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The Low-Density Lipoprotein Receptor Genotype Is a Significant Determinant of the Rebound in Low-Density Lipoprotein Cholesterol Concentration After Lipoprotein Apheresis Among Patients With Homozygous Familial Hypercholesterolemia

2017; Lippincott Williams & Wilkins; Volume: 136; Issue: 9 Linguagem: Inglês

10.1161/circulationaha.117.029435

1524-4539

Jean‐Philippe Drouin‐Chartier, André Tremblay, Jean Bergeron, Benoı̂t Lamarche, Patrick Couture,

Lipid metabolism and disorders

HomeCirculationVol. 136, No. 9The Low-Density Lipoprotein Receptor Genotype Is a Significant Determinant of the Rebound in Low-Density Lipoprotein Cholesterol Concentration After Lipoprotein Apheresis Among Patients With Homozygous Familial Hypercholesterolemia Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBThe Low-Density Lipoprotein Receptor Genotype Is a Significant Determinant of the Rebound in Low-Density Lipoprotein Cholesterol Concentration After Lipoprotein Apheresis Among Patients With Homozygous Familial Hypercholesterolemia Jean-Philippe Drouin-Chartier, MSc, André J. Tremblay, PhD, Jean Bergeron, MD, MSc, Benoît Lamarche, PhD and Patrick Couture, MD, PhD Jean-Philippe Drouin-ChartierJean-Philippe Drouin-Chartier From Institute on Nutrition and Functional Foods, Université Laval, Quebec City, Quebec, Canada (J.-P.D.-C., A.J.T., B.L., P.C.); and Centre Hospitalier Universitaire de Québec Research Center, Université Laval, Quebec City, Canada (J.B., P.C.). , André J. TremblayAndré J. Tremblay From Institute on Nutrition and Functional Foods, Université Laval, Quebec City, Quebec, Canada (J.-P.D.-C., A.J.T., B.L., P.C.); and Centre Hospitalier Universitaire de Québec Research Center, Université Laval, Quebec City, Canada (J.B., P.C.). , Jean BergeronJean Bergeron From Institute on Nutrition and Functional Foods, Université Laval, Quebec City, Quebec, Canada (J.-P.D.-C., A.J.T., B.L., P.C.); and Centre Hospitalier Universitaire de Québec Research Center, Université Laval, Quebec City, Canada (J.B., P.C.). , Benoît LamarcheBenoît Lamarche From Institute on Nutrition and Functional Foods, Université Laval, Quebec City, Quebec, Canada (J.-P.D.-C., A.J.T., B.L., P.C.); and Centre Hospitalier Universitaire de Québec Research Center, Université Laval, Quebec City, Canada (J.B., P.C.). and Patrick CouturePatrick Couture From Institute on Nutrition and Functional Foods, Université Laval, Quebec City, Quebec, Canada (J.-P.D.-C., A.J.T., B.L., P.C.); and Centre Hospitalier Universitaire de Québec Research Center, Université Laval, Quebec City, Canada (J.B., P.C.). Originally published29 Aug 2017https://doi.org/10.1161/CIRCULATIONAHA.117.029435Circulation. 2017;136:880–882In homozygous familial hypercholesterolemia (HoFH) caused by mutations in the low-density lipoprotein (LDL) receptor (LDLR) gene, patients with 2 receptor-negative mutations have higher cholesterol concentrations and coronary heart disease risk than patients with double receptor-defective mutations.1Pharmacological treatment is insufficient to achieve an efficient reduction in LDL-cholesterol (C) or lipoprotein (a) (Lp(a)) concentrations in patients with HoFH, and repetitive long-term lipoprotein apheresis (LA) remains the gold-standard therapy. LA induces an acute decrease in LDL-C and Lp(a) concentrations, which is then followed by a rebound in the following days. The rebound after LA constitutes a major determinant of LA efficacy because it directly affects the average concentrations between treatments, considered the best estimate of the physiological effects of long-term LA.2 However, our understanding of the determinants of rebound after treatment in LDL-C and Lp(a) is limited.2This study aimed to determine the extent to which the LDLR genotype modulates the rebound after LA in LDL-C and Lp(a) concentrations among patients with HoFH. We hypothesized that the rebound in LDL-C and Lp(a) concentrations is greater among patients with receptor-negative HoFH than among patients with receptor-defective HoFH.Data on all consecutive LA treatments performed between August 2008 and February 2016 among patients with HoFH with genetically defined defective/defective LDLR mutations (n=3), negative/negative LDLR mutations (n=8), and defective/negative LDLR mutations (n=4) treated at the CHU de Québec-Université Laval were collected. For each patient, the compiled data included: (1) date of LA, (2) cumulative number of LA treatments received, (3) interval between LA treatments, (4) LA system used, (5) volume of filtered plasma per treatment, (6) duration of treatments, (7) lipoprotein concentrations before and after LA, and (8) cumulative interval since the first compiled LA treatment. Data on LDL-C and Lp(a) rebound covered 1999 and 1567 treatments, respectively. The rebound was calculated as the percentage difference between concentrations after LA and before the subsequent LA treatment. Mixed models for repeated measures with patients as a random effect were used for statistics. The study was approved by the Laval University Medical Center ethical review committee, and informed consent was obtained from each patient.At baseline, patients (34.2±14.3 years of age; women, n=8/15; coronary heart disease history, n=8/15) were treated with a maximally tolerated dose of statin (atorvastatin: 80 mg, n=7; 40 mg, n=1; rosuvastatin: 40 mg, n=6; 5 mg, n=1) and ezetimibe and had cutaneous and tendinous xanthomas. Patients were French-Canadian (n=13), Lebanese (n=1), and Hondurian (n=1).The LDLR genotype was significantly associated with LDL-C rebound (P=0.003). Negative/negative patients had a greater mean rebound in LDL-C concentrations compared with defective/defective patients and defective/negative patients, independent of the interval since the last treatment and drug therapy (Figure, A). Similar observations were obtained when the analysis was conducted with the rebound in absolute LDL-C levels in mmol/L. No interaction was observed between the LDLR genotype and the interval between treatments for the rebound in LDL-C (Pgenotype*interval =0.06). Therefore, differences in the rebound in LDL-C levels between LDLR genotypes were maintained over time. Moreover, weekly treatments were associated with significantly lower rebound in LDL-C levels compared with treatments conducted at longer intervals, independent of the LDLR genotype and drug therapy (Figure, B).Download figureDownload PowerPointFigure. Rebound in LDL-C concentrations after lipoprotein apheresis according to the LDLR genotype.A, Mean rebound in LDL-C concentrations after lipoprotein apheresis according to the LDLR genotype among patients with homozygous familial hypercholesterolemia (HoFH) independent of the interval since previous treatment. Patients with receptor-defective HoFH (defective/defective, n=3) were carriers of the W66G mutation in exon 3. Patients with receptor-negative HoFH (negative/negative, n=8) were carriers of the >15 kb deletion at the 5' end of the gene (del15kb, n=5), the splice site mutation in intron 7 (LDLR1061(-1) G to C, n=1), and the C660X Lebanese alleles (n=1), and 1 subject was a carrier of the del15kb and the C646Y mutation in exon 14. Patients with defective/negative LDLR mutations (n=4) were carriers of the del15kb and the W66G mutation. Different superscript letters (a, b) denote significant differences (P 28 days. The patient-specific time interval since the first compiled LA for each treatment was treated as a repeated measure in the models. The spatial power covariance structure was used. Normality of the models was assessed by the distribution of the scaled residual values. The Tukey-Kramer adjustment was used for multiple comparison tests. LA indicates lipoprotein apheresis; LDL-C, low-density lipoprotein cholesterol; and LDLR, low-density lipoprotein receptor.No difference was found in the rebound in Lp(a) concentrations according to the LDLR genotype. Nonetheless, the rebound in Lp(a) associated with weekly treatment was significantly lower than the rebound associated with bimonthly treatments (117±37% versus 166±36%, P=0.0002).This retrospective longitudinal study demonstrates that the LDLR genotype is a significant determinant of the rebound in LDL-C concentration after LA among patients with HoFH. It was estimated that the patients with receptor-negative HoFH treated every 3 to 5 days would exhibit a rebound in LDL-C concentrations similar to one of the patients with receptor-defective HoFH treated at an interval of 7 to 14 days. Mechanisms underlying the greater rebound in LDL-C observed in receptor negative patients than in receptor defective patients remain unclear, but they are likely to rely on the impact of LDLR deficiency on apolipoprotein B metabolism. Indeed, several studies have reported a direct inverse association between LDLR functionality and apolipoprotein B secretion.3 In addition, it is likely that the efficacy of statins to inhibit cholesterol synthesis, which differs between receptor-negative and receptor-defective patients, could modulate LDL-C rebound after LA.4,5 Nevertheless, patients with receptor-negative HoFH may benefit from more frequent LA to reduce their exposure to apolipoprotein B-containing lipoproteins.The number of treatments and the ≈8 year follow-up are major strengths of the present study. However, these observations are reported from a limited number of mutations in the LDLR gene highly prevalent among the French-Canadians. A similar assessment among patients carrying other common LDLR mutations is warranted.This study demonstrated that the rebound in LDL-C levels was markedly greater among receptor-negative than among receptor-defective HoFH patients. To optimize long-term benefits of LA in an era of precision medicine, this study underscores the importance of the screening for the LDLR mutation, the relevance of adapting LA therapy to the severity of the disease, and the benefits associated with more frequent treatments.Jean-Philippe Drouin-Chartier, MScAndré J. Tremblay, PhDJean Bergeron, MD, MScBenoît Lamarche, PhDPatrick Couture, MD, PhDAcknowledgmentsDrs Couture and Lamarche designed the study. J.-P. Drouin-Chartier collected the data. J.-P. Drouin-Chartier and Drs Lamarche, and Couture analyzed the data. J.-P. Drouin-Chartier and Drs Tremblay, Bergeron, Lamarche, and Couture wrote the article. Dr Couture has full access to all the data and takes responsibility for its integrity and the data analysis.Sources of FundingJ.-P. Drouin-Chartier is a recipient of doctoral scholarships from the Fonds de Recherche du Québec–Santé and the Canadian Institutes of Health Research.DisclosuresDr Couture has received funding in the past 5 years from the Canadian Institutes of Health Research, Agriculture, and Agri-Food Canada (Growing Forward program supported by the Dairy Farmers of Canada, Canola Council of Canada, Flax Council of Canada, Dow Agrosciences), Dairy Research Institute, Dairy Australia, Danone Institute, Merck, Pfizer, Atrium Innovations, and the Kaneka Corporation. Dr Lamarche is the Chair of Nutrition at Laval University, which is supported by private endowments from Pfizer, La Banque Royale du Canada, and Provigo-Loblaws; and he has received funding in the past 5 years from the Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Merck. The other authors report no conflicts of interest.FootnotesCirculation is available at http://circ.ahajournals.org.Correspondence to: Patrick Couture, MD, PhD, Institute of Nutrition and Functional Foods, Laval University, 2440 Hochelaga Boulevard, Quebec City, Quebec, Canada G1V 0A6. E-mail [email protected]References1. Moorjani S, Roy M, Torres A, Bétard C, Gagné C, Lambert M, Brun D, Davignon J, Lupien P. Mutations of low-density-lipoprotein-receptor gene, variation in plasma cholesterol, and expression of coronary heart disease in homozygous familial hypercholesterolaemia.Lancet. 1993; 341:1303–1306.CrossrefMedlineGoogle Scholar2. Thompson GR, Barbir M, Davies D, Dobral P, Gesinde M, Livingston M, Mandry P, Marais AD, Matthews S, Neuwirth C, Pottle A, le Roux C, Scullard D, Tyler C, Watkins S. Efficacy criteria and cholesterol targets for LDL apheresis.Atherosclerosis. 2010; 208:317–321. doi: 10.1016/j.atherosclerosis.2009.06.010.CrossrefMedlineGoogle Scholar3. Sniderman AD, De Graaf J, Couture P, Williams K, Kiss RS, Watts GF. Regulation of plasma LDL: the apoB paradigm.Clin Sci (Lond). 2009; 118:333–339. doi: 10.1042/CS20090402.CrossrefMedlineGoogle Scholar4. Stein EA, Raal FJ, Raichlen JS, Carlsson SC, Blasetto JW, Sundén M, Kastelein JJ. Abstract 15499: low-density lipoprotein cholesterol response with rosuvastatin in children and adults with homozygous familial hypercholesterolemia as it relates to underlying genetic mutations.Circulation. 2016; 134:A15499.LinkGoogle Scholar5. Couture P, Brun LD, Szots F, Lelièvre M, Gaudet D, Després JP, Simard J, Lupien PJ, Gagné C. Association of specific LDL receptor gene mutations with differential plasma lipoprotein response to simvastatin in young French Canadians with heterozygous familial hypercholesterolemia.Arterioscler Thromb Vasc Biol. 1998; 18:1007–1012.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Drouin-Chartier J, Tremblay A, Godbout D, Gagnon A, Clavel M, Clisson M, Arsenault B, Pibarot P, Larose É and Couture P (2021) Correlates of Coronary Artery Calcification Prevalence and Severity in Patients With Heterozygous Familial Hypercholesterolemia, CJC Open, 10.1016/j.cjco.2020.09.010, 3:1, (62-70), Online publication date: 1-Jan-2021. Wen J, Dong Q, Liu G, Gao Y, Li X, Jin J, Li J and Guo Y (2019) Improvement of oxidative stress status by lipoprotein apheresis in Chinese patients with familial hypercholesterolemia, Journal of Clinical Laboratory Analysis, 10.1002/jcla.23161, 34:5, Online publication date: 1-May-2020. Yu Z, Peng Q, Li S, Hao H, Deng J, Meng L, Shen Z, Yu W, Nan D, Bai Y and Huang Y (2020) Myriocin and d -PDMP ameliorate atherosclerosis in ApoE−/− mice via reducing lipid uptake and vascular inflammation , Clinical Science, 10.1042/CS20191028, 134:5, (439-458), Online publication date: 13-Mar-2020. Watts G, Gidding S, Mata P, Pang J, Sullivan D, Yamashita S, Raal F, Santos R and Ray K (2020) Familial hypercholesterolaemia: evolving knowledge for designing adaptive models of care, Nature Reviews Cardiology, 10.1038/s41569-019-0325-8, 17:6, (360-377), Online publication date: 1-Jun-2020. Drouin-Chartier J, Tremblay A, Bergeron J, Lamarche B and Couture P (2018) High serum triglyceride concentrations in patients with homozygous familial hypercholesterolemia attenuate the efficacy of lipoprotein apheresis by dextran sulfate adsorption, Atherosclerosis, 10.1016/j.atherosclerosis.2018.01.005, 270, (26-32), Online publication date: 1-Mar-2018. Brunham L, Ruel I, Aljenedil S, Rivière J, Baass A, Tu J, Mancini G, Raggi P, Gupta M, Couture P, Pearson G, Bergeron J, Francis G, McCrindle B, Morrison K, St-Pierre J, Henderson M, Hegele R, Genest J, Goguen J, Gaudet D, Paré G, Romney J, Ransom T, Bernard S, Katz P, Joy T, Bewick D and Brophy J (2018) Canadian Cardiovascular Society Position Statement on Familial Hypercholesterolemia: Update 2018, Canadian Journal of Cardiology, 10.1016/j.cjca.2018.09.005, 34:12, (1553-1563), Online publication date: 1-Dec-2018. Beliard S, Gallo A, Duchêne E, Carrié A, Bittar R, Chapman M, Bruckert E and Saheb S (2018) Lipoprotein-apheresis in familial hypercholesterolemia: Long-term patient compliance in a French cohort, Atherosclerosis, 10.1016/j.atherosclerosis.2018.08.007, 277, (66-71), Online publication date: 1-Oct-2018. August 29, 2017Vol 136, Issue 9 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.117.029435PMID: 28847800 Originally publishedAugust 29, 2017 Keywordsapheresischolesterolgenotypefamilial hypercholesterolemialipoproteinPDF download Advertisement SubjectsLipids and CholesterolMetabolism