Cholesterol Metabolism and Vascular Disease

Abstract

Cholesterol is packaged into lipoprotein particles in the liver and intestine and transported to peripheral tissues for normal cellular function. Reverse cholesterol transport is the mechanism by which excess cholesterol is transported back to the liver and is facilitated by high‐density lipoproteins (HDLs). Increased plasma concentrations of cholesterol within the low‐density lipoprotein (LDL) molecule contribute to atherosclerotic vascular disease that commonly affects the coronary, cerebral and peripheral vascular circulation.

There is now strong evidence to support the use of the statin class of drugs to decrease the risk of cardiovascular disease. Statins inhibit hepatic cholesterol synthesis, increase hepatic low‐density lipoprotein cholesterol (LDLc) receptor expression and consequently decrease plasma LDLc, to reduce the risk of myocardial infarction in people at widely varying risk of heart disease. At present, there is limited evidence to support the use of alternative classes of lipid‐lowering medications to reduce the risk of cardiovascular disease. Clinical trials are currently ongoing to assess the safety and efficacy of new types of medications to treat dyslipidaemias, the most promising of which are targeted against proprotein convertase subtilysin kexin 9 (PCSK9).

Key Concepts

  • Endogenous and exogenous lipid pathways exist within the body.
  • There are both inherited and acquired forms of hypercholesterolaemia.
  • Low‐density lipoprotein cholesterol (LDLc) is associated with the development of coronary heart disease.
  • Disordered lipid metabolism plays a crucial role in the development of atherosclerotic vascular disease.
  • There is much clinical trial evidence now showing the effectiveness of certain classes of lipid‐lowering medication in lowering cholesterol levels and reducing the risk of cardiovascular disease.

Keywords: hypercholesterolaemia; atherosclerotic vascular disease; lipid‐lowering medication; clinical trials; cardiovascular risk

Figure 1. Relationship among dietary nutrients, lipid synthesis, lipoproteins and atherosclerotic disease.
Figure 2. Relationship between various lipoprotein transport pathways.
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References

Abramson J, Rosenberg H, Jewell N and Wright J (2013) Should people at low risk of cardiovascular disease take a statin? BMJ 347: f6123.

Baigent C, Keech A, Kearney PM, et al. (2005) Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol‐lowering treatment: prospective meta‐analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366 (9493): 1267–1278.

Benlian P, Cansier C, Hennache G, et al. (2000) Comparison of a new method for the direct and simultaneous assessment of LDL‐ and HDL‐cholesterol with ultracentrifugation and established methods. Clinical Chemistry 46 (4): 493–505.

Boekholdt SM, Arsenault BJ, Mora S, et al. (2012) Association of LDL cholesterol, non‐HDL cholesterol, and apolipoprotein B levels with risk of cardiovascularevents among patients treated with statins: a meta‐analysis. JAMA 307 (12): 1302–1309.

Boren J, Ekstrom U, Agren B, Nilsson‐Ehle P and Innerarity TL (2001) The molecular mechanisms for the genetic disorder familial defective apolipoprotein B100. Journal of Biological Chemistry 276 (12): 9214–9218.

Byrne CD and Targher G (2014) Ectopic fat, insulin resistance, and nonalcoholic fatty liver disease: implications for cardiovascular disease. Arteriosclerosis, Thrombosis, and Vascular Biology 34 (6): 1155–1161.

Cannon CP, Braunwald E, McCabe CH, et al. (2004) Intensive versus moderate lipid lowering with statins after acute coronary syndromes. The New England Journal of Medicine 350: 1495.

Chapman MJ, Laplaud PM, Luc G, et al. (1988) Further resolution of the low density lipoprotein spectrum in normal human plasma: physicochemical characteristics of discrete subspecies separated by density gradient ultracentrifugation. Journal of Lipid Research 29 (4): 442–458.

Cohen JC, Boerwinkle E, Mosley TH Jr and Hobbs HH (2006) Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. The New England Journal of Medicine 354: 1264–1272.

Cortellaro M, Cofrancesco E, Arbustini E, et al. (2002) Atorvastatin and thrombogenicity of the carotid atherosclerotic plaque: the ATROCAP study. Thrombosis and Haemostasis 88: 41–47.

Cuchel M, Bloedon LT, Szapary PO, et al. (2007) Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. The New England Journal of Medicine 356: 148–156.

Cuchel M, Meagher EA, du Toit Theron H, et al. (2013) Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single‐arm, open label, phase 3 study. Lancet 381: 40–46.

Daskalopoulou SS and Mikhailidis DP (2006) Reaching goal in hypercholesterolaemia: dual inhibition of cholesterol synthesis and absorption with simvastatin plus ezetimibe. Current Medical Research and Opinion 22: 511–528.

Deedwania P, Stone PH, Bairey Merz CN, et al. (2007) Effects of intensive versus moderate lipid‐lowering therapy in myocardial ischaemia in older patients with coronary heart disease: results of the Study Assessing Goals in the Elderly (SAGE). Circulation 115: 700.

Franklin B, Durstine J, Roberts C and Barnard R (2014) Impact of diet and exercise on lipid management in the modern era. Best Practice & Research Clinical Endocrinology & Metabolism 28 (3): 405–421.

Ibrahim S, Guillot N, Pruneta‐Deloche V, et al. (2009) Alterations in the transfer of phospholipids from very‐low density lipoproteins to activated platelets in type 2 diabetes. Atherosclerosis 203 (1): 119–125.

Kamanna VS and Kashyap ML (2008) Mechanism of action of niacin. The American Journal of Cardiology 101: 20B–26B.

Keene D, Price C, Shun‐Shin M and Francis D (2014) Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta‐analysis of randomised controlled trials including 117 411 patients. BMJ 349: g4379.

Koltsova EK, Garcia Z, Chodaczek G, et al. (2012) Dynamic T cell‐APC interactions sustain chronic inflammation in atherosclerosis. Journal of Clinical Investigation 122: 3114–3126.

Koren MJ, Scott R, Kim JB, et al. (2012) Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double‐blind, placebo‐controlled, phase 2 study. Lancet 380: 1995–2006.

La Rosa JC, Grundy SM, Waters DD, et al. (2005) Intensive lipid lowering with atorvastatin in patients with stable coronary artery disease. The New England Journal of Medicine 352: 1425.

Lee L‐M, Shiroma EJ, Lobelo F, et al. (2012) Effect of physical inactivity on major non‐communicable disease worldwide: an analysis of burden of disease and life expectancy. Lancet 380: 219–229.

Levinson SS and Wagner SG (2015) Implications of reverse cholesterol transport: recent studies. Clinica Chimica Acta 439: 154–161.

Libby P (2013) Mechanisms of acute coronary syndromes and their implications for therapy. The New England Journal of Medicine 368: 2004–2013.

The LIPID Study Group (2002) Long‐term effectiveness and safety of pravastatin in 9,014 patients with coronary heart disease and average cholesterol concentrations: the LIPID trial follow‐up. Lancet 359: 1379–1387.

Lichtman AH (2012) T cell costimulatory and coinhibitory pathways in vascular inflammatory diseases. Frontiers in Physiology 3: 18.

Marais AD, Solomon GA and Blom DJ (2014) Dysbetalipoproteinaemia: a mixed hyperlipidaemia of remnant lipoproteins due to mutations in apolipoprotein E. Critical Reviews in Clinical Laboratory Sciences 51 (1): 46–62.

McCullough PA, Ahmed AB, Zughaib MT, et al. (2011) Treatment of hypertriglyceridemia with fibric acid derivatives: impact on lipid subfractions and translation into a reduction in cardiovascular events. Reviews in Cardiovascular Medicine 12 (4): 173–185.

Mikhailidis DP, Lawson RW, McCormick A‐L, et al. (2011) Comparative efficacy of the addition of ezetimibe to statin vs statin titration in patients with hypercholesterolaemia: systematic review and meta‐analysis. Current Medical Research and Opinion 27 (6): 1191–1210.

Miller YI, Choi SH, Fang L and Tsimikas S (2010) Lipoprotein modification and macrophage uptake: role of pathologic cholesterol transport in atherogenesis. Subcellular Biochemistry 51: 229–251.

Murtagh EM, Nichols L, Mohammed M, et al. (2015) The effect of walking on risk factors for cardiovascular disease: an updated systematic review and meta‐analysis of randomised control trials. Preventive Medicine 72: 34–43.

Pedersen TR, Faergeman O, Kastelein JJ, et al. (2005) High‐dose atorvastatin vs usual dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomised controlled trial. JAMA 294: 2437.

Raal FJ, Santos RD, Blom DJ, et al. (2010) Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double‐blind, placebo‐controlled trial. Lancet 375: 998–1006.

Rees K, Dyakova M, Wilson N, et al. (2013) Dietary advice for reducing cardiovascular risk. Cochrane Database of Systematic Reviews 12: CD002128.

Robinson JG, Farnier M, Krempf M, et al. (2015) Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. The New England Journal of Medicine 372: 1489–1499.

Sabatine MS, Giugliano RP, Wiviott SD, et al. (2015) Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. The New England Journal of Medicine 372: 1500–1509.

The Scandinavian Simvastatin Survival Study Group (1994) Randomised trial of cholesterol lowering in 4,444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344: 1383–1389.

Sniderman AD (2001) Scantlebury T and Cianflone K Hypertriglyceridemic hyperapob: the unappreciated atherogenic dyslipoproteinemia in type 2 diabetes mellitus. Annals of Internal Medicine 135 (6): 447–459.

Stamler J, Daviglus ML, Garside DB, et al. (2000) 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 284 (3): 311–318.

Stein EA, Dufour R, Gagne C, et al. (2012a) Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double‐blind, placebo‐controlled trial to assess efficacy and safety as add‐on therapy in patients with coronary artery disease. Circulation 126: 2283–2292.

Stein EA, Gipe D, Bergeron J, et al. (2012b) Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low‐density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 380: 29–36.

Stone GW, Maehara A, Lansky AJ, et al. (2011) PROSPECT investigators. A prospective natural‐history study of coronary atherosclerosis. The New England Journal of Medicine 364 (3): 226–235.

Stone NJ, Robinson JG, Lichenstein AH, et al. (2014) 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. Journal of the American College of Cardiology 63 (25 pt B): 2889–2934.

Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, Armitage J, Bowman L, et al. (2010) Intensive lowering of LDL cholesterol with 80mg versus 20mg simvastatin daily in 12,064 survivors of myocardial infarction: a double‐blind randomised trial. Lancet 376 (9753): 1658–1669.

Taylor F, Huffman MD, Macedo AF, et al. (2013) Statins for the primary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 1: CD004816.

Veerkamp MJ, de Graaf J, Hendriks JC, et al. (2004) Nomogram to diagnose familial combined hyperlipidemia on the basis of results of a 5‐year follow‐up study. Circulation 109: 2980–2985.

Wierzbicki A and Viljoen A (2014) Fibrates and niacin: is there a place for them in clinical practice? Expert Opinion on Pharmacotherapy 15 (18): 2673–2680.

Ylä‐Herttuala S, Bentzon JF, Daemen M, et al. (2011) Stabilisation of atherosclerotic plaques. Position paper of the European Society of Cardiology (ESC) Working Group on atherosclerosis and vascular biology. Thrombosis and Haemostasis 106 (1): 1–19.

Further Reading

National Institute for Health and Care Excellence (2014) Lipid Modification: Cardiovascular Risk Assessment and the Modification of Blood Lipids for the Primary and Secondary Prevention of Cardiovascular Disease. CG 181. London: National Institute for Health and Care Excellence.

Nordestgaard BG and Varbo A (2014) Triglycerides and cardiovascular disease. Lancet 384 (9943): 626–635.

Rader DJ and Hovingh GK (2014) HDL and cardiovascular disease. Lancet 384 (9943): 618–625.

Ridker PM (2014) LDL cholesterol: controversies and future therapeutic directions. Lancet 384 (9943): 607–617.

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Wainwright, Patrick, Ryan, Aidan, Olufadi, Rasaq, and Byrne, Christopher D(Nov 2015) Cholesterol Metabolism and Vascular Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002264.pub3]