Genetic profiling of fatty acid desaturase polymorphisms identifies patients who may benefit from high-dose omega-3 fatty acids in cardiac remodeling after acute myocardial infarction—Post-hoc analysis from the OMEGA-REMODEL randomized controlled trial


Autoři: Raymond Y. Kwong aff001;  Bobak Heydari aff003;  Yin Ge aff001;  Shuaib Abdullah aff001;  Kana Fujikura aff001;  Kyoichi Kaneko aff001;  William S. Harris aff004;  Michael Jerosch-Herold aff001;  Elliott M. Antman aff002;  Jonathan G. Seidman aff006;  Marc A. Pfeffer aff002
Působiště autorů: Noninvasive Cardiovascular Imaging Section, Cardiovascular Division, Department of Medicine and Department of Radiology, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America aff001;  Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America aff002;  Cardiovascular Division, Department of Medicine, University of Calgary, Calgary, Alberta, Canada aff003;  Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Fall, South Dakota, United States of America aff004;  OmegaQuant Analytics, LLC, Sioux Falls, South Dakota, United States of America aff005;  Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America aff006
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: 10.1371/journal.pone.0222061

Souhrn

Background

The double-blind OMEGA-REMODEL placebo-controlled randomized trial of high-dose omega-3 fatty acids (O-3FA) post-acute myocardial infarction (AMI) reported improved cardiac remodeling and attenuation of non-infarct myocardial fibrosis. Fatty acid desaturase 2 (FADS2) gene cluster encodes key enzymes in the conversion of essential omega-3 and omega-6 fatty acids into active arachidonic (ArA) and eicosapentaenoic acids (EPA), which influence cardiovascular outcomes.

Methods and results

We tested the hypothesis that the genotypic status of FADS2 (rs1535) modifies therapeutic response of O-3FA in post-AMI cardiac remodeling in 312 patients. Consistent with known genetic polymorphism of FADS2, patients in our cohort with the guanine-guanine (GG) genotype had the lowest FADS2 activity assessed by arachidonic acid/linoleic acid (ArA/LA) ratio, compared with patients with the adenine-adenine (AA) and adenine-guanine (AG) genotypes (GG:1.62±0.35 vs. AA: 2.01±0.36, p<0.0001; vs. AG: 1.76±0.35, p = 0.03). When randomized to 6-months of O-3FA treatment, GG patients demonstrated significant lowering of LV end-systolic volume index (LVESVi), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and galectin-3 levels compared to placebo (-4.4 vs. 1.2 ml/m2, -733 vs. -181 pg/mL, and -2.0 vs. 0.5 ng/mL; p = 0.006, 0.006, and 0.03, respectively). In contrast, patients with either AA or AG genotype did not demonstrate significant lowering of LVESVi, NT-proBNP, or galectin-3 levels from O-3FA treatment, compared to placebo. The odds ratios for improving LVESVi by 10% with O-3FA treatment was 7.2, 1.6, and 1.2 in patients with GG, AG, and AA genotypes, respectively.

Conclusion

Genetic profiling using FADS2 genotype can predict the therapeutic benefits of O-3FA treatment against adverse cardiac remodeling during the convalescent phase of AMI.

Clinical trial registration information

clinicaltrials.gov Identifier: NCT00729430.

Klíčová slova:

Biology and life sciences – Biochemistry – Lipids – Fatty acids – Biomarkers – Proteins – Lipoproteins – Developmental biology – Fibrosis – Genetics – Heredity – Genetic mapping – Variant genotypes – Medicine and health sciences – Immunology – Immune response – Inflammation – Diagnostic medicine – Signs and symptoms – Pathology and laboratory medicine – Cardiology – Myocardial infarction – Vascular medicine – Coronary heart disease


Zdroje

1. Bhatt AS, Ambrosy AP, Velazquez EJ. Adverse Remodeling and Reverse Remodeling After Myocardial Infarction. Curr Cardiol Rep. 2017;19(8):71. Epub 2017/07/01. doi: 10.1007/s11886-017-0876-4 28660552.

2. Heydari B, Abdullah S, Pottala JV, Shah R, Abbasi S, Mandry D, et al. Effect of Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction: The OMEGA-REMODEL Randomized Clinical Trial. Circulation. 2016;134(5):378–91. Epub 2016/08/03. doi: 10.1161/CIRCULATIONAHA.115.019949 27482002; PubMed Central PMCID: PMC4973577.

3. Bisgaard H, Stokholm J, Chawes BL, Vissing NH, Bjarnadottir E, Schoos AM, et al. Fish Oil-Derived Fatty Acids in Pregnancy and Wheeze and Asthma in Offspring. N Engl J Med. 2016;375(26):2530–9. Epub 2016/12/29. doi: 10.1056/NEJMoa1503734 28029926.

4. Caspi A, Williams B, Kim-Cohen J, Craig IW, Milne BJ, Poulton R, et al. Moderation of breastfeeding effects on the IQ by genetic variation in fatty acid metabolism. Proc Natl Acad Sci U S A. 2007;104(47):18860–5. Epub 2007/11/07. doi: 10.1073/pnas.0704292104 17984066; PubMed Central PMCID: PMC2141867.

5. Martinelli N, Girelli D, Malerba G, Guarini P, Illig T, Trabetti E, et al. FADS genotypes and desaturase activity estimated by the ratio of arachidonic acid to linoleic acid are associated with inflammation and coronary artery disease. Am J Clin Nutr. 2008;88(4):941–9. Epub 2008/10/10. doi: 10.1093/ajcn/88.4.941 18842780.

6. Jiang B, Liao R. The paradoxical role of inflammation in cardiac repair and regeneration. J Cardiovasc Transl Res. 2010;3(4):410–6. doi: 10.1007/s12265-010-9193-7 20559773.

7. Westman PC, Lipinski MJ, Luger D, Waksman R, Bonow RO, Wu E, et al. Inflammation as a Driver of Adverse Left Ventricular Remodeling After Acute Myocardial Infarction. Journal of the American College of Cardiology. 2016;67(17):2050–60. Epub 2016/04/30. doi: 10.1016/j.jacc.2016.01.073 27126533.

8. Sansbury BE, Spite M. Resolution of Acute Inflammation and the Role of Resolvins in Immunity, Thrombosis, and Vascular Biology. Circ Res. 2016;119(1):113–30. Epub 2016/06/25. doi: 10.1161/CIRCRESAHA.116.307308 27340271; PubMed Central PMCID: PMC5260827.

9. Serhan CN, Clish CB, Brannon J, Colgan SP, Chiang N, Gronert K. Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing. J Exp Med. 2000;192(8):1197–204. Epub 2000/10/18. doi: 10.1084/jem.192.8.1197 11034610; PubMed Central PMCID: PMC2195872.

10. Serhan CN, Hong S, Gronert K, Colgan SP, Devchand PR, Mirick G, et al. Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J Exp Med. 2002;196(8):1025–37. Epub 2002/10/23. doi: 10.1084/jem.20020760 12391014; PubMed Central PMCID: PMC2194036.

11. Leaf A, Weber PC. A new era for science in nutrition. Am J Clin Nutr. 1987;45(5 Suppl):1048–53. Epub 1987/05/01. doi: 10.1093/ajcn/45.5.1048 3578100.

12. Kim RJ, Wu E, Rafael A, Chen EL, Parker MA, Simonetti O, et al. The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. The New England journal of medicine. 2000;343(20):1445–53. Epub 2000/11/18. doi: 10.1056/NEJM200011163432003 11078769.

13. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation. 2002;105(4):539–42. Epub 2002/01/30. doi: 10.1161/hc0402.102975 11815441.

14. Deichmann R HA. Quantification of T1 Values by SNAPSHOT-FLASH NMR imaging. Journal of Magnetic Resonance. 1992;96:608–12.

15. Coelho-Filho OR, Mongeon FP, Mitchell R, Moreno H Jr., Nadruz W Jr., Kwong R, et al. Role of transcytolemmal water-exchange in magnetic resonance measurements of diffuse myocardial fibrosis in hypertensive heart disease. Circulation Cardiovascular imaging. 2013;6(1):134–41. Epub 2012/11/20. doi: 10.1161/CIRCIMAGING.112.979815 23159497; PubMed Central PMCID: PMC3587170.

16. Jerosch-Herold M, Sheridan DC, Kushner JD, Nauman D, Burgess D, Dutton D, et al. Cardiac magnetic resonance imaging of myocardial contrast uptake and blood flow in patients affected with idiopathic or familial dilated cardiomyopathy. American journal of physiology Heart and circulatory physiology. 2008;295(3):H1234–H42. Epub 2008/07/29. doi: 10.1152/ajpheart.00429.2008 18660445; PubMed Central PMCID: PMC2544489.

17. Desta L, Jernberg T, Lofman I, Hofman-Bang C, Hagerman I, Spaak J, et al. Incidence, temporal trends, and prognostic impact of heart failure complicating acute myocardial infarction. The SWEDEHEART Registry (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies): a study of 199,851 patients admitted with index acute myocardial infarctions, 1996 to 2008. JACC Heart Fail. 2015;3(3):234–42. Epub 2015/03/07. doi: 10.1016/j.jchf.2014.10.007 25742760.

18. Hung J, Teng TH, Finn J, Knuiman M, Briffa T, Stewart S, et al. Trends from 1996 to 2007 in incidence and mortality outcomes of heart failure after acute myocardial infarction: a population-based study of 20,812 patients with first acute myocardial infarction in Western Australia. J Am Heart Assoc. 2013;2(5):e000172. Epub 2013/10/10. doi: 10.1161/JAHA.113.000172 24103569; PubMed Central PMCID: PMC3835218.

19. Seropian IM, Toldo S, Van Tassell BW, Abbate A. Anti-inflammatory strategies for ventricular remodeling following ST-segment elevation acute myocardial infarction. Journal of the American College of Cardiology. 2014;63(16):1593–603. Epub 2014/02/18. doi: 10.1016/j.jacc.2014.01.014 24530674.

20. Mozaffarian D, Wu JH. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. Journal of the American College of Cardiology. 2011;58(20):2047–67. Epub 2011/11/05. doi: 10.1016/j.jacc.2011.06.063 22051327.

21. Gani OA, Sylte I. Molecular recognition of docosahexaenoic acid by peroxisome proliferator-activated receptors and retinoid-X receptor alpha. J Mol Graph Model. 2008;27(2):217–24. Epub 2008/06/13. doi: 10.1016/j.jmgm.2008.04.008 18547851.

22. Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell. 2010;142(5):687–98. Epub 2010/09/04. doi: 10.1016/j.cell.2010.07.041 20813258; PubMed Central PMCID: PMC2956412.

23. Zhao Y, Joshi-Barve S, Barve S, Chen LH. Eicosapentaenoic acid prevents LPS-induced TNF-alpha expression by preventing NF-kappaB activation. J Am Coll Nutr. 2004;23(1):71–8. Epub 2004/02/14. doi: 10.1080/07315724.2004.10719345 14963056.

24. Spite M, Claria J, Serhan CN. Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases. Cell Metab. 2014;19(1):21–36. Epub 2013/11/19. doi: 10.1016/j.cmet.2013.10.006 24239568; PubMed Central PMCID: PMC3947989.

25. Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510(7503):92–101. Epub 2014/06/06. doi: 10.1038/nature13479 24899309; PubMed Central PMCID: PMC4263681.

26. Keyes KT, Ye Y, Lin Y, Zhang C, Perez-Polo JR, Gjorstrup P, et al. Resolvin E1 protects the rat heart against reperfusion injury. Am J Physiol Heart Circ Physiol. 2010;299(1):H153–64. Epub 2010/05/04. doi: 10.1152/ajpheart.01057.2009 20435846.

27. Kain V, Ingle KA, Colas RA, Dalli J, Prabhu SD, Serhan CN, et al. Resolvin D1 activates the inflammation resolving response at splenic and ventricular site following myocardial infarction leading to improved ventricular function. J Mol Cell Cardiol. 2015;84:24–35. Epub 2015/04/15. doi: 10.1016/j.yjmcc.2015.04.003 25870158; PubMed Central PMCID: PMC4468047.

28. Endo J, Arita M. Cardioprotective mechanism of omega-3 polyunsaturated fatty acids. J Cardiol. 2016;67(1):22–7. Epub 2015/09/12. doi: 10.1016/j.jjcc.2015.08.002 26359712.

29. Liu Y, Wang R, Li J, Rao J, Li W, Falck JR, et al. Stable EET urea agonist and soluble epoxide hydrolase inhibitor regulate rat pulmonary arteries through TRPCs. Hypertens Res. 2011;34(5):630–9. Epub 2011/02/11. doi: 10.1038/hr.2011.5 21307870; PubMed Central PMCID: PMC4548928.

30. Spector AA, Kim HY. Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism. Biochim Biophys Acta. 2015;1851(4):356–65. Epub 2014/08/06. doi: 10.1016/j.bbalip.2014.07.020 25093613; PubMed Central PMCID: PMC4314516.

31. Endo J, Sano M, Isobe Y, Fukuda K, Kang JX, Arai H, et al. 18-HEPE, an n-3 fatty acid metabolite released by macrophages, prevents pressure overload-induced maladaptive cardiac remodeling. J Exp Med. 2014;211(8):1673–87. Epub 2014/07/23. doi: 10.1084/jem.20132011 25049337; PubMed Central PMCID: PMC4113943.

32. Lemaitre RN, Tanaka T, Tang W, Manichaikul A, Foy M, Kabagambe EK, et al. Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium. PLoS Genet. 2011;7(7):e1002193. Epub 2011/08/11. doi: 10.1371/journal.pgen.1002193 21829377; PubMed Central PMCID: PMC3145614.

33. Tanaka T, Shen J, Abecasis GR, Kisialiou A, Ordovas JM, Guralnik JM, et al. Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI Study. PLoS Genet. 2009;5(1):e1000338. Epub 2009/01/17. doi: 10.1371/journal.pgen.1000338 19148276; PubMed Central PMCID: PMC2613033.

34. Hu Y, Li H, Lu L, Manichaikul A, Zhu J, Chen YD, et al. Genome-wide meta-analyses identify novel loci associated with n-3 and n-6 polyunsaturated fatty acid levels in Chinese and European-ancestry populations. Hum Mol Genet. 2016;25(6):1215–24. Epub 2016/01/09. doi: 10.1093/hmg/ddw002 26744325; PubMed Central PMCID: PMC4764197.


Článek vyšel v časopise

PLOS One


2019 Číslo 9

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…


Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

Imunitní trombocytopenie (ITP) u dospělých pacientů
nový kurz
Autoři: prof. MUDr. Tomáš Kozák, Ph.D., MBA

Pěnová skleroterapie
Autoři: MUDr. Marek Šlais

White paper - jak vidíme optimální péči o zubní náhrady
Autoři: MUDr. Jindřich Charvát, CSc.

Hemofilie - série kurzů

Faktory ovlivňující léčbu levotyroxinem
Autoři:

Všechny kurzy
Kurzy Doporučená témata