotein A-I, kinetic analysis, Biochemistry, QD415-436
Abstract: The aim of the study was to assess the isolation of HDL by fast protein liquid chromatography (FPLC) to perform kinetics studies of apolipoprotein (apo)A-I-HDL labelled with a stable isotope. Comparison between FPLC and ultracentrifugation has been made. ApoA-I-HDL kinetics were studied by infusion of [5.5.5-2H3]leucine for 14 h in five subjects. Using FPLC, preβ1 HDL and αHDL (HDL2 and HDL3) were separated from 200 μl of plasma samples. Total HDL was isolated by sequential ultracentrifugation (HDL-UC). The tracer-to-tracee ratio was higher in preβ1 HDL than in total HDL-UC. The higher leucine enrichment found in total HDL-UC compared to αHDL suggested the existence of a mixture of apoA-I-HDL sub-classes. From this difference in enrichments, the turnover rate of total HDL-UC, usually assumed to be αHDL, was probably overestimated in previous studies. To our knowledge, this study is the first report which provides a convenient tool to distinguish enrichments of apoA-I in preβ1 HDL and αHDL from total HDL previously used for kinetic measurements.This original and new method should help to understand the kinetics of HDL in humans and the reverse cholesterol transport dynamics.
Published: 2002
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18. Omega 3 fatty acids promote macrophage reverse cholesterol transport in hamster fed high fat diet.

Author: Fatima Kasbi Chadli, Hassane Nazih, Michel Krempf, Patrick Nguyen, and Khadija Ouguerram
Subjects: Medicine, Science
Abstract: The aim of this study was to investigate macrophage reverse cholesterol transport (RCT) in hamster, a CETP-expressing species, fed omega 3 fatty acids (ω3PUFA) supplemented high fat diet (HFD). Three groups of hamsters (n = 6/group) were studied for 20 weeks: 1) control diet: Control, 2) HFD group: HF and 3) HFD group supplemented with ω3PUFA (EPA and DHA): HFω3. In vivo macrophage-to-feces RCT was assessed after an intraperitoneal injection of (3)H-cholesterol-labelled hamster primary macrophages. Compared to Control, HF presented significant (p
Published: 2013
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19. Utilização de espectrometria de massa para o estudo do metabolismo protéico e aminoacídico, em medicina

Author: Júlio Sérgio Marchini, Anibal Basile Filho, Helio Vannucchi, Dominique Darmaun, and Michel Krempf
Subjects: Espectrometria de Massa. Metabolismo. Nutrição. Aminoácidos. Proteínas., Medicine
Abstract: O desenvolvimento e uso de técnicas laboratoriais, envolvendo espectrometria de massa, permitiram que os isótopos estáveis pudessem ser utilizados na avaliação do metabolismo aminoacídico e protéico, em seres biológicos. Assim, medidas precisas de enriquecimento isotópico, ao nível de 3-6% além do basal, após infusão de 13C-, 15N- ou de ²H2 -aminoácido, tornaram possível realizar a avaliação das interrelações metabólicas protéicas no organismo, in vivo. O método pode ser considerado pouco invasivo, sendo necessário, geralmente, coleta de ar expirado e sangue periférico, para determinação de substratos na concentração em torno de nanomolar. Desta maneira, períodos de infusão isotópica, de 4-6 horas, de 13C-leucina, permitem estimativa do metabolismo protéico corpóreo total, pela medida direta da oxidação, via determinação do 13CO2, no ar expirado, e da 13C-Leu ou seu metabólito, 13C-KIC, no sangue, assim como estimativa da degradação e síntese protéica. Mais recentemente, o advento de nova técnica, ou seja, a da associação de combustão da amostra à cromatografia e espectrometria, tornou o método mais sensível, sendo possível a determinação de substrato, marcado em amostras diluídas por um fator mínimo de 10. O método também permite o estudo da interrelação do metabolismo protéico com o de hidrato de carbono e lipídeo, quando aplicado a aminoácidos, essenciais ou não, associados a glicídios e a triglicerídeos.
Published: 1997
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20. Effect of omega-3 fatty acid ethyl esters on postprandial arterial elasticity in patients with familial hypercholesterolemia

Author: Qidi Ying, Dick C. Chan, Jing Pang, Mikaël Croyal, Valentin Blanchard, Michel Krempf, and Gerald F. Watts
Subjects: Nutrition and Dietetics, Endocrinology, Diabetes and Metabolism
Published: 2023
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21. Model Free iPID Control for Glycemia Regulation of Type-1 Diabetes.

Author: Taghreed MohammadRidha, Mourad Ait-Ahmed, Lucy Chaillous, Michel Krempf, Isabelle Guilhem, Jean-Yves Poirier, and Claude H. Moog
Published: 2018
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22. Description des pratiques de l’insulinothérapie basale dans le diabète de type 2 en médecine générale en France : l’étude PRACTISULINE®

Author: Pierre Gourdy, Amar Bahloul, Sarah Safsaf, Baptiste Roux, Gilles Le Pape, and Michel Krempf
Subjects: Nutrition and Dietetics, Endocrinology, Diabetes and Metabolism, Internal Medicine, Cardiology and Cardiovascular Medicine
Published: 2022
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23. Les nouveaux traitements du cholestérol

Author: Michel Krempf
Subjects: Nutrition and Dietetics
Published: 2022
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24. Maternal Inheritance of Familial Hypercholesterolemia Gene Mutation Predisposes to Coronary Atherosclerosis as Assessed by Calcium Score in Adulthood

Author: Florian Mourre, Roch Giorgi, Antonio Gallo, Franck Boccara, Eric Bruckert, Alain Carrié, Regis Hankard, Jocelyn Inamo, Sandrine Laboureau, Philippe Moulin, René Valéro, Sophie Béliard, Denis Angoulvant, Sophie Beliard, Bertrand Cariou, Valérie Carreau, Alain Carrie, Sybil Charrieres, Yves Cottin, Mathilde Di Filippo, Pierre Henri Ducluzeau, Sonia Dulong, Vincent Durlach, Michel Farnier, Emile Ferrari, Dorota Ferrieres, Jean Ferrieres, Olga Kalmykova, Michel Krempf, Julie Lemale, François Paillard, Noel Peretti, Agnes Perrin, Alain Pradignac, Jean Pierre Rabes, Vincent Rigalleau, François Schiele, Ariane Sultan, Patrick Tounian, René Valero, Bruno Verges, Cecile Yelnik, Olivier Ziegler, 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), and 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)
Subjects: [SDV]Life Sciences [q-bio], hyperlipidemia, maternal inheritance, risk factors, atherosclerosis, Cardiology and Cardiovascular Medicine, cardiovascular diseases
Abstract: Background: Animal studies have demonstrated that fetal exposure to high maternal cholesterol levels during pregnancy predisposes to aortic atheroma in the offspring. In humans, little is known about the consequences of this exposure on the development of atherosclerotic cardiovascular disease later in life. We wanted to assess whether maternal/paternal inheritance of familial hypercholesterolemia (FH) gene mutation could be associated with subclinical coronary atherosclerosis. Methods: We retrospectively included 1350 patients, followed in the French registry of FH, with a documented genetic diagnosis. We selected 556 age- and sex-matched pair of patients based on the sex of the parents who transmitted the FH gene mutation, free of coronary cardiovascular event, and with a subclinical coronary atherosclerosis evaluation assessed using coronary artery calcium (CAC) score. We performed univariate and multivariate analysis to assess the individual effect of parental inheritance of the FH gene mutation on the CAC score. Results: In the whole population, patients with maternal inheritance of FH gene mutation (n=639) less frequently had a family history of premature cardiovascular events (27.7% versus 45%, P P =0.02) than those with paternal inheritance (n=711). There was no difference in the prevalence of cardiovascular events between the two groups. In the matched subgroup, maternal inheritance was significantly associated with an increase in CAC score value by 86% (95% CI, 23%–170%; P =0.003), a 1.81-fold risk of having a CAC score ≥100 Agatston units (95% CI, 1.06–3.11; P =0.03), and a 2.72-fold risk of having a CAC score ≥400 Agatston units (95% CI, 1.39–5.51; P =0.004) when compared with paternal inheritance in multivariate analysis. Conclusions: Maternal inheritance of FH gene mutation was associated with more severe subclinical coronary atherosclerosis assessed by CAC score and may be considered as a potential cardiovascular risk factor.
Published: 2023
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25. A Long-Term Model of the Glucose-Insulin Dynamics of Type 1 Diabetes.

Author: Nicolas Magdelaine, Lucy Chaillous, Isabelle Guilhem, Jean-Yves Poirier, Michel Krempf, Claude H. Moog, and Eric Le Carpentier
Published: 2015
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26. The Added Value of Coronary Calcium Score in Predicting Cardiovascular Events in Familial Hypercholesterolemia

Author: Antonio Gallo, Leopoldo Pérez de Isla, Sybil Charrière, Alexandre Vimont, Rodrigo Alonso, Ovidio Muñiz-Grijalvo, José L. Díaz-Díaz, Daniel Zambón, Philippe Moulin, Eric Bruckert, Pedro Mata, Sophie Béliard, Denis Angoulvant, Sophie Beliard, Franck Boccara, Bertrand Cariou, Valérie Carreau, Alain Carrie, Sybil Charrieres, Yves Cottin, Mathilde Di Filippo, Pierre Henri Ducluzeau, Sonia Dulong, Vincent Durlach, Michel Farnier, Emile Ferrari, Dorota Ferrieres, Jean Ferrieres, Philippe Giral, Sophie Gonbert, Regis Hankard, Jocelyn Inamo, Olga Kalmykova, Michel Krempf, Julie Lemale, François Paillard, Noel Peretti, Agnes Perrin, Alain Pradignac, Jean Pierre Rabes, Vincent Rigalleau, François Schiele, Ariane Sultan, Patrick Tounian, René Valero, Bruno Verges, Cecile Yelnik, Olivier Ziegler, Rocío Aguado, Ma Pilar Álvarez-Baños, Rosa Argüeso, Francisco Arrieta, Miguel Ángel Barba, Marta Casañas, José María Cepeda, Raimundo De Andrés, Gonzalo Díaz-Soto, Jose Luis Díaz-Diaz, Marta Dieguez, Ceferino Faedo, Francisco Fuentes, Juan A. Garrido, Aurora González, Pablo González-Bustos, Ma Dolores Mañas, Marta Mauri, Juan Diego Mediavilla, Alfredo Michán, Pablo Miramontes, Ovidio Muñiz, Leire Pérez, Leopoldo Perez De Isla, Xavier Pintó, Manuel J. Romero, Patricia Rubio, Juan F. Sánchez Muñoz-Torrero, Jose I. Vidal-Pardo, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Public Health Expertise [Paris, France], Hospital Universitario Virgen del Rocío [Sevilla], Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), 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), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), 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], Hospital Abente y Lago, Fundación Hipercolesterolemia Familiar, and ANR-16-RHUS-0007,CHOPIN,CHOPIN(2016)
Subjects: Adult, Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Coronary Artery Disease, Disease, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Risk Assessment, Sudden death, Cohort Studies, Hyperlipoproteinemia Type II, risk prediction, 03 medical and health sciences, 0302 clinical medicine, cardiovascular disease, genetic disease, Predictive Value of Tests, Risk Factors, Interquartile range, Internal medicine, Humans, Medicine, Radiology, Nuclear Medicine and imaging, 030212 general & internal medicine, Vascular Calcification, Stroke, coronary artery calcium, ComputingMilieux_MISCELLANEOUS, familial hypercholesterolemia, business.industry, Proportional hazards model, nutritional and metabolic diseases, Middle Aged, Atherosclerosis, medicine.disease, 3. Good health, Coronary Calcium Score, Cardiology, Calcium, Cardiology and Cardiovascular Medicine, business, coronary imaging, Cohort study
Abstract: International audience; ObjectivesThis study aimed at investigating the additional contribution of coronary artery calcium (CAC) score to SAFEHEART (Spanish Familial Hypercholesterolemia Cohort Study) risk equation (SAFEHEART-RE) for cardiovascular risk prediction in heterozygous familial hypercholesterolemia (HeFH).BackgroundCommon cardiovascular risk equations are imprecise for HeFH. Because of the high phenotype variability of HeFH, CAC score could help to better stratify the risk of atherosclerotic cardiovascular disease (ASCVD).MethodsREFERCHOL (French Registry of Familial Hypercholesterolemia) and SAFEHEART are 2 ongoing national registries on HeFH. We analyzed data from primary prevention HeFH patients undergoing CAC quantification. We used probability-weighted Cox proportional hazards models to estimate HRs. Area under the receiver-operating characteristic curve (AUC) and net reclassification improvement (NRI) were used to compare the incremental contribution of CAC score when added to the SAFEHEART-RE for ASCVD prediction. ASCVD was defined as coronary heart disease, stroke or transient ischemic attack, peripheral artery disease, resuscitated sudden death, and cardiovascular death.ResultsWe included 1,624 patients (mean age: 48.5 ± 12.8 years; men: 45.7%) from both registries. After a median follow-up of 2.7 years (interquartile range: 0.4-5.0 years), ASCVD occurred in 81 subjects. The presence of a CAC score of >100 was associated with an HR of 32.05 (95% CI: 10.08-101.94) of developing ASCVD as compared to a CAC score of 0. Receiving-operating curve analysis showed a good performance of CAC score alone in ASCVD prediction (AUC: 0.860 [95% CI: 0.853-0.869]). The addition of log(CAC + 1) to SAFEHEART-RE resulted in a significantly improved prediction of ASCVD (AUC: 0.884 [95% CI: 0.871-0.894] for SAFEHEART-RE + log(CAC + 1) vs AUC: 0.793 [95% CI: 0.779-0.818] for SAFEHEART-RE; P < 0.001). These results were confirmed also when considering only hard cardiovascular endpoints. The addition of CAC score was associated with an estimated overall net reclassification improvement of 45.4%.ConclusionsCAC score proved its use in improving cardiovascular risk stratification and ASCVD prediction in statin-treated HeFH.
Published: 2021
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27. Effect of Omega-3 Fatty Acid Supplementation on the Postprandial Metabolism of Apolipoprotein(a) in Familial Hypercholesterolemia

Author: Qidi Ying, Mikaël Croyal, Dick C Chan, Valentin Blanchard, Jing Pang, Michel Krempf, and Gerald F Watts
Subjects: Biochemistry (medical), Internal Medicine, Cardiology and Cardiovascular Medicine
Abstract: Lipoprotein(a) (Lp(a)) is a low-density lipoprotein-like particle containing apolipoprotein(a) (apo(a)) that increases the risk of atherosclerotic cardiovascular disease (ASCVD) in familial hypercholesterolemia (FH). Postprandial redistribution of apo(a) protein from Lp(a) to triglyceride-rich lipoproteins (TRLs) may also increase the atherogenicity of TRL particles. Omega-3 fatty acid (ω3FA) supplementation improves postprandial TRL metabolism in FH subjects. However, its effect on postprandial apo(a) metabolism has yet to be investigated.We carried out an 8-week open-label, randomized, crossover trial to test the effect of ω3FA supplementation (4 g/day) on postprandial apo(a) responses in FH patients following ingestion of an oral fat load. Postprandial plasma total and TRL-apo(a) concentrations were measured by liquid chromatography with tandem mass spectrometry, and the corresponding areas under the curve (AUCs) (0-10h) were determined using the trapezium rule.Compared with no ω3FA treatment, ω3FA supplementation significantly lowered the concentrations of postprandial TRL-apo(a) at 0.5 (-17.9%), 1 (-18.7%), 2 (-32.6%), and 3 h (-19.2%) (P＜0.05 for all). Postprandial TRL-apo(a) AUC was significantly reduced with ω3FA by 14.8% (P＜0.05). By contrast, ω3FA had no significant effect on the total AUCs of apo(a), apoC-III, and apoE (P＞0.05 for all). The decrease in postprandial TRL-apo(a) AUC was significantly associated with changes in the AUC of triglycerides (r=0.600; P ＜0.01) and apoB-48 (r=0.616; P＜0.01).Supplementation with ω3FA reduces postprandial TRL-apo(a) response to a fat meal in FH patients; this novel metabolic effect of ω3FA may have implications on decreasing the risk of ASCVD in patients with FH, especially in those with elevated plasma triglyceride and Lp(a) concentrations. However, the clinical implications of these metabolic findings require further evaluation in outcome or surrogate endpoint trials.
Published: 2022

28. Proposal for a standardized discharge letter after hospital stay for acute myocardial infarction

Author: Francois Schiele, Gilles Lemesle, Denis Angoulvant, Michel Krempf, Serge Kownator, Saida Cheggour, Loic Belle, Jean Ferrières, Christophe Bauters, Cyrille Bergerot, Farzin Beygui, Franck Boccara, Eric Bonnefoy, Eric Bruckert, Guillaume Cayla, Jean-Philippe Collet, Pierre Coste, Vincent Descotes-Genon, Gregory Ducrocq, Meyer Elbaz, Michel Farnier, Emile Ferrari, Dominique Guedj, Laszlo Levai, Jacques Mansourati, Nicolas Mansencal, Nicolas Meneveau, Christophe Meune, Olivier Morel, Patrick Ohlmann, Francois Paillard, Christophe Piot, Etienne Puymirat, Gilles Rioufol, François Roubille, Pierre Sabouret, Emmanuel Teiger, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Universitaire de Lille (CHU de Lille), Université Francois Rabelais [Tours], Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), Centre Cardiologique et Vasculaire, Partenaires INRAE, Centre Hospitalier Henri Duffaut (Avignon), Centre Hospitalier d'Annecy Genevois, Hôpital de Rangueil, and CHU Toulouse [Toulouse]
Subjects: medicine.medical_specialty, Consensus, Primary care, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Antithrombotic, Humans, Medicine, 030212 general & internal medicine, Myocardial infarction, Risk management, communication, business.industry, discharge, primary care, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Patient Discharge, 3. Good health, Residual risk, Regimen, Emergency medicine, Cardiology and Cardiovascular Medicine, business, Risk assessment, Fibrinolytic agent
Abstract: In patients admitted for acute myocardial infarction, the communication and transition from specialists to primary care physicians is often delayed, and the information imparted to subsequent healthcare providers (HCPs) may be sub-optimal. A French group of cardiologists, lipidologists and diabetologists decided to establish a consensus to optimize the discharge letter after hospitalization for acute myocardial infarction. The aim is to improve both the timeframe and the quality of the content transmitted to subsequent HCPs, including information regarding baseline assessment, procedures during hospitalization, residual risk, discharge treatments, therapeutic targets and follow-up recommendations in compliance with European Society of Cardiology guidelines. A consensus was obtained regarding a template discharge letter, to be released within two days after patient’s discharge, and containing the description of the patient’s history, risk factors, acute management, risk assessment, discharge treatments and follow-up pathway. Specifically for post acute MI patients, tailored details are necessary regarding the antithrombotic regimen, lipid-lowering and anti-diabetic treatments, including therapeutic targets. Lastly, the follow-up pathway needs to be precisely mentioned in the discharge letter. Additional information such as technical descriptions, imaging, and quality indicators may be provided separately. A template for a standardized discharge letter based on 8 major headings could be useful for implementation in routine practice and help to improve the quality and timing of information transmission between HCPs after acute MI.
Published: 2020
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29. Omega 3 Improves Both apoB100-containing Lipoprotein Turnover and their Sphingolipid Profile in Hypertriglyceridemia

Author: Véronique Ferchaud-Roucher, Yassine Zair, Michel Krempf, Khadija Ouguerram, Audrey Aguesse, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Recherche en Nutrition Humaine Ouest [UNIV Nantes] (CRNHO), and Université de Nantes (UN)
Subjects: Adult, Male, Very low-density lipoprotein, medicine.medical_specialty, Apolipoprotein B, hypertriglyceridemia, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Pilot Projects, Lipoproteins, VLDL, 030204 cardiovascular system & hematology, n-3 long chain polyunsaturated fatty acid, Biochemistry, sphingomyelin, [SHS]Humanities and Social Sciences, apolipoprotein B100, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Internal medicine, Fatty Acids, Omega-3, medicine, Humans, ceramide, 030304 developmental biology, Sphingolipids, 0303 health sciences, Triglyceride, biology, Biochemistry (medical), modeling, Middle Aged, Eicosapentaenoic acid, Sphingolipid, Treatment Outcome, chemistry, Docosahexaenoic acid, Apolipoprotein B-100, Dietary Supplements, kinetic analysis, biology.protein, lipids (amino acids, peptides, and proteins), Sphingomyelin, Lipoprotein
Abstract: Context Evidence for an association between sphingolipids and metabolic disorders is increasingly reported. Omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) improve apolipoprotein B100 (apoB100)-containing lipoprotein metabolism, but their effects on the sphingolipid content in lipoproteins remain unknown. Objectives In subjects with hypertriglyceridemia, we analyzed the effect of n-3 LC-PUFAs on the turnover apoB100-containing lipoproteins and on their sphingolipid content and looked for the possible association between these lipid levels and apoB100-containing lipoprotein turnover parameters. Methods Six subjects underwent a kinetic study before and after n-3 supplementation for 2 months with 1 g of fish oil 3 times day containing 360 mg of eicosapentaenoic acid (EPA) and 240 mg of docosahexaenoic acid (DHA) in the form of triglycerides. We examined apoB100-containing lipoprotein turnover by primed perfusion labeled [5,5,5-2H3]-leucine and determined kinetic parameters using a multicompartmental model. We quantified sphingolipid species content in lipoproteins using mass spectrometry. Results Supplementation decreased very low-density lipoprotein (VLDL), triglyceride, and apoB100 concentrations. The VLDL neutral and polar lipids showed increased n-3 LC-PUFA and decreased n-6 LC-PUFA content. The conversion rate of VLDL1 to VLDL2 and of VLDL2 to LDL was increased. We measured a decrease in total apoB100 production and VLDL1 production. Supplementation reduced the total ceramide concentration in VLDL while the sphingomyelin content in LDL was increased. We found positive correlations between plasma palmitic acid and VLDL ceramide and between VLDL triglyceride and VLDL ceramide, and inverse correlations between VLDL n-3 LC-PUFA and VLDL production. Conclusion Based on these results, we hypothesize that the improvement in apoB100 metabolism during n-3 LC-PUFA supplementation is contributed to by changes in sphingolipids
Published: 2020
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30. A high-throughput mass spectrometry-based assay for large-scale profiling of circulating human apolipoproteins[S]

Author: Mikaël Croyal, Amada Torres, Catherine Jaunet, Gilles Lambert, Kévin Chemello, Michel Krempf, Kalyane Bach-Ngohou, Cédric Le May, Matthieu Pichelin, Audrey Aguesse, Edith Bigot-Corbel, Stéphanie Billon-Crossouard, Samy Hadjadj, Gilles Famchon, Aya Garfa, Valentin Blanchard, Bertrand Cariou, Damien Garçon, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), ANR-16-RHUS-0007,ANR-16-RHUS-0007,CHOPIN(2016), Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Centre hospitalier universitaire de Nantes (CHU Nantes), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Mass Spectrometry Core Facility [Nantes] (CRNH-O ), Centre de Recherche en Nutrition Humaine Ouest [UNIV Nantes] (CRNHO), Université de Nantes (UN), The Enteric Nervous System in gut and brain disorders [U1235] (TENS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and ANR-16-RHUS-0007,CHOPIN,CHOPIN(2016)
Subjects: 0301 basic medicine, Apolipoprotein E, assay development, Apolipoprotein B, Peptide, serum lipid, QD415-436, 030204 cardiovascular system & hematology, Mass spectrometry, Proteomics, Biochemistry, Mass Spectrometry, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, proteomics, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Limit of Detection, lipid metabolism, medicine, Methods, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, isotopic labeling, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, lipoprotein metabolism, Reproducibility, Chromatography, biology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, Repeatability, plasma lipid, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Trypsin, metabolic disease, 030104 developmental biology, Apolipoproteins, chemistry, biology.protein, Blood Chemical Analysis, medicine.drug, Chromatography, Liquid
Abstract: International audience; Apolipoproteins govern lipoprotein metabolism and are promising biomarkers of metabolic and cardiovascular diseases. Unlike immunoassays, MS enables the quantification and phenotyping of multiple apolipoproteins. Hence, here, we aimed to develop a LC-MS/MS assay that can simultaneously quantitate 18 human apolipoproteins [A-I, A-II, A-IV, A-V, B48, B100, C-I, C-II, C-III, C-IV, D, E, F, H, J, L1, M, and (a)] and determined apoE, apoL1, and apo(a) phenotypes in human plasma and serum samples. The plasma and serum apolipoproteins were trypsin digested through an optimized procedure and peptides were extracted and analyzed by LC-MS/MS. The method was validated according to standard guidelines in samples spiked with known peptide amounts. The LC-MS/MS results were compared with those obtained with other techniques, and reproducibility, dilution effects, and stabilities were also assessed. Peptide markers were successfully selected for targeted apolipoprotein quantification and phenotyping. After optimization, the assay was validated for linearity, lower limits of quantification, accuracy (biases: -14.8% to 12.1%), intra-assay variability [coefficients of variation (CVs): 1.5-14.2%], and inter-assay repeatability (CVs: 4.1-14.3%). Bland-Altman plots indicated no major statistically significant differences between LC-MS/MS and other techniques. The LC-MS/MS results were reproducible over five repeated experiments (CVs: 1.8-13.7%), and we identified marked differences among the plasma and serum samples. The LC-MS/MS assay developed here is rapid, requires only small sampling volumes, and incurs reasonable costs, thus making it amenable for a wide range of studies of apolipoprotein metabolism. We also highlight how this assay can be implemented in laboratories.
Published: 2020
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31. Hypoglycaemia‐free artificial pancreas project

Author: Anne-Laure Fournier-Guilloux, Nicolas Magdelaine, Lucy Chaillous, Taghreed Mohammadridha, Pablo S. Rivadeneira, Mourad Ait-Ahmed, Michel Krempf, and Claude H. Moog
Subjects: Adult, Blood Glucose, Pancreas, Artificial, Pediatrics, medicine.medical_specialty, Adolescent, Remote patient monitoring, 0206 medical engineering, 02 engineering and technology, Artificial pancreas, 03 medical and health sciences, Bolus (medicine), Diabetes mellitus, Genetics, medicine, Humans, Hypoglycemic Agents, Insulin, Computer Simulation, Child, Molecular Biology, 030304 developmental biology, 0303 health sciences, Type 1 diabetes, Control algorithm, business.industry, Fasting, Cell Biology, Positive systems, medicine.disease, 020601 biomedical engineering, Hypoglycemia, 3. Good health, Clinical trial, Diabetes Mellitus, Type 1, Hyperglycemia, Modeling and Simulation, business, Algorithms, Research Article, Biotechnology
Abstract: Driving blood glycaemia from hyperglycaemia to euglycaemia as fast as possible while avoiding hypoglycaemia is a major problem for decades for type‐1 diabetes and is solved in this study. A control algorithm is designed that guaranties hypoglycaemia avoidance for the first time both from the theory of positive systems point of view and from the most pragmatic clinical practice. The solution consists of a state feedback control law that computes the required hyperglycaemia correction bolus in real‐time to safely steer glycaemia to the target. A rigorous proof is given that shows that the control‐law respects the positivity of the control and of the glucose concentration error: as a result, no hypoglycaemic episode occurs. The so‐called hypo‐free strategy control is tested with all the UVA/Padova T1DM simulator patients (i.e. ten adults, ten adolescents, and ten children) during a fasting‐night scenario and in a hybrid closed‐loop scenario including three meals. The theoretical results are assessed by the simulations on a large cohort of virtual patients and encourage clinical trials.
Published: 2020
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32. Bariatric Surgery Improves the Atherogenic Profile of Circulating Methylarginines in Obese Patients: Results from a Pilot Study

Author: Mikaël Croyal, Chloé Cloteau, Xavier Billot, Audrey Aguesse, Julie Poirier, René Valéro, Marie Maraninchi, Etienne A. Thévenot, Michel Krempf, Centre de Recherche en Nutrition Humaine Ouest (CRNH Ouest), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire Sciences des Données et de la Décision (LS2D), Département Métrologie Instrumentation & Information (DM2I), Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, MetaboHUB, Clinique Bretéché [Nantes], 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), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Centre hospitalier universitaire de Nantes (CHU Nantes), We are grateful to the Biogenouest Corsaire Core Facility for their financial support, and RANCHON, GUILLAUME
Subjects: medicine.medical_specialty, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, Endocrinology, Diabetes and Metabolism, bariatric surgery, Renal function, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Microbiology, Biochemistry, Article, Insulin resistance, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], SDMA, medicine, methylarginines, Molecular Biology, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, business.industry, Fatty liver, Retrospective cohort study, NMMA, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, QR1-502, Surgery, ADMA, Basal (medicine), DMGV, Statistical analysis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Liver function, business, Body mass index, Dyslipidemia, data processing
Abstract: Bariatric surgery improves obesity-related comorbidities. Methylarginines are biomarkers of cardiometabolic risk, liver steatosis, and insulin resistance. Here, we aimed to investigate methylarginines in obese patients undergoing bariatric surgery and compared them to age- and sex-matched healthy subjects. Thirty-one obese patients who underwent bariatric surgery and 31 healthy individuals were used for this retrospective study. The basal serum methylarginine levels were determined in the healthy individuals and the obese patients, before surgery and 6 and 12 months after surgery, by mass spectrometry. Compared with the healthy individuals, the obese patients displayed elevated monomethylarginine (mean change: +95%, p &lt, 0.001), asymmetric-dimethylarginine (+105%, p &lt, 0.001), symmetric-dimethylarginine (+25%, p = 0.003), and dimethylguanidino valerate (+32%, p = 0.008) concentrations. Bariatric surgery durably reduced the body mass index by 28% (12 months, 95%CI: 24–33, p = 0.002) and improved plasma lipids, insulin resistance, and liver function. Bariatric surgery reduced the serum levels of monomethylarginine and asymmetric-dimethylarginine by 12% (95%CI: 6–17) and 36% (95%CI: 27–45) (12 months, p = 0.003), respectively, but not symmetric-dimethylarginine or dimethylguanidino valerate. The monomethylarginine and asymmetric-dimethylarginine concentrations were strongly correlated with markers of dyslipidemia, insulin resistance, and a fatty liver. Serum dimethylguanidino valerate was primarily correlated with glycemia and renal function, whereas serum symmetric-dimethylarginine was almost exclusively associated with renal function. In conclusion, the monomethylarginine and asymmetric-dimethylarginine levels are efficiently decreased by bariatric surgery, leading to a reduced atherogenic profile in obese patients. Methylarginines follow different metabolic patterns, which could help for the stratification of cardiometabolic disorders in obese patients.
Published: 2021
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33. Myalgies et statines : démêler le vrai du faux

Author: Patrick Henry, Eric Bruckert, Jean-Jacques Mourad, Michel Krempf, Michel Farnier, Jacques Blacher, and Jean Ferrières
Subjects: Pediatrics, medicine.medical_specialty, Statin, business.industry, medicine.drug_class, Incidence (epidemiology), General Medicine, 030204 cardiovascular system & hematology, Therapeutic trial, 3. Good health, Discontinuation, Nocebo Effect, 03 medical and health sciences, 0302 clinical medicine, medicine, Observational Studies as Topic, Observational study, 030212 general & internal medicine, Adverse effect, business
Abstract: In therapeutic trials, the incidence of adverse muscle effects under statin is low, exceptional for some authors
Published: 2019
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34. Efficacy and safety of volanesorsen in patients with multifactorial chylomicronaemia (COMPASS): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial

Author: Linda C. Hemphill, Alberto Yataco, John P. Kane, Qingqing Yang, S.G. Hughes, Sotirios Tsimikas, Joseph L. Witztum, Robert A. Hegele, Manuel Castro-Cabezas, Robert Dufour, Steven Martin, Clinton Corder, Ulrich Julius, Seth J. Baum, Michel Krempf, James Powell, Mark Cervi, Steven Hamstead, Lawrence Galitz, Patrick M. Moriarty, Frank L.J. Visseren, Basil Issa, Traci Turner, Pankaj Vyas, Daniel Gaudet, Eunju Hurh, Erik S.G. Stroes, Peter P. Toth, Christie M. Ballantyne, Bruno Vergès, Cynthia Huffman, Jean Bergeron, Craig Thompson, Richard Shultzaberger, Ioanna Gouni-Berthold, Louis O'Dea, Cecil Murray Farrington, René Valéro, Eric Bruckert, Elisabeth Steinhagen-Thiessen, Abhay Agarwal, Letitia Thompson-Hargrave, Gordon A. Francis, Veronica J. Alexander, Richard Burdick, Experimental Vascular Medicine, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), and 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)
Subjects: Adult, Male, medicine.medical_specialty, Internationality, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Oligonucleotides, Phases of clinical research, 030209 endocrinology & metabolism, Placebo, law.invention, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Endocrinology, Randomized controlled trial, Double-Blind Method, law, Internal medicine, Internal Medicine, medicine, Humans, 030212 general & internal medicine, Dosing, ComputingMilieux_MISCELLANEOUS, Aged, Triglyceride, business.industry, Middle Aged, Oligonucleotides, Antisense, medicine.disease, Clinical trial, Causality, Clinical research, Treatment Outcome, chemistry, Acute pancreatitis, Female, Hyperlipoproteinemia Type I, business, Follow-Up Studies
Abstract: Background: Volanesorsen is an antisense oligonucleotide that targets hepatic apolipoprotein C-III synthesis and reduces plasma triglyceride concentration. The aim of this study was to explore the safety and efficacy of volanesorsen in patients with multifactorial chylomicronaemia syndrome. Methods: The COMPASS trial was a randomised, placebo-controlled, double-blind, phase 3 study done at 38 international clinical sites in Canada, France, Germany, the Netherlands, UK, and USA. Eligible patients were aged 18 years or older with multifactorial severe hypertriglyceridaemia or familial chylomicronaemia syndrome, who had a BMI of 45 kg/m 2 or less and fasting plasma triglyceride of 500 mg/dL or higher. Patients were randomly assigned (2:1) with an interactive response system using an allocation sequence and permuted block randomisation to receive subcutaneous volanesorsen (300 mg) or a matched volume of placebo (1·5 mL) once a week for 26 weeks. After 13 weeks of treatment, dosing was changed to 300 mg of volanesorsen or placebo every 2 weeks for all patients, except those who had completed 5 months or more of treatment as of May 27, 2016. Participants, investigators, sponsor personnel, and clinical research staff were all masked to the treatment assignments. The primary outcome was percentage change from baseline to 3 months in fasting triglyceride in the full analysis set (all patients who were randomly assigned and received at least one dose of study drug and had a baseline fasting triglyceride assessment). This trial is registered with ClinicalTrials.gov, NCT02300233 (completed). Findings: Between Feb 5, 2015, and Jan 24, 2017, 408 patients were screened for eligibility. 294 were excluded and 114 randomly assigned to receive either volanesorsen (n=76) or placebo (n=38). One patient in the volanesorsen group discontinued before receiving the study drug. The total number of dropouts was 28 (four in the placebo group and 24 in the treatment group). Volanesorsen reduced mean plasma triglyceride concentration by 71·2% (95% CI −79·3 to −63·2) from baseline to 3 months compared with 0·9% (−13·9 to 12·2) in the placebo group (p
Published: 2021
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35. Large-scale screening of lipase acid deficiency in at risk population

Author: Victor de Ledinghen, Marie-Thérèse Abi Warde, Eric Nguyen-Khac, Marietta Musikas, Soumeya Bekri, Eloi Blanchet, Alice Thebaut, Isabelle Tragin, Anaïs Brassier, Dominique Larrey, Sarah Snanoudj, Myriam Dabbas, Michel Krempf, Edouard Bardou-Jacquet, Carine Pilon, Denis Ouzan, Corinne Borderon, Jean-Marc Perarnau, Armand Abergel, Maeva Guillaume, Reda Belbouab, Thierry Thevenot, Claire Carette, Valérie Triolo, Jean-Pierre Bronowicki, Hélène Dranguet, Jean Ferrières, Rodolphe Anty, Sabrina Vergnaud, Vincent Leroy, Vlad Ratzlu, Bertrand Cariou, Bruno Vergès, Abdellah Tebani, Bénédicte Sudrié-Arnaud, Hela Boudabous, Florence Lacaille, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Université de Tunis El Manar (UTM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), CHU Clermont-Ferrand, CHU Strasbourg, Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Pontchaillou [Rennes], Centre Hospitalo-Universitaire Mustapha Bacha, Service de psychiatrie, groupe hospitalier de La Rochelle-Ré-Aunis, CH La Rochelle, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Pessac, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Clinique Bretéché [Nantes], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Groupe de Recherche sur l'alcool et les pharmacodépendances - UMR INSERM_S 1247 (GRAP), Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Arnault Tzanck, CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Nice [Cimiez], Hôpital Cimiez [Nice] (CHU), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, CHU Grenoble, This research was funded by Alexion Pharmaceuticals., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université Nice Sophia Antipolis (... - 2019) (UNS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CRHU Nancy, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Jonchère, Laurent
Subjects: 0301 basic medicine, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Acid lipase deficiency, DBS, Spleen, Dried blood spot, Lysosomal acid lipase deficiency, Biochemistry, Gastroenterology, CESD, Cholesterol ester storage disease, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Lysosome, Internal medicine, medicine, Humans, Allele, business.industry, Biochemistry (medical), Infant, Newborn, Wolman Disease, Lipase, General Medicine, LAL, Sterol Esterase, medicine.disease, Phenotype, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Wolman, 030220 oncology & carcinogenesis, Cohort, Screening, Female, Cholesterol Esters, business
Abstract: International audience; BACKGROUND: Lysosomal acid lipase deficiency (LALD, OMIM#278000) is a rare lysosomal disorder with an autosomal recessive inheritance. The main clinical manifestations are related to a progressive accumulation of cholesteryl esters, triglycerides or both within the lysosome in different organs such as the liver, spleen, and cardiovascular system. A wide range of clinical severity is associated with LALD including a severe very rare antenatal/neonatal/infantile phenotype named Wolman disease and a late-onset form named cholesteryl ester storage disease (CESD). METHODS: This study aimed to investigate a cohort of at-risk patients (4174) presenting with clinical or biological signs consistent with LALD using the assessment of LAL activity on dried blood spots. RESULTS: LAL activity was lower than 0.05 nmol/punch/L (cut-off: 0.12) in 19 patients including 13 CESD and 6 Wolman. Molecular study has been conducted in 17 patients and succeeded in identifying 34 mutated alleles. Fourteen unique variants have been characterized, 7 of which are novel. CONCLUSION: This study allowed to identify a series of patients and expanded the molecular spectrum knowledge of LALD. Besides, a new screening criteria grid based on the clinical/biological data from our study and the literature has been proposed in order to enhance the diagnosis rate in at risk populations.
Published: 2021
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36. Carrot Supplementation Improves Blood Pressure and Reduces Aortic Root Lesions in an Atherosclerosis-Prone Genetic Mouse Model

Author: Patricia Mallegol, Julien Chaigneau, Khadija Ouguerram, Ramaroson Andriantsitohaina, Michel Krempf, Jérôme Boursier, Raffaella Soleti, Fatima Kasbi-Chadli, Emmanuel Geoffriau, Lionel Fizanne, Marine Coué, Charlotte Trenteseaux, Grégory Hilairet, Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Recherche en Nutrition Humaine Ouest [Nantes] (UN), Université de Nantes (UN), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Clinique Bretéché [Nantes], Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-INSTITUT AGRO Agrocampus Ouest, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), 'Region Pays de la Loire' INUMAMET project, Universite d'Angers, Institut National de la Sante et de la Recherche Medicale (Inserm), European Commission., BOURGEAIS, Véronique, Université d'Angers (UA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA)
Subjects: Apolipoprotein E, ApoE(-/-), Apolipoprotein B, 030309 nutrition & dietetics, [SDV]Life Sciences [q-bio], Hemodynamics, Blood Pressure, Lipoproteins, VLDL, Weight Gain, Mice, Cardiac Output, Cecum, Aorta, 2. Zero hunger, Mice, Knockout, 0303 health sciences, Nutrition and Dietetics, biology, ApoE−/−, high fat diet, atheroscleros, Plaque, Atherosclerotic, ishigh fat diet, 3. Good health, Daucus carota, [SDV] Life Sciences [q-bio], Cardiovascular Diseases, Lipogenesis, medicine.symptom, lcsh:Nutrition. Foods and food supply, ApoE, medicine.medical_specialty, lcsh:TX341-641, Diet, High-Fat, Article, Lesion, 03 medical and health sciences, Apolipoproteins E, Lipid oxidation, Internal medicine, medicine, Animals, carrot supplementation, Triglycerides, 030304 developmental biology, business.industry, Cardiometabolic Risk Factors, Disease Models, Animal, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Endocrinology, Blood pressure, hemodynamic parameter, Dietary Supplements, biology.protein, Lipid Peroxidation, Propionates, atherosclerosis, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Food Science, Lipoprotein
Abstract: International audience; Epidemiological studies have shown that carrot consumption may be associated with a lower risk of developing several metabolic dysfunctions. Our group previously determined that the Bolero (Bo) carrot variety exhibited vascular and hepatic tropism using cellular models of cardiometabolic diseases. The present study evaluated the potential metabolic and cardiovascular protective effect of Bo, grown under two conditions (standard and biotic stress conditions (BoBS)), in apolipoprotein E-knockout (ApoE−/−) mice fed with high fat diet (HFD). Effects on metabolic/hemodynamic parameters and on atherosclerotic lesions have been assessed. Both Bo and BoBS decreased plasma triglyceride and expression levels of genes implicated in hepatic de novo lipogenesis and lipid oxidation. BoBS supplementation decreased body weight gain, secretion of very-low-density lipoprotein, and increased cecal propionate content. Interestingly, Bo and BoBS supplementation improved hemodynamic parameters by decreasing systolic, diastolic, and mean blood pressure. Moreover, Bo improved cardiac output. Finally, Bo and BoBS substantially reduced the aortic root lesion area. These results showed that Bo and BoBS enriched diets corrected most of the metabolic and cardiovascular disorders in an atherosclerosis-prone genetic mouse model and may therefore represent an interesting nutritional approach for the prevention of cardiovascular diseases.
Published: 2021
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37. Effect of fasting and feeding on apolipoprotein A-I kinetics in preβ1-HDL, α-HDL, and triglyceride-rich lipoproteins

Author: Laurent Flet, E. Nobecourt, Yassine Zair, Fanta Fall, Mikaël Croyal, Khadija Ouguerram, Michel Krempf, Maud Chétiveaux, Mass Spectrometry Core Facility [Nantes] (CRNH-O ), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Saint-Pierre, and Clinique Bretéché [Nantes]
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Very low-density lipoprotein, Apolipoprotein B, Physiology, Lipoproteins, Kinetics, lcsh:Medicine, Lipoproteins, VLDL, 030204 cardiovascular system & hematology, Triglycerides blood, Biochemistry, Article, Feeding Methods, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Humans, lcsh:Science, Triglycerides, Multidisciplinary, Apolipoprotein A-I, Triglyceride, biology, lcsh:R, nutritional and metabolic diseases, Fasting, 030104 developmental biology, Endocrinology, chemistry, Apolipoprotein B-100, [SDE]Environmental Sciences, biology.protein, lcsh:Q, lipids (amino acids, peptides, and proteins), Lipoproteins, HDL, Clearance rate, Biomarkers, Lipoprotein
Abstract: The aim of this study was to compare the kinetics of apolipoprotein (apo)A-I during fed and fasted states in humans, and to determine to what extent the intestine contributes to apoA-I production. A stable isotope study was conducted to determine the kinetics of apoA-I in preβ1 high-density lipoprotein (HDL) and α-HDL. Six healthy male subjects received a constant intravenous infusion of 2H3-leucine for 14 h. Subjects in the fed group also received small hourly meals. Blood samples were collected hourly during tracer infusion and then daily for 4 days. Tracer enrichments were measured by mass spectrometry and then fitted to a compartmental model using asymptotic plateau of very-low-density lipoprotein (VLDL) apoB100 and triglyceride-rich lipoprotein (TRL) apoB48 as estimates of hepatic and intestinal precursor pools, respectively. The clearance rate of preβ1-HDL-apoA-I was lower in fed individuals compared with fasted subjects (p 1-HDL. Total apoA-I synthesis was not significantly increased in fed subjects. Hepatic production was not significantly different between the fed group (17.17 ± 2.75 mg/kg/day) and the fasted group (18.67 ± 1.69 mg/kg/day). Increase in intestinal apoA-I secretion in fed subjects was 2.20 ± 0.61 mg/kg/day. The HDL-apoA-I kinetics were similar in the fasted and fed groups, with 13% of the total apoA-I originating from the intestine with feeding.
Published: 2020
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38. SAFEHEART risk-equation and cholesterol-year-score are powerful predictors of cardiovascular events in French patients with familial hypercholesterolemia

Author: Antonio Gallo, Sybil Charriere, Alexandre Vimont, M. John Chapman, Denis Angoulvant, Franck Boccara, Bertrand Cariou, Valérie Carreau, Alain Carrié, Eric Bruckert, Sophie Béliard, Sophie Beliard, Alain Carrie, Yves Cottin, Mathilde DI. Filippo, Sonia Dulong, Vincent Durlach, Michel Farnier, Emile Ferrari, Dorota Ferrieres, Jean Ferrieres, Philippe Giral, Sophie Gonbert, Regis Hankard, Jocelyn Inamo, Olga Kalmykova, Michel Krempf, Philippe Moulin, François Paillard, Noel Peretti, Agnes Perrin, Jean Pierre Rabes, Ariane Sultan, Patrick Tounian, René Valero, Bruno Verges, Cecile Yelnik, Olivier Ziegler, Inserm UMR1069, Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire catalyse et spectrochimie (LCS), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Cardiologie (CHU Trousseau, Tours), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre recherche en CardioVasculaire et Nutrition (C2VN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service d'endocrinologie-métabolisme [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), CHU Pitié-Salpêtrière [AP-HP], Station d'Amélioration Génétique des Animaux (SAGA), Institut National de la Recherche Agronomique (INRA), Centre Hospitalier Universitaire de Lyon, Service de Cardiologie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Pôle Thoracique Cardiovasculaire et Neurologique, Hôpital Robert Debré, Point médical (Dijon), Hôpital Pasteur [Nice] (CHU), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Istituto di Scienze degli Alimenti e della Nutrizione, Università Cattolica del Sacro Cuore, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Centre d' investigation clinique-plurithématique du CHU de Poitiers, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de cardiologie, Hôpital Pierre Zobda-Quitman [CHU de la Martinique], CHU de la Martinique [Fort de France]-CHU de la Martinique [Fort de France], Samara State Technical University, Biologie et physiopathologie intestinales. Pharmacologie nutritionnelle, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Hôpital Femme Mère Enfant, Laboratoire Interuniversitaire des Systèmes Atmosphériques (LISA (UMR_7583)), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service de gastro-entérologie [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Endocrinologie, Diabétologie et Maladies Métaboliques (CHU de Dijon), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Jeanne d'Arc, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours, Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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], Hospices Civils de Lyon (HCL), Public Health Expertise [Paris, France], Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), Service d'Endocrinologie, Métabolisme et Prévention des Maladies Cardio-vasculaires [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Cardiologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de recherche de l'institut du thorax (ITX-lab), Service d'endocrinologie, diabète, maladies métaboliques [Hôpital de la Conception - APHM], Aix Marseille Université (AMU), 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), French REgistry of Familial hypERCHOLesterolemia (REFERCHOL) investigators, ANR-16-RHUS-0007,CHOPIN,CHOPIN(2016), Gestionnaire, Hal Sorbonne Université, CHOPIN - - CHOPIN2016 - ANR-16-RHUS-0007 - RHUS - VALID, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)
Subjects: cardiovascular risk, 0301 basic medicine, medicine.medical_specialty, cardiovascular risk equation, Population, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Risk Assessment, Cohort Studies, Hyperlipoproteinemia Type II, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Humans, education, ComputingMilieux_MISCELLANEOUS, Risk equation, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Entire population, education.field_of_study, familial hypercholesterolemia, business.industry, Cholesterol, External validation, Cholesterol, LDL, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 030104 developmental biology, cholesterol-year-score, chemistry, Cardiovascular Diseases, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Clinical diagnosis, primary cardiovascular prevention, Cohort, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cardiology and Cardiovascular Medicine, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: Background and aims Patients with heterozygous familial hypercholesterolemia (HeFH) present elevated cardiovascular (CV) risk. Current CV risk stratification algorithms developed for the general population are not adapted for heFH patients. It is therefore of singular importance to develop and validate CV prediction tools, which are dedicated to the HeFH population. Methods Our first objective was to validate the Spanish SAFEHEART-risk equation (RE) in the French HeFH cohort (REFERCHOL), and the second to compare SAFEHEART-RE with the low-density-lipoprotein-cholesterol (LDL-C)-year-score for the prediction of CV events in the HeFH French population. Results We included HeFH (n = 1473) patients with a genetic or clinical diagnosis (DLCN score ≥8). Among them, 512 patients with a 5-year follow-up were included to validate the 5 year-CV-RE. A total of 152 events (10.3%) occurred in the entire population of 1473 patients during a mean follow-up of 3.9 years. Over the five-year follow-up, non-fatal CV events occurred in 103 patients (20.2%). Almost all the parameters used in the SAFEHEART-RE were confirmed as strong predictors of CV events in the REFERCHOL cohort. The C-statistic revealed a satisfactory performance of both the SAFEHEART-RE and LDL-C-year-scores in predicting CV events for all the patients (primary and secondary prevention) (C-index 0.77 and 0.70, respectively) as well as for those in primary prevention at inclusion (C-index 0.78 and 0.77, respectively). Conclusions This analysis represents the first external validation of the SAFEHEART-RE and demonstrated that both SAFEHEART-RE and the LDL-C-year-score are good predictors of CV events in primary prevention HeFH patients.
Published: 2020
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39. Efficacy and Safety of Alirocumab in Patients With Autosomal Dominant Hypercholesterolemia Associated With Proprotein Convertase Subtilisin/Kexin Type 9 Gain-of-Function or Apolipoprotein B Loss-of-Function Mutations

Author: Eric Bruckert, Shane Lee, Michel Krempf, Paul N. Hopkins, Stephen Donahue, University of Utah, CIC Pitié BT, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Adult, Male, medicine.medical_specialty, Genotype, Apolipoprotein B, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Antibodies, Monoclonal, Humanized, Gastroenterology, law.invention, Hyperlipoproteinemia Type II, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Loss of Function Mutation, law, Internal medicine, medicine, Humans, 030212 general & internal medicine, Adverse effect, Genes, Dominant, Alirocumab, Chromosome Aberrations, biology, business.industry, PCSK9, Middle Aged, Proprotein convertase, Long-Term Care, 3. Good health, Clinical trial, Treatment Outcome, Gain of Function Mutation, Apolipoprotein B-100, biology.protein, Cardiology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Kexin, Female, lipids (amino acids, peptides, and proteins), Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, business, Lipoprotein
Abstract: International audience; Autosomal dominant hypercholesterolemia results from mutations affecting the low-density lipoprotein receptor pathway, including proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GoFm) and apolipoprotein B (APOB) loss-of-function mutations (LoFm). This study examined the long-term efficacy and safety of alirocumab in patients with PCSK9 GoFm and APOB LoFm who participated in the open-label extension to a Phase 2 double-blind study (NCT01604824). Of the 23 patients who completed the 14-week double-blind period and 8-week follow-up, 21 opted to continue in the open-label extension (PCSK9 GoFm, n = 15; APOB LoFm, n = 6). Patients received alirocumab 150 mg every 2 weeks from week 32 up to 3 years for PCSK9 GoFm and 2 years for APOB LoFm. Mean duration of alirocumab exposure was 129 weeks (median: 144 weeks). After initiation of alirocumab treatment, low-density lipoprotein cholesterol (LDL-C) decreased in both groups. At week 80, mean percent reduction in LDL-C from baseline was 58.0% and 47.1% for PCSK9 GoFm and APOB LoFm groups, respectively. Treatment-emergent adverse events were reported in 19 patients (90.5%); no patients discontinued treatment due to treatment-emergent adverse events. In patients with autosomal dominant hypercholesterolemia and elevated LDL-C levels despite receiving maximally tolerated lipid-lowering therapies, alirocumab 150 mg every 2 weeks resulted in clinically meaningful reductions in LDL-C, sustained through to 3 years and 2 years for patients with PCSK9 GoFm and APOB LoFm, respectively. Alirocumab was generally well tolerated with no unexpected safety concerns.
Published: 2020
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40. Roux-en-Y gastric bypass, but not sleeve gastrectomy, decreases plasma PCSK9 levels in morbidly obese patients

Author: Séverine Ledoux, L. Van Gaal, Matthieu Wargny, L. Arnaud, Ann Verhaegen, M. Perrocheau Guillouche, E. Letessier, Michel Krempf, Bertrand Cariou, N. Huten, David Jacobi, M. Le Bras, C. Le May, Claire Blanchard, Matthieu Pichelin, A. Stepanian, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre hospitalier universitaire de Nantes (CHU Nantes), Hopital Louis Mourier - AP-HP [Colombes], Antwerp University Hospital [Edegem] (UZA), Hôpital Lariboisière, Centre Hospitalier Régional Universitaire de Tours (CHRU de Tours), Physiopathologie des Adaptations Nutritionnelles, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut du Thorax, and Université de Nantes (UN)
Subjects: Blood Glucose, Male, Dyslipidaemia, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, 030204 cardiovascular system & hematology, Gastroenterology, Cohort Studies, PCSK9, 0302 clinical medicine, Endocrinology, Prospective Studies, ComputingMilieux_MISCELLANEOUS, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Roux-en-Y anastomosis, Obesity, Morbid, Treatment Outcome, Kexin, lipids (amino acids, peptides, and proteins), Female, Proprotein Convertase 9, medicine.medical_specialty, Sleeve gastrectomy, bariatric surgery, Gastric bypass, Gastric Bypass, 030209 endocrinology & metabolism, 03 medical and health sciences, RYGB, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Gastrectomy, Internal medicine, Internal Medicine, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Obesity, Dyslipidemias, Glycated Hemoglobin, business.industry, Cholesterol, HDL, nutritional and metabolic diseases, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cholesterol, LDL, medicine.disease, Dyslipidemia, LDL receptor, Human medicine, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Homeostasis
Abstract: Aim. - Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a master regulator of low-density lipoprotein cholesterol (LDL-C) metabolism, acting as an endogenous inhibitor of the LDL receptor. While it has been shown that bariatric surgery differentially affects plasma LDL-C levels, little is known of its effects on plasma PCSK9 concentrations. Therefore, the present study aimed to: (i) investigate the effect of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on plasma PCSK9 concentrations; and (ii) correlate baseline or postoperative plasma PCSK9 concentration variations with anthropometric and metabolic parameters. Methods. - Fasting plasma PCSK9 levels were measured by ELISA in morbidly obese patients before and 6 months after bariatric surgery. Patients were recruited from three prospective cohorts (in Nantes and Colombes in France, and Antwerp in Belgium). Results. - A total of 156 patients (34 SG, 122 RYGB) were included. Plasma PCSK9, LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) levels were significantly reduced after RYGB (-19.6%, -16.6% and -19.5%, respectively; P < 0.0001), but not after SG. In all patients, postoperative PCSK9 change was positively correlated with fasting plasma glucose (FPG; r = 0.22, P = 0.007), HOMA-IR (r = 0.24, P = 0.005), total cholesterol (r = 0.17, P = 0.037) and non-HDL-C (r = 0.17, P = 0.038) variations, but not LDL-C. In contrast to what was observed for glucose parameters (FPG, HOMA-IR), correlation between PCSK9 and non-HDL-C changes after RYGB was independent of total weight loss. Conclusion. - RYGB, but not SG, promotes a significant reduction in plasma PCSK9 levels, and such changes in circulating PCSK9 levels after RYGB appear to be more associated with glucose improvement than with lipid homoeostasis parameters. (C) 2020 Published by Elsevier Masson SAS.
Published: 2020
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41. VLDL (Very-Low-Density Lipoprotein)-Apo E (Apolipoprotein E) May Influence Lp(a) (Lipoprotein [a]) Synthesis or Assembly

Author: Bertrand Cariou, Maud Chétiveaux, Laurent Flet, Audrey Aguesse, Valentin Blanchard, Karine Bernardeau, Gilles Lambert, Cédric Le May, Samy Hadjadj, Thomas Moyon, Estelle Nobécourt-Dupuy, Mikaël Croyal, Léa Cabioch, Michel Krempf, Khadija Ouguerram, Stéphanie Billon-Crossouard, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Mass Spectrometry Core Facility [Nantes] (CRNH-O ), Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Biogenouest-Corsaire platform [Saint Gilles, France], Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre hospitalier universitaire de Nantes (CHU Nantes), ELSAN, Partenaires INRAE, Service de Néphrologie [Saint-Pierre, La Réunion], Groupe Hospitalier Sud Réunion (GHSR), ANR-16-RHUS-0007,CHOPIN,CHOPIN(2016), Physiopathologie des Adaptations Nutritionnelles, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de recherche en nutrition humaine Ouest, Université de La Réunion (UR), Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Génomique Santé Biogenouest®, Centre Hospitalier Universitaire Sud Reunion, ANR: ANR-16-RHUS-0007, Le May, Cedric, CHOPIN - - CHOPIN2016 - ANR-16-RHUS-0007 - RHUS - VALID, Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de recherche de l'institut du thorax (ITX-lab), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Apolipoprotein E, Very low-density lipoprotein, Apolipoprotein B, Familial hypercholesterolemia, niacin, Lipoproteins, VLDL, 030204 cardiovascular system & hematology, 0302 clinical medicine, ComputingMilieux_MISCELLANEOUS, Randomized Controlled Trials as Topic, apolipoprotein E, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, biology, Chemistry, Anticholesteremic Agents, Lipoprotein(a), Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Phenotype, Treatment Outcome, Female, lipids (amino acids, peptides, and proteins), Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, Adult, Heterozygote, medicine.medical_specialty, Adolescent, loss of function mutation, Hyperlipoproteinemia Type II, Young Adult, 03 medical and health sciences, Apolipoproteins E, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine, Humans, Genetic Predisposition to Disease, isotopes, 030304 developmental biology, PCSK9, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Endocrinology, Receptors, LDL, kinetics, Case-Control Studies, Delayed-Action Preparations, Mutation, LDL receptor, biology.protein, Biomarkers, Lipoprotein
Abstract: Objective: To clarify the association between PCSK9 (proprotein convertase subtilisin/kexin type 9) and Lp(a) (lipoprotein [a]), we studied Lp(a) kinetics in patients with loss-of-function and gain-of-function PCSK9 mutations and in patients in whom extended-release niacin reduced Lp(a) and PCSK9 concentrations. Approach and Results: Six healthy controls, 9 heterozygous patients with familial hypercholesterolemia (5 with low-density lipoprotein receptor [ LDLR ] mutations and 4 with PCSK9 gain-of-function mutations) and 3 patients with heterozygous dominant-negative PCSK9 loss-of-function mutations were included in the preliminary study. Eight patients were enrolled in a second study assessing the effects of 2 g/day extended-release niacin. Apolipoprotein kinetics in VLDL (very-low-density lipoprotein), LDL (low-density lipoprotein), and Lp(a) were studied using stable isotope techniques. Plasma Lp(a) concentrations were increased in PCSK9 -gain-of-function and familial hypercholesterolemia- LDLR groups compared with controls and PCSK9 -loss-of-function groups (14±12 versus 5±4 mg/dL; P =0.04), but no change was observed in Lp(a) fractional catabolic rate. Subjects with PCSK9 -loss-of-function mutations displayed reduced apoE (apolipoprotein E) concentrations associated with a VLDL-apoE absolute production rate reduction. Lp(a) and VLDL-apoE absolute production rates were correlated ( r =0.50; P r =0.96; P r =0.83; P =0.015). In contrast, PCSK9 reduction (−35%; P =0.008) was only correlated with that of VLDL-apoE absolute production rate ( r =0.79; P =0.028). Conclusions: VLDL-apoE production could determine Lp(a) production and/or assembly. As PCSK9 inhibitors reduce plasma apoE and Lp(a) concentrations, apoE could be the link between PCSK9 and Lp(a).
Published: 2020
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42. 10-year comparative follow up of familial versus multifactorial chylomicronemia syndromes

Author: Hanane Bada, Eric Bruckert, Maeva Nolin, Eric Van Ganse, Manon Belhassen, René Valéro, Marjorie Bérard, Michel Krempf, Philippe Moulin, Vinciane Rebours, PELyon Pharmaco Epidémiologie [Lyon] (Santé Publique et Epidémiologie), Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Health Service and Performance Research (HESPER), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-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), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (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), Assistance Publique - Hôpitaux de Marseille (APHM), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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], Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-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 CarMeN, laboratoire
Subjects: Male, Time Factors, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, DNA Mutational Analysis, pancreatitis, 030204 cardiovascular system & hematology, Biochemistry, 0302 clinical medicine, Endocrinology, Risk Factors, Hyperchylomicronemia, 030212 general & internal medicine, education.field_of_study, diabetes, Incidence (epidemiology), Hazard ratio, Syndrome, Middle Aged, Prognosis, humanities, 3. Good health, ischemic cardiovascular events, [SDV] Life Sciences [q-bio], Acute pancreatitis, Female, Hyperlipoproteinemia Type I, lipids (amino acids, peptides, and proteins), France, Adult, medicine.medical_specialty, Population, Context (language use), 03 medical and health sciences, Young Adult, Internal medicine, Diabetes mellitus, medicine, Humans, Genetic Predisposition to Disease, education, Retrospective Studies, business.industry, Biochemistry (medical), Odds ratio, medicine.disease, Case-Control Studies, Pancreatitis, business, Follow-Up Studies
Abstract: Context The relative incidence of acute pancreatitis, ischemic cardiovascular disease, and diabetes in hyperchylomicronemic patients exhibiting familial chylomicronemia syndrome (FCS) or multifactorial chylomicronemia syndrome (MCS) is unknown. Objective The objective was to study the occurrence of these events in FCS and MCS patients compared with the general population. Methods Twenty-nine FCS and 124 MCS patients, with genetic diagnosis, in 4 lipid clinics were matched with 413 controls. Individual hospital data linked to the national claims database were collected between 2006 and 2016. The occurrence of complications was retrospectively assessed before follow-up and during a median follow-up time of 9.8 years, for 1500 patient years of follow-up. Results Patients with FCS were younger than those with MCS (34.3 ± 13.6 vs 45.2 ± 12.6 years, P Conclusion The incidence of AHP was much higher in FCS than in MCS patients, whereas the incidence of ischemic cardiovascular events was found to be increased in MCS versus FCS patients and a representative matched control group. Differences in both triglyceride-rich lipoproteins metabolism and comorbidities in MCS versus FCS drive the occurrence of different patterns of complications.
Published: 2020
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43. Hypercholestérolémie familiale peu diagnostiquée, insuffisamment traitée. Enquête auprès de 495 médecins

Author: Jean Ferrières, Eric Bruckert, Bertrand Cariou, Nicolas Danchin, Jean-Pierre Rabès, Michel Krempf, Michel Farnier, and Sophie Béliard
Subjects: Gynecology, 03 medical and health sciences, medicine.medical_specialty, 0302 clinical medicine, business.industry, Medicine, 030212 general & internal medicine, General Medicine, 030204 cardiovascular system & hematology, business, 3. Good health
Abstract: Resume Introduction L’hypercholesterolemie familiale heterozygote (HF) est l’une des maladies genetiques les plus frequentes avec une incidence de l’ordre de 1/250. Elle est caracterisee par un taux de cholesterol tres eleve depuis la naissance souvent responsable de maladies cardiovasculaires (CV) atteignant des patients jeunes. Alors qu’un diagnostic precoce et une prise en charge therapeutique adaptee permettent d’eviter les complications CV de la maladie, l’HF est largement sous-diagnostiquee et donc sous-traitee. Methodes Afin de faire un etat des lieux de la prise en charge de l’HF en France, nous avons mene une enquete aupres de 495 medecins generalistes (n = 200) et specialistes (n = 295) susceptibles de suivre ces patients. Resultats Les resultats ont revele une large sous-estimation du risque CV et une forte inertie therapeutique dans la prise en charge des patients atteints. Les medecins ont fait etat d’un reel besoin d’information sur la maladie. Conclusion Compte tenu de la frequence de l’HF et du poids de la morbi-mortalite cardiovasculaire associee, les medecins generalistes ont un role decisif a jouer dans l’identification et la prise en charge de ces patients. La publication recente de recommandations de la HAS sur les modalites de depistage familial de l’HF devrait permettre une amelioration de la prise en charge de cette maladie.
Published: 2018
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44. PCSK9 inhibition with alirocumab reduces lipoprotein(a) levels in nonhuman primates by lowering apolipoprotein(a) production rate

Author: Ilya Khantalin, Stéphane Ramin-Mangata, Brice Nativel, Stéphanie Billon-Crossouard, Mikaël Croyal, Rose Hélène Blanchard, Etienne Guillot, Kévin Chemello, Michel Krempf, Valentin Blanchard, Gilles Lambert, Audrey Aguesse, Bruno Poirier, Philip Janiak, Elise F. Villard, Christophe Boixel, Jean-Christophe Le Bail, Aurélie Thedrez, Thi-Thu-Trang Tran, Nutrition périnatale [Nantes] (Centres de Recherche en Nutrition Humaine - CRNH), Centre de Recherche en Nutrition Humaine - Ouest, Sanofi-Aventis R&D, SANOFI Recherche, Physiologie des Adaptations Nutritionnelles [UMR_A1280] (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Groupe d'Etude sur l'Inflammation Chronique et l'Obésité (GEICO), Université de La Réunion (UR), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), INRA: UMR1280 Physiologie des adaptations (UMR1280), Institut National de la Recherche Agronomique (INRA), Bureau d'Économie Théorique et Appliquée (BETA), Institut National de la Recherche Agronomique (INRA)-Université de Strasbourg (UNISTRA)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie des Adaptations Nutritionnelles (PhAN), and Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA)
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, plasma lipoproteins, Apolipoprotein B, [SDV]Life Sciences [q-bio], receptors, 030204 cardiovascular system & hematology, Antibodies, Monoclonal, Humanized, Apoprotein(a), PCSK9, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, low-density lipoproteins, medicine, Animals, Receptor, ComputingMilieux_MISCELLANEOUS, Alirocumab, Cross-Over Studies, biology, Chemistry, Catabolism, Anticholesteremic Agents, PCSK9 Inhibitors, Antibodies, Monoclonal, General Medicine, Lipoprotein(a), Lipids, Macaca fascicularis, Cholesterol, 030104 developmental biology, Endocrinology, biology.protein, Kexin, Female, lipids (amino acids, peptides, and proteins), Lipoprotein
Abstract: Therapeutic antibodies targeting proprotein convertase subtilisin kexin type 9 (PCSK9) (e.g. alirocumab) lower low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) [Lp(a)] levels in clinical trials. We recently showed that PCSK9 enhances apolipoprotein(a) [apo(a)] secretion from primary human hepatocytes but does not affect Lp(a) cellular uptake. Here, we aimed to determine how PCSK9 neutralization modulates Lp(a) levels in vivo. Six nonhuman primates (NHP) were treated with alirocumab or a control antibody (IgG1) in a crossover protocol. After the lowering of lipids reached steady state, NHP received an intravenous injection of [2H3]-leucine, and blood samples were collected sequentially over 48 h. Enrichment of apolipoproteins in [2H3]-leucine was assessed by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Kinetic parameters were calculated using numerical models with the SAAMII software. Compared with IgG1, alirocumab significantly reduced total cholesterol (TC) (−28%), LDL-C (−67%), Lp(a) (−56%), apolipoprotein B100 (apoB100) (−53%), and apo(a) (−53%). Alirocumab significantly increased the fractional catabolic rate of apoB100 (+29%) but not that of apo(a). Conversely, alirocumab sharply and significantly reduced the production rate (PR) of apo(a) (−42%), but not significantly that of apoB100, compared with IgG1, respectively. In line with the observations made in human hepatocytes, the present kinetic study establishes that PCSK9 neutralization with alirocumab efficiently reduces circulating apoB100 and apo(a) levels by distinct mechanisms: apoB primarily by enhancing its catabolism and apo(a) primarily by lowering its production.
Published: 2018
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45. Les déterminants biopsychosociaux de la qualité de vie subjective des patients diabétiques

Author: Nathalie Cornet-Lemoine, Anne Sauvaget, Jean-Marie Vanelle, Tianna Loose, Vincent Pialoux, Samuel Bulteau, F. Salomé, Marie Guitteny, and Michel Krempf
Subjects: 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, Arts and Humanities (miscellaneous), 030212 general & internal medicine, Psychology, Humanities, Applied Psychology, 030227 psychiatry
Abstract: Resume La qualite de vie subjective des patients diabetiques peut etre determinee par une interaction des facteurs biologiques, sociaux et psychologiques. Cette conception de l’individu est reconnue dans la pratique clinique, mais peu de travaux ont etudie ses benefices de maniere quantitative. Dans une approche locale, on examine l’influence de chaque facteur sur la qualite de vie. A l’inverse, dans une approche Bio-Psycho-Sociale ou globale, la qualite de vie est apprehendee au regard de l’interaction de ces differents facteurs. L’etude a inclus 28 patients diabetiques hospitalises. Pour la qualite de vie, l’evaluation a ete realisee avec l’echelle SF-36. Pour les facteurs qui influencent la qualite de vie, l’outil INTERMED a ete utilise. Il a ete demontre que chaque facteur est associe de maniere negative, et statistiquement significative, a la qualite de vie subjective. De plus, l’interaction des facteurs permet de mieux expliquer cette qualite de vie que la simple prise en compte de n’importe quel facteur pris isolement. Ces resultats soulignent la necessite de prendre en charge les elements psychosociaux aupres des patients afin d’assurer au mieux le vecu subjectif de leur etat de sante.
Published: 2018
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46. Hypercholestérolémie familiale : un risque cardiovasculaire largement sous-estimé

Author: B. Cariou, Jean Ferrières, M. Farnier, Michel Krempf, Jean-Pierre Rabès, S. Béliard, Nicolas Danchin, and Eric Bruckert
Subjects: Gynecology, 03 medical and health sciences, medicine.medical_specialty, 0302 clinical medicine, business.industry, medicine, 030212 general & internal medicine, Cascade screening, 030204 cardiovascular system & hematology, Cardiology and Cardiovascular Medicine, business, 3. Good health
Abstract: Resume Contexte L’hypercholesterolemie familiale est une dyslipidemie hereditaire monogenique (autosomique dominante) caracterisee par une augmentation permanente et isolee du cholesterol transporte par les lipoproteines de basse densite. La prevalence de sa forme heterozygote est estimee entre 1/500 et 1/250, et en l’absence de traitement specifique, l’hypercholesterolemie familiale heterozygote est responsable d’une augmentation d’un facteur 13 du risque de coronaropathie precoce par rapport aux patients non atteints par la maladie. Objectifs Faire un etat des lieux de la connaissance de l’hypercholesterolemie familiale heterozygote en France aupres des medecins impliques dans la prise en charge de la pathologie. Methodes Au travers de questionnaires soumis par telephone et par Internet, une enquete a ete menee aupres d’un echantillon representatif de 495 medecins (cardiologues, endocrinologues/diabetologues, gynecologues, medecins generalistes) qui, en parallele, ont complete 579 fiches patient. Resultats Trente-deux pour cent (IC 95 % [27,8 ; 36,2]) des medecins declaraient faire la difference entre hypercholesterolemie polygenique et hypercholesterolemie familiale. La presence de xanthomes tendineux, un element cle du diagnostic, etait spontanement citee par 44 % (IC 95 % [34 ; 54,2]) des cardiologues. Six pour cent (IC 95 % [2,2 ; 12,6]) d’entre eux donnaient une estimation correcte de la prevalence de l’hypercholesterolemie familiale. La probabilite de transmission de l’hypercholesterolemie familiale heterozygote, quand un des parents est atteint, etait connue pour 59 % (IC 95 % [48,7 ; 68,7]) des cardiologues interroges. Un depistage en cascade etait effectue de facon systematique par 4 % (IC 95 % [1,1 ; 9,9]) d’entre eux. Dix-huit pour cent (IC 95 % [11 ; 26,9]) des cardiologues estimaient le risque cardiovasculaire supplementaire de l’hypercholesterolemie familiale heterozygote superieur a 10. Cinquante-sept pour cent (IC 95 % [46,7 ; 66,8]) des cardiologues admettaient etre mal informes sur l’hypercholesterolemie familiale heterozygote et 83 % (IC 95 % [74,1 ; 89,7]) exprimaient un besoin d’informations sur cette pathologie. Conclusion Le manque de connaissance de l’hypercholesterolemie familiale heterozygote et de son risque cardiovasculaire associe est probablement a l’origine d’un defaut de diagnostic conduisant a une prise en charge inadaptee de cette maladie.
Published: 2018
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47. Plasma Trimethylamine N-Oxide and Risk of Cardiovascular Events in Patients With Type 2 Diabetes

Author: Elise Gand, Michel Krempf, Jean-Michel Halimi, Pierre-Jean Saulnier, Gregory Ducrocq, David Montaigne, Ronan Roussel, Bertrand Cariou, Matthieu Wargny, Stéphanie Ragot, Audrey Aguesse, Samy Hadjadj, and Mikaël Croyal
Subjects: Male, Risk, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Trimethylamine N-oxide, Type 2 diabetes, Biochemistry, Gastroenterology, chemistry.chemical_compound, Methylamines, Endocrinology, Interquartile range, Internal medicine, Diabetes mellitus, medicine, Humans, Risk factor, Aged, business.industry, Biochemistry (medical), Hazard ratio, Middle Aged, medicine.disease, Survival Rate, Quartile, chemistry, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Female, business, Mace
Abstract: Objective Even though trimethylamine N-oxide (TMAO) has been demonstrated to interfere with atherosclerosis and diabetes pathophysiology, the association between TMAO and major adverse cardiovascular events (MACE) has not been specifically established in type 2 diabetes (T2D). Research Design and Methods We examined the association of plasma TMAO concentrations with MACE and all-cause mortality in a single-center prospective cohort of consecutively recruited patients with T2D. Results The study population consisted in 1463 SURDIENE participants (58% men), aged 65 ± 10 years. TMAO concentrations were significantly associated with diabetes duration, renal function, high-density lipoprotein cholesterol, soluble tumor necrosis factor receptor 1 (sTNFR1) concentrations (R2 = 0.27) and were significantly higher in patients on metformin, even after adjustment for estimated glomerular filtration rate (eGFR): 6.7 (8.5) vs 8.5 (13.6) µmol/L, respectively (PeGFR-adjusted = 0.0207). During follow-up (median duration [interquartile range], 85 [75] months), 403 MACE and 538 deaths were registered. MACE-free survival and all-cause mortality were significantly associated with the quartile distribution of TMAO concentrations, patients with the highest TMAO levels displaying the greatest risk of outcomes (P Conclusions We revealed an association between higher TMAO concentrations and increased risk of MACE and all-cause mortality, thereby opening some avenues on the role of dysbiosis in cardiovascular risk, in T2D patients.
Published: 2019

48. L’Idefi Man-Imal : une formation One-Health de la pluri- à l’interdisciplinarité

Author: C. Magras, Mathieu Eveillard, Anne-Laure Diguet, Nathalie Ruvoen-Clouet, Didier Lepelletier, Sébastien Couvreur, and Michel Krempf
Subjects: epidemiology, nutrition, new teaching practices, cross-disciplinary cooperation, education, One Health degree program, General Veterinary, Philosophy, biosecurité, alimentation, crises sanitaires, formation, interdisciplinarité, pluridisciplinarité, épidémiologie, Humanities
Abstract: Magras Catherine, Diguet Anne-Laure, Lepelletier Didier, Eveillard Mathieu, Couvreur Sébastien, Ruvoen-Clouet Nathalie, Krempf Michel. L’Idefi Man-Imal : une formation One-Health de la pluri- à l’interdisciplinarité. In: Bulletin de l'Académie Vétérinaire de France tome 171 n°2, 2018. pp. 100-102.
Published: 2018
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49. Maternal obesity leads to long-term altered levels of plasma ceramides in the offspring as revealed by a longitudinal lipidomic study in children

Author: Francisco Bolaños-Jiménez, Fengyang Huang, Michel Krempf, Laurence A. Marchat, Mikaël Croyal, Isabelle Romieu, Véronique Ferchaud-Roucher, Khadija Ouguerram, Rosalio Mercado-Camargo, Albino Barraza-Villarreal, Luis Felipe León-Aguilar, Usha Ramakrishnan, Nutrition périnatale [Nantes] (Centres de Recherche en Nutrition Humaine - CRNH), Centre de Recherche en Nutrition Humaine - Ouest, Université de Nantes (UN), Laboratory of Pharmacology and Toxicology, Hospital Infantil de México Federico Gómez, Instituto Politecnico Nacional [Mexico] (IPN), Center for Population Health Research, Insituto Nacional de Salud Publica, INRA: UMR1280 Physiologie des adaptations (UMR1280), Institut National de la Recherche Agronomique (INRA), Physiologie des Adaptations Nutritionnelles [UMR_A1280] (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Hospital Infantil de México Federico Gómez (HIMFG), and Physiopathologie des Adaptations Nutritionnelles (PhAN)
Subjects: Adult, Male, Ceramide, Pediatric Obesity, obesity, Offspring, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Ideal Body Weight, Medicine (miscellaneous), Physiology, 030209 endocrinology & metabolism, Overweight, Ceramides, Umbilical cord, metabolic syndrome, Obesity, Maternal, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Pregnancy, Lipidomics, medicine, Humans, 030212 general & internal medicine, Longitudinal Studies, Risk of obesity, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, Nutrition and Dietetics, business.industry, Infant, Newborn, Infant, medicine.disease, Obesity, 3. Good health, medicine.anatomical_structure, chemistry, Child, Preschool, symptoms, Female, Disease Susceptibility, medicine.symptom, Metabolic syndrome, business, Biomarkers
Abstract: International audience; Background/objectives Maternal obesity is associated with increased risk of obesity and other symptoms of the metabolic syndrome in the offspring. Nevertheless, the molecular mechanisms and cellular factors underlying this enhanced disease susceptibility remain to be determined. Here, we aimed at identifying changes in plasma lipids in offspring of obese mothers that might underpin, and serve as early biomarkers of, their enhanced metabolic disease risk. Subjects/methods We performed a longitudinal lipidomic profiling in plasma samples from normal weight, overweight, and obese pregnant women and their children that participated in the Prenatal Omega-3 Fatty Acid Supplementation, Growth, and Development trial conducted in Mexico. At recruitment women were aged between 18 and 35 years and in week 18–22 of pregnancy. Blood samples were collected at term delivery by venipuncture from mothers and from the umbilical cord of their newborns and from the same infants at 4 years old under non-fasting conditions. Lipidomic profiling was done using ultra-performance liquid chromatography high-resolution mass spectrometry. Results Analysis of the lipidomic data showed that overweight and obese mothers exhibited a significant reduction in the total abundance of ceramides (Cer) in plasma, mainly of Cer (d18:1/20:0), Cer (d18:1/22:0), Cer (d18:1/23:0), and Cer (d18:1/24:0), compared with mothers of normal body weight. This reduction was confirmed by the direct quantification of these and other ceramide species. Similar quantitative differences in the plasma concentration of Cer (d18:1/22:0), Cer (d18:1/23:0), and Cer (d18:1/24:0), were also found between 4-year-old children of overweight and obese mothers compared with children of mothers of normal body weight. Noteworthy, children exhibited equal daily amounts of energy and food intake independently of the BMI of their mothers. Conclusions Maternal obesity results in long-lasting changes in plasma ceramides in the offspring suggesting that these lipids might be used as early predictors of metabolic disease risk due to maternal obesity.
Published: 2019
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50. IN-FOCUS France: an epidemiological survey on severe hypertriglyceridaemiae assessing the comparative burden of illness of familial chylomicronaemia syndrome (FCS) and multifactorial chylomicronaemia syndrome (MCS)

Author: Philippe Moulin, Benoit Bouquillon, Olivier Ziegler, Michel Krempf, Vincent Rigalleau, Bruno Vergès, Edouard Verdier, Eric Bruckert, Jean-Michel Lecerf, René Valéro, and Sybil Charrière
Subjects: medicine.medical_specialty, Focus (computing), business.industry, Epidemiology, medicine, Intensive care medicine, business
Published: 2019
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