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通过管理血脂预防动脉粥样硬化性心血管疾病
Lipid Management for the Prevention of Atherosclerotic Cardiovascular Disease


Erin D. Michos ... 心脑血管疾病 • 2019.10.17
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1961年,弗雷明汉心脏研究(Framingham Heart Study)的研究者发现血清胆固醇是冠心病的“危险因素”之一1。此后,大量流行病学研究和随机临床试验证实,低密度脂蛋白(LDL)胆固醇水平升高是动脉粥样硬化性心血管疾病的一个重要促发因素2,3。因此,血清胆固醇水平管理已成为心血管事件预防工作的一个核心目标。目前的有效治疗方法(见补充附录表S1,补充附录与本文全文可在NEJM.org获取)主要针对载脂蛋白B相关脂蛋白,而载脂蛋白B相关脂蛋白体现为LDL胆固醇、非高密度脂蛋白胆固醇(非HDL胆固醇)和甘油三酯水平(图1)。

 

图1. 脂质代谢和药物治疗靶点

胃内脂质包含摄入的游离胆固醇、胆固醇酯、植物甾醇、甘油三酯、磷脂和脂肪酸(见外源性途径)。胃和胰脂肪酶可水解脂质酯。胆汁酸、磷脂和胆固醇是由肝细胞通过特定转运蛋白(ABCG5、ABCG8和ABCB11)分泌到胆管系统内。相反,尼曼-匹克C1样蛋白1(NPC1L1)可促使胆固醇从胆汁转运回肝细胞。依折麦布可阻断胆汁中的NPC1L1。胆汁酸和脂质生成复杂的胆汁胶束(biliary micelle),将脂质转运到肠道微绒毛吸收部位。NPC1L1可促使胆固醇进入肠上皮细胞,这一步骤也可被依折麦布阻断。脂肪酸转运蛋白(如CD36)可调节去酯化脂肪酸和单酰甘油的吸收。胆汁酸一旦离开胶束就会通过回肠胆汁酸转运蛋白(IBAT)被重吸收,并释放到门脉循环中,重新回到肝脏。胆汁酸螯合剂可阻断胆汁酸在回肠内的重吸收。胆固醇和甘油三酯通过依赖于微粒体甘油三酯转运蛋白和载脂蛋白B48的合成途径被组装成乳糜微粒。乳糜微粒被分泌到肠道淋巴系统内,然后进入胸导管循环。富含甘油三酯的脂蛋白(如乳糜微粒和极低密度脂蛋白[VLDL])在肌肉和脂肪细胞血管床内通过与载脂蛋白胆固醇Ⅱ和脂蛋白脂肪酶(LPL)相互作用被脂解(核心甘油三酯和表面磷脂的水解),从而使脂肪酸内化并在肌肉内被用作能量来源,或者用于合成甘油三酯并在脂肪细胞内储存能量。LPL对乳糜微粒的作用降低了其脂肪酸含量,生成乳糜微粒残体(remnant);同样,VLDL被转化为VLDL残体(中密度脂蛋白[IDL])。

胆固醇的肝脏合成(见内源性途径)始于葡萄糖通过依赖于底物乙酰辅酶A(CoA,CoA是在三羧酸循环中生成)的合成途径转化为丙酮酸。β-羟基-β-甲戊二酸单酰辅酶A(HMG-CoA)还原酶是这一途径的限速酶,可形成角鲨烯和数种固醇中间体,并最终形成胆固醇。他汀类药物可抑制HMG-CoA还原酶。bempedoic acid是一种前体药物,由非常长链酰基辅酶A合成酶1(一种存在于肝细胞内,但不存在于肌细胞内的酶)转化为活性代谢物,该活性代谢物通过抑制ATP柠檬酸裂合酶减少肝细胞内乙酰辅酶A的生成,从而减少肝脏内的胆固醇代谢。通过依赖微粒体甘油三酯转运蛋白发挥作用的合成途径,甘油三酯与胆固醇、胆固醇酯、磷脂、载脂蛋白B-100一起组装VLDL胆固醇颗粒,然后被分泌到循环内。高密度脂蛋白(HDL)是通过胆固醇和磷脂流出(通过膜转运蛋白ATP结合盒转运蛋白A1[ABCA1])到载脂蛋白A-Ⅰ(apoA-Ⅰ)或者较小的HDL内而形成。HDL胆固醇有一项功能被称为巨噬细胞胆固醇逆转运,而胆固醇从动脉壁泡沫细胞流出到HDL胆固醇是这一功能的一个关键而特殊的部分。低密度脂蛋白(LDL)胆固醇颗粒与LDL胆固醇受体结合,并被清除出血浆。肝脏合成并分泌前蛋白转化酶枯草溶菌素-9(PCSK9),PCSK9与LDL胆固醇受体结合,当被内体和溶酶体内化时,可引起受体的分解代谢。PCSK9抑制剂可阻断这一过程。当含有载脂蛋白B的颗粒(包括数量最多的LDL胆固醇分子,以及乳糜微粒和VLDL残体)进入动脉壁、被氧化、被巨噬细胞内化并形成泡沫细胞时,就会发生动脉粥样硬化。





作者信息

Erin D. Michos, M.D., M.H.S., John W. McEvoy, M.B., B.Ch., M.H.S., and Roger S. Blumenthal, M.D.
From the Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore (E.D.M., R.S.B), and the National Institute for Prevention and Cardiovascular Health, National University of Ireland, Galway (J.W.M.). Address reprint requests to Dr. Michos at the Division of Cardiology, Johns Hopkins School of Medicine, Blalock 524-B, 600 N. Wolfe St., Baltimore, MD 21287, or at edonnell@jhmi.edu.

 

参考文献

1. Kannel WB, Dawber TR, Kagan A, Revotskie N, Stokes J III. Factors of risk in the development of coronary heart disease — six year follow-up experience: the Framingham Study. Ann Intern Med 1961;55:33-50.

2. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670-1681.

3. Cholesterol Treatment Trialists’ (CTT) Collaboration. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581-590.

4. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:3168-3209.

5. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol March 17 2019;74:1376-1414.

6. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129:Suppl 2:S76-S99.

7. Khera AV, Emdin CA, Drake I, et al. Genetic risk, adherence to a healthy lifestyle, and coronary disease. N Engl J Med 2016;375:2349-2358.

8. Brinton EA. Management of hypertriglyceridemia for prevention of atherosclerotic cardiovascular disease. Cardiol Clin 2015;33:309-323.

9. Trejo-Gutierrez JF, Fletcher G. Impact of exercise on blood lipids and lipoproteins. J Clin Lipidol 2007;1:175-181.

10. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-2472.

11. Castelli WP. Lipids, risk factors and ischaemic heart disease. Atherosclerosis 1996;124:Suppl:S1-S9.

12. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129:Suppl 2:S1-S45.

13. Koskinas KC, Siontis GCM, Piccolo R, et al. Effect of statins and non-statin LDL-lowering medications on cardiovascular outcomes in secondary prevention: a meta-analysis of randomized trials. Eur Heart J 2018;39:1172-1180.

14. Navarese EP, Robinson JG, Kowalewski M, et al. Association between baseline LDL-C level and total and cardiovascular mortality after LDL-C lowering: a systematic review and meta-analysis. JAMA 2018;319:1566-1579.

15. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-2397.

16. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-1722.

17. Martin SS, Sperling LS, Blaha MJ, et al. Clinician-patient risk discussion for atherosclerotic cardiovascular disease prevention: importance to implementation of the 2013 ACC/AHA Guidelines. J Am Coll Cardiol 2015;65:1361-1368.

18. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129:Suppl 2:S49-S73.

19. Michos ED, Blaha MJ, Blumenthal RS. Use of the coronary artery calcium score in discussion of initiation of statin therapy in primary prevention. Mayo Clin Proc 2017;92:1831-1841.

20. Budoff MJ, Young R, Burke G, et al. Ten-year association of coronary artery calcium with atherosclerotic cardiovascular disease (ASCVD) events: the Multi-Ethnic Study of Atherosclerosis (MESA). Eur Heart J 2018;39:2401-2408.

21. Nasir K, Bittencourt MS, Blaha MJ, et al. Implications of coronary artery calcium testing among statin candidates according to American College of Cardiology/American Heart Association Cholesterol management guidelines: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2015;66:1657-1668.

22. Mahabadi AA, Möhlenkamp S, Lehmann N, et al. CAC score improves coronary and CV risk assessment above statin indication by ESC and AHA/ACC primary prevention guidelines. JACC Cardiovasc Imaging 2017;10:143-153.

23. Valenti V, Ó Hartaigh B, Heo R, et al. A 15-year warranty period for asymptomatic individuals without coronary artery calcium: a prospective follow-up of 9,715 individuals. JACC Cardiovasc Imaging 2015;8:900-909.

24. Mitchell JD, Fergestrom N, Gage BF, et al. Impact of statins on cardiovascular outcomes following coronary artery calcium scoring. J Am Coll Cardiol 2018;72:3233-3242.

25. McEvoy JW, Blaha MJ, Rivera JJ, et al. Mortality rates in smokers and nonsmokers in the presence or absence of coronary artery calcification. JACC Cardiovasc Imaging 2012;5:1037-1045.

26. Shapiro MD, Blankstein R. Reclassifying risk in familial hypercholesterolemia: the power of a coronary artery calcium score of zero. JACC Cardiovasc Imaging 2018;12:1805-1807.

27. Martin SS, Joshi PH, Michos ED. Lipids in coronary heart disease: from epidemiology to therapeutics. In: Aronow WS, McClung JA, eds. Translational research in coronary artery disease. Boston: Academic Press, 2016:67-80.

28. Silverman MG, Ference BA, Im K, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA 2016;316:1289-1297.

29. Newman CB, Preiss D, Tobert JA, et al. Statin safety and associated adverse events: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol 2019;39(2):e38-e81.

30. Thompson PD. What to believe and do about statin-associated adverse effects. JAMA 2016;316:1969-1970.

31. Gupta A, Thompson D, Whitehouse A, et al. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase. Lancet 2017;389:2473-2481.

32. Ford I, Murray H, McCowan C, Packard CJ. Long-term safety and efficacy of lowering low-density lipoprotein cholesterol with statin therapy: 20-year follow-up of West of Scotland Coronary Prevention Study. Circulation 2016;133:1073-1080.

33. Liu K, Colangelo LA, Daviglus ML, et al. Can antihypertensive treatment restore the risk of cardiovascular disease to ideal levels? The Coronary Artery Risk Development in Young Adults (CARDIA) Study and the Multi-Ethnic Study of Atherosclerosis (MESA). J Am Heart Assoc 2015;4:e002275-e002275.

34. Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003;34:154-156.

35. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264-1272.

36. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097-2107.

37. O’Donoghue ML, Fazio S, Giugliano RP, et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk: insights from the FOURIER trial. Circulation 2019;139:1483-1492.

38. Bonaca MP, Nault P, Giugliano RP, et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Circulation 2018;137:338-350.

39. Sabatine MS, De Ferrari GM, Giugliano RP, et al. Clinical benefit of evolocumab by severity and extent of coronary artery disease. Circulation 2018;138:756-766.

40. Giugliano RP, Pedersen TR, Park JG, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet 2017;390:1962-1971.

41. Arrieta A, Hong JC, Khera R, Virani SS, Krumholz HM, Nasir K. Updated cost-effectiveness assessments of PCSK9 inhibitors from the perspectives of the health system and private payers: insights derived from the FOURIER trial. JAMA Cardiol 2017;2:1369-1374.

42. Baum SJ, Toth PP, Underberg JA, Jellinger P, Ross J, Wilemon K. PCSK9 inhibitor access barriers-issues and recommendations: improving the access process for patients, clinicians and payers. Clin Cardiol 2017;40:243-254.

43. Pirillo A, Catapano AL. Update on the management of severe hypertriglyceridemia — focus on free fatty acid forms of omega-3. Drug Des Devel Ther 2015;9:2129-2137.

44. Dietary supplementation with n–3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999;354:447-455.

45. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090-1098.

46. Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials involving 77 917 individuals. JAMA Cardiol 2018;3:225-234.

47. Abdelhamid AS, Brown TJ, Brainard JS, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev 2018;11:CD003177-CD003177.

48. Manson JE, Cook NR, Lee I-M, et al. Marine n−3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med 2019;380:23-32.

49. The ASCEND Study Collaborative Group. Effects of n−3 fatty acid supplements in diabetes mellitus. N Engl J Med 2018;379:1540-1550.

50. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.

51. Arsenault BJ, Perrot N, Puri R. Therapeutic agents targeting cardiometabolic risk for preventing and treating atherosclerotic cardiovascular diseases. Clin Pharmacol Ther 2018;104:257-268.

52. Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med 2017;376:1430-1440.

53. Ray KK, Bays HE, Catapano AL, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med 2019;380:1022-1032.

54. Lupo MG, Ferri N. Angiopoietin-like 3 (ANGPTL3) and atherosclerosis: lipid and non-lipid related effects. J Cardiovasc Dev Dis 2018;5:5-5.

55. Rosenson RS, Baker S, Banach M, et al. Optimizing cholesterol treatment in patients with muscle complaints. J Am Coll Cardiol 2017;70:1290-1301.

56. Backes JM, Ruisinger JF, Gibson CA, Moriarty PM. Statin-associated muscle symptoms — managing the highly intolerant. J Clin Lipidol 2017;11:24-33.

57. Quispe R, Hendrani A, Elshazly MB, et al. Accuracy of low-density lipoprotein cholesterol estimation at very low levels. BMC Med 2017;15:83-83.

58. Martin SS, Blaha MJ, Elshazly MB, et al. Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile. JAMA 2013;310:2061-2068.

59. Sathiyakumar V, Park J, Golozar A, et al. Fasting versus nonfasting and low-density lipoprotein cholesterol accuracy. Circulation 2018;137:10-19.

60. US Preventive Services Task Force. Statin use for the primary prevention of cardiovascular disease in adults: US Preventive Services Task Force recommendation statement. JAMA 2016;316:1997-2007.

61. Downs JR, O’Malley PG. Management of dyslipidemia for cardiovascular disease risk reduction: synopsis of the 2014 U.S. Department of Veterans Affairs and U.S. Department of Defense clinical practice guideline. Ann Intern Med 2015;163:291-297.

62. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: full report. J Clin Lipidol 2015;9:129-169.

63. Jellinger PS, Handelsman Y, Rosenblit PD, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract 2017;23:Suppl 2:1-87.

64. Mach F, Bagient C, Catapano AL, et al. Guidelines for the 19; management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J August 31 2019 (Epub ahead of print).

65. Arps K, Pallazola VA, Cardoso R, et al. Clinician’s guide to the updated ABCs of cardiovascular disease prevention: a review part 1. Am J Med 2019;132(6):e569-e580.

66. Arps K, Pallazola VA, Cardoso R, et al. Clinician’s guide to the updated ABCs of cardiovascular disease prevention: a review part 2. Am J Med 2019;132(7):e599-e699.

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