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The Role of Early LDL Lowering to Prevent the Onset of Atherosclerotic Disease

  • Coronary Heart Disease (JA Farmer, Section Editor)
  • Published:
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Abstract

Coronary atherosclerosis is a chronic progressive disease that begins early in life and progresses slowly over several decades before becoming clinically manifest. The causal relationship between low-density lipoprotein cholesterol (LDL-C) and the risk of coronary atherosclerosis is well established. Multiple randomized trials have demonstrated that lowering LDL-C levels during treatment with a statin reduces the risk of major atherosclerotic coronary events. However, individuals being treated with a statin continue to experience a high residual risk of events. Here we review the evidence that lowering LDL-C levels beginning earlier in life, and therefore earlier in the atherosclerotic disease process, can prevent or substantially delay the development of atherosclerosis and thereby substantially improve the clinical benefit of therapies that lower LDL-C levels. We focus on providing a critical appraisal of the naturally randomized evidence that is emerging from recently conducted genetic association studies.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Prospective Studies Collaboration, Lewington S, Whitlock G, Clarke R, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet. 2007;370(9602):1829–39.

    Article  PubMed  Google Scholar 

  2. • Emerging Risk Factors Collaboration, Di Angelantonio E, Sarwar N, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302:1993–2000. This study provided a meta-analysis of prospective epidemiologic cohort studies quantifying the nonrandomized observational association between each 1 mmol/l long-term exposure to lower directly measured LDL-C levels and the risk of CHD.

    Article  PubMed  Google Scholar 

  3. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267–78.

    Article  PubMed  CAS  Google Scholar 

  4. Cholesterol Treatment Trialists' (CTT) Collaborators, Mihaylova B, Emberson J, Blackwell L, et al. 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(9841):581–90.

    PubMed  CAS  Google Scholar 

  5. • 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;376:1670–81. This study provided an updated meta-analysis of statin randomized trials quantifying the association between each 1 mmol/l reduction in LDL-C concentration and the risk of CHD.

    Article  Google Scholar 

  6. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665.

    Article  PubMed  CAS  Google Scholar 

  7. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357(21):2109–22.

    Article  PubMed  CAS  Google Scholar 

  8. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367(22):2089–99.

    Article  PubMed  CAS  Google Scholar 

  9. AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255–67.

    Article  PubMed  Google Scholar 

  10. ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1563–74.

    Article  PubMed  Google Scholar 

  11. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685–95.

    Article  PubMed  CAS  Google Scholar 

  12. Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation. 2005;111(25):3481–8.

    Article  PubMed  Google Scholar 

  13. Holman RL, McGill Jr HC, Strong JP, Geer JC. The natural history of atherosclerosis: the early aortic lesions as seen in New Orleans in the middle of the 20th century. Am J Pathol. 1958;34:209–35.

    PubMed  CAS  Google Scholar 

  14. Strong JP, McGill Jr HC. The natural history of coronary atherosclerosis. Am J Pathol. 1962;40:37–49.

    PubMed  CAS  Google Scholar 

  15. Strong JP, McGill Jr HC. The pediatric aspects of atherosclerosis. J Atheroscler Res. 1969;9:251–65.

    Article  PubMed  CAS  Google Scholar 

  16. Tejada C, Strong JP, Montenegro MR, Restrepo C, Solberg LA. Distribution of coronary and aortic atherosclerosis by geographic location, race, and sex. Lab Invest. 1968;18:509–26.

    PubMed  CAS  Google Scholar 

  17. Newman III WP, Freedman DS, Voors AW, et al. Relation of serum lipoprotein levels and systolic blood pressure to early atherosclerosis: the Bogalusa Heart Study. N Engl J Med. 1986;314:138–44.

    Article  PubMed  Google Scholar 

  18. Enos WF, Holmes RH, Beyer J. Coronary disease among United States soldiers killed in action in Korea: preliminary report. JAMA. 1953;152:1090–3.

    Article  CAS  Google Scholar 

  19. McNamara JJ, Molot MA, Stremple JF, Cutting RT. Coronary artery disease in combat casualties in Vietnam. JAMA. 1971;216:1185–7.

    Article  PubMed  CAS  Google Scholar 

  20. Strong JP, Malcom GT, McMahan CA, et al. Prevalence and extent of atherosclerosis in adolescents and young adults: implications for prevention from the Pathobiological Determinants of Atherosclerosis in Youth Study. JAMA. 1999;281:727–35.

    Article  PubMed  CAS  Google Scholar 

  21. McGill Jr HC, McMahan CA, Zieske AW, et al. Association of coronary heart disease risk factors with microscopic qualities of coronary atherosclerosis in youth. Circulation. 2000;102:374–9.

    Article  PubMed  Google Scholar 

  22. McGill Jr HC, McMahan CA, Malcom GT, Oalmann MC, Strong JP. Effects of serum lipoproteins and smoking on atherosclerosis in young men and women. Arterioscler Thromb Vasc Biol. 1997;17:95–106.

    Article  PubMed  Google Scholar 

  23. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295(13):1556–65.

    Article  PubMed  CAS  Google Scholar 

  24. Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med. 2007;356(13):1304–16.

    Article  PubMed  CAS  Google Scholar 

  25. Nicholls SJ, Tuzcu EM, Sipahi I, et al. Statins, highdensity lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA. 2007;297:499–508.

    Article  PubMed  CAS  Google Scholar 

  26. • Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011;365(22):2078–87. This study demonstrated that lowering LDL-C levels can slow and potentially halt the progression of advanced atherosclerotic plaques.

    Article  PubMed  CAS  Google Scholar 

  27. O’Keefe JH, Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower Is better and physiologically mormal. J Am Coll Cardiol. 2004;43:2142–6.

    Article  PubMed  Google Scholar 

  28. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333:1301–7.

    Article  PubMed  CAS  Google Scholar 

  29. Ford I, Murray H, Packard CJ, et al. Long-term follow-up of the West of Scotland Coronary Prevention Study. N Engl J Med. 2007;357(15):1477–86.

    Article  PubMed  CAS  Google Scholar 

  30. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):7–22.

    Article  Google Scholar 

  31. Heart Protection Study Collaborative Group, Bulbulia R, Bowman L, Wallendszus K, et al. Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20,536 high-risk individuals: a randomised controlled trial. Lancet. 2011;378(9808):2013–20.

    PubMed  CAS  Google Scholar 

  32. Chen Z, Peto R, Collins R, et al. Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations. BMJ. 1991;303:276–82.

    Article  PubMed  CAS  Google Scholar 

  33. Eaton SB, Konner M, Shostak M. Stone agers in the fast lane: chronic degenerative diseases in evolutionary perspective. Am J Med. 1988;84:739–49.

    Article  PubMed  CAS  Google Scholar 

  34. Vint F. Post-mortem findings in the natives of Kenya. E Afr Med J. 1937;13:332–40.

    Google Scholar 

  35. Grundy SM, Wilhelmsen L, Rose R, Campbell RWF, Assman G. Coronary heart disease in high-risk populations: lessons from Finland. Eur Heart J. 11:462–471.

  36. Keys A, Arvanis C, Blackburn H. Seven countries: a multivariate analysis of death and coronary heart disease. Cambridge: Harvard University Press; 1980. p. 381.

    Google Scholar 

  37. Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? BMJ. 1994;308:367–72.

    Article  PubMed  CAS  Google Scholar 

  38. Stamler J, Daviglus ML, Garside DB, et al. Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity. JAMA. 2000;284:311–8.

    Article  PubMed  CAS  Google Scholar 

  39. Klag MJ, Ford DE, Mead LA, et al. Serum cholesterol in young men and subsequent cardiovascular disease. N Engl J Med. 1993;328:313–8.

    Article  PubMed  CAS  Google Scholar 

  40. •• Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010;466:707–13. This study reported the results of a meta-analysis of genome-wide association studies quantifying the association between numerous polymorphisms and circulating levels of LDL-C.

    Article  PubMed  CAS  Google Scholar 

  41. Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey Smith G. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med. 2008;27:1133–63.

    Article  PubMed  Google Scholar 

  42. Davey Smith G, Ebrahim S. What can mendelian randomisation tell us about modifiable behavioural and environmental exposures? BMJ. 2005;330(7499):1076–9.

    Article  PubMed  Google Scholar 

  43. Nitsch D, Molokhia M, Smeeth L, DeStavola BL, Whittaker JC, Leon DA. Limits to causal inference based on Mendelian randomization: a comparison with randomized controlled trials. Am J Epidemiol. 2006;163:397–403.

    Article  PubMed  Google Scholar 

  44. Cohen JC, Boerwinkle E, Mosley Jr TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264–72.

    Article  PubMed  CAS  Google Scholar 

  45. Kathiresan S. A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction. N Engl J Med. 2008;358:2299–300.

    Article  PubMed  CAS  Google Scholar 

  46. Benn M, Nordestgaard BG, Grande P, Schnohr P, Tybjaerg-Hansen A. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. J Am Coll Cardiol. 2010;55:2833–42.

    Article  PubMed  CAS  Google Scholar 

  47. •• Ference BA, Yoo W, Alesh I, et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol. 2012;60(25):2631–9. This study provided an estimate of the quantitative magnitude of the association between long-term exposure to lower LDL-C levels and the risk of CHD mediated by polymorphism in multiple different loci. It demonstrated that natural random allocation to long-term exposure to lower LDL-C levels was associated with a threefold greater reduction in the risk of CHD per 1 mmol/l lower LDL-C concentration as compared with treatment with a statin started later in life, that this effect was log-linear, and that this effect was independent of the mechanism by which the LDL-C level is lowered.

    Article  PubMed  CAS  Google Scholar 

  48. • Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet. 2012;380(9841):572–80. doi:10.1016/S0140-6736(12)60312-2. This study provided independent confirmation of the quantitative magnitude of the association between long-term exposure to lower LDL-C levels and the risk of CHD, while at the same time demonstrating that contrary to the epidemiologic evidence, long-term exposure to higher levels of high-density lipoprotein cholesterol may not be associated with the risk of CHD.

    Article  PubMed  CAS  Google Scholar 

  49. • Hopewell JC, Stari T, Parish S, et al. The impact of genetic variants related to LDL-cholesterol on risk of ischemic stroke and coronary heart disease. Circulation. 2012;126:A11959. This study provided a second independent confirmation of the quantitative magnitude of the association between long-term exposure to lower LDL-C levels and the risk of CHD.

    Google Scholar 

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Authors and Affiliations

  1. Division of Translational Research and Clinical Epidemiology (TRaCE), Wayne State University School of Medicine, UHC, 4H-34, Detroit, MI, 48201, USA

    Brian A Ference

  2. Division of Cardiovascular Medicine, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Brian A Ference & Nitin Mahajan

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  1. Brian A Ference
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  2. Nitin Mahajan
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Correspondence to Brian A Ference.

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This article is part of the Topical Collection on Coronary Heart Disease

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Ference, B.A., Mahajan, N. The Role of Early LDL Lowering to Prevent the Onset of Atherosclerotic Disease. Curr Atheroscler Rep 15, 312 (2013). https://doi.org/10.1007/s11883-013-0312-1

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