Atherosclerosis

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oPatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.

Atherosclerosis is a condition affecting large- and medium-sized arteries. It leads to the formation of atherosclerotic plaques which may eventually disrupt the blood flow to target organs.

The term comes from athere, the Greek word meaning gruel, referring to the deposition within the arterial walls, and sclerosis meaning hardening.

Atherosclerotic plaques form in the arterial wall. Previously, plaque formation was considered as a cholesterol storage disease. It is now regarded as a complex process involving interaction between the arterial wall and blood components, with inflammation playing a major role.

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Plaque formation

Plaque formation involves smooth muscle cells, leukocytes, and various mediators of inflammation and immunity, including cytokines and complement components.[1] The first lesion seen is the fatty streak, which may develop into a plaque. Plaques have a lipid core and a fibrous cap.

Atherosclerotic plaques tend to occur in regions where vessels branch, curve or are irregular, where blood undergoes sudden changes in velocity and in direction of flow.

The traditional view of atherosclerosis was that plaques produce arterial narrowing, ie stenoses. The degree of stenosis was thought to be the main factor in diseases such as coronary artery disease. Recent understanding is that plaques grow outward rather than inward for much of their life history, so that substantial atherosclerosis can exist without producing stenosis. Hence, significant atherosclerosis may be silent clinically and invisible on angiograms. Stenoses are the 'tip of the iceberg' of atherosclerosis.

Nitric oxide may play a key role in the pathogenesis of atherosclerosis.[2]

Plaque rupture and thrombosis

Acute clinical complications of atherosclerosis, such as acute coronary syndromes and ischaemic stroke, are usually due to rupture of a plaque, leading to thrombosis, with partial or complete obstruction of the artery.

Some plaques are more prone to rupture than others. 'High-risk' plaques are those with a thin cap and a large lipid core containing relatively more inflammatory cells and fewer smooth muscle cells. These 'vulnerable plaques' may be widespread and yet may not produce stenosis or ischaemia, so they are a hidden threat to health. This type of plaque tends to produce an acute problem (eg, acute coronary syndrome), whereas a more stable and stenotic plaque will produce a more chronic clinical picture (eg, stable angina).

These concepts of widespread and vulnerable plaques have implications for management, making it important to treat cardiovascular disease (CVD) not only with revascularisation procedures, but with systemic treatments aimed at stabilising plaques and reducing thromboses.

Although atherosclerosis usually manifests in later life, its early phases are present in teenagers and young adults.[3] 

The clinical manifestations of atherosclerosis, such as CVD, are common in Western and urban populations, and are an important and common cause of death and disease.

Many risk factors have been identified for atherosclerotic disease; the main ones are listed here. Note that most of the literature on this topic relates to the clinical manifestations of atherosclerosis, mainly rates of cardiovascular disease and coronary heart disease.

Risk factors for CVD[4]

Permanent factors

  • Increasing age.
  • Male gender.
  • Family history of early coronary heart disease (eg, in men <55 years and in women <65 years).
  • Race - eg, many South Asian races are at higher risk.

Lifestyle, social and environmental factors

  • Cigarette smoking.
  • Lack of regular physical exercise.
  • Diet:
    • Lack of fruit and vegetables.
    • High-fat - the type of fat is important - eg trans fats increase CVD risk.
    • Lower intake of omega-3 fatty acids (eg, in fish oils).[5]
  • High alcohol intake (moderate alcohol intake may be protective).
  • Psychosocial factors (eg, stress at work or home, depression and deprivation).[4][6]
  • Air pollution (possibly).[7]

Co-existing conditions

  • Hypertension.
  • Diabetes mellitus (probably through mechanisms of hyperglycaemia, lipoprotein abnormalities, and inflammation[8]).
  • Hyperlipidaemia:
    • Raised low-density lipoprotein (LDL) cholesterol.
    • High-density lipoprotein (HDL) cholesterol and its apolipoproteins (apos) A-I and A-II are protective.[9]
    • Raised triglycerides (possibly).[10]
  • Obesity, particularly abdominal obesity (including metabolic syndrome).[11]
  • Systemic inflammation - eg, in systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, human immunodeficiency virus, systemic sclerosis, vasculitis and periodontitis.[12]
  • Low levels of vitamin D (possibly).[13]
  • Obstructive sleep apnoea (possibly).[14]

Metabolic factors

  • Raised C-reactive protein.
  • Raised fibrinogen and raised lipoprotein (a) (possibly).
  • Homocysteine - raised plasma homocysteine levels have been linked to atherosclerosis, but there seems to be no cardiovascular benefit from vitamins lowering homocysteine (folic acid and B vitamins).[15]
  • Atherosclerosis in its early stages is silent.
  • The clinical presentation is usually with complications (see section below).
  • Possible signs are:
    • Xanthelasmata (from hyperlipidaemia).
    • Bruits over large arteries (eg, carotid bruits).
    • Aortic aneurysm.
    • Poor peripheral pulses.
    • Reduced ankle brachial index.[16]

Investigation of atherosclerosis itself (rather than its clinical manifestations) is not routine in clinical practice, but has been used as a research tool. Possible techniques are:[3]

  • Ultrasound measurement of carotid intima-media thickness using B-mode ultrasound - this has some limitations.[18]
  • Intravascular ultrasound - this can detect atherosclerotic plaques not visible on angiography; it may show up recent plaque disruption.
  • High-resolution MRI.
  • CT - multi-slice spiral CT or electron-beam CT to quantify coronary artery calcium.[19]

Established management

There are existing guidelines for:

As an overview, standard prevention and treatment involve:

  • Lifestyle modifications:
    • Smoking cessation.
    • Diet - increased fruit and vegetables, reduced fat intake, increased omega-3 fatty acid intake.
    • Regular physical exercise.
    • Avoiding excess alcohol.
  • Treatment of a contributing disease - eg, diabetes, and hypertension; treat complications.
  • Drug treatment:
    • Statins - these have effects on both lipids and inflammation. There is some evidence that statins prevent progression and may even reverse coronary atherosclerosis.[3]
    • Omega-3 fatty acids - these are currently prescribable as adjunct in secondary prevention for those with myocardial infarction in the previous three months, or for hypertriglyceridaemia.[21] They are also available as over-the-counter supplements.
    • Antiplatelet drugs - aspirin and others, are used for those at greatest risk (eg, in the secondary prevention of CVD).[1]

Newer treatments and research

Note that when considering the effectiveness of new treatments, it is important to consider whether they improve patient outcomes, rather than focusing on biomarkers such as lipid levels.[22] 

Drugs[23]

  • Nicotinic acid can effectively raise HDL cholesterol levels. Research on prolonged-acting nicotinic acid is ongoing.
  • Fibrates reduce LDL cholesterol, reduce triglycerides and increase HDL cholesterol, and may improve CVD outcomes.
  • The cholesterol-absorption inhibitor, ezetimibe, has a small effect in raising HDL cholesterol, which is potentiated by combining it with a statin or fibrate.
  • Pharmacological inhibitors of the cholesteryl ester transfer protein (CETP) offer a potentially novel mechanism for raising HDL cholesterol levels.

Diet

  • Plant stanols and sterols reduce LDL cholesterol levels and have other potentially beneficial effects, but their effect on CVD and atherosclerosis is unknown.[24]
  • A diet rich in fruit and vegetables is protective for CVD. The mechanism is uncertain, but it may be related to dietary inorganic nitrate, found particularly in leafy green vegetables.[25]
  • Specific foods that may be protective for CVD are lycopenes (a carotenoid found in tomatoes),[26] polyphenols (found in red wine and tea)[27] and pomegranate juice.[28]
  • Dietary patterns and markers of inflammation are linked, and this may be relevant to the development of atherosclerosis.[29]
  • Moderate alcohol intake may protect against coronary artery disease, by various mechanisms. However, when advising patients about alcohol consumption and heart health there are various factors to consider.[30]

Further reading & references

  1. Libby P, Theroux P; Pathophysiology of coronary artery disease. Circulation. 2005 Jun 28;111(25):3481-8.
  2. Cook S; Coronary artery disease, nitric oxide and oxidative stress: the "Yin-Yang" Swiss Med Wkly. 2006 Feb 18;136(7-8):103-13.
  3. Toth PP; Subclinical atherosclerosis: what it is, what it means and what we can do about Int J Clin Pract. 2008 Aug;62(8):1246-54. Epub 2008 Jun 28.
  4. Yusuf S, Hawken S, Ounpuu S, et al; Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004 Sep 11-17;364(9438):937-52.
  5. He K, Liu K, Daviglus ML, et al; Intakes of long-chain n-3 polyunsaturated fatty acids and fish in relation to Am J Clin Nutr. 2008 Oct;88(4):1111-8.
  6. Kim D, Diez Roux AV, Kiefe CI, et al; Do neighborhood socioeconomic deprivation and low social cohesion predict Am J Epidemiol. 2010 Aug 1;172(3):288-98. Epub 2010 Jul 7.
  7. Mills NL, Donaldson K, Hadoke PW, et al; Adverse cardiovascular effects of air pollution. Nat Clin Pract Cardiovasc Med. 2009 Jan;6(1):36-44. Epub 2008 Nov 25.
  8. Mazzone T, Chait A, Plutzky J; Cardiovascular disease risk in type 2 diabetes mellitus: insights from Lancet. 2008 May 24;371(9626):1800-9.
  9. Chapman MJ, Le Goff W, Guerin M, et al; Cholesteryl ester transfer protein: at the heart of the action of Eur Heart J. 2010 Jan;31(2):149-64. Epub 2009 Oct 12.
  10. Le NA, Walter MF; The role of hypertriglyceridemia in atherosclerosis. Curr Atheroscler Rep. 2007 Aug;9(2):110-5.
  11. Fantuzzi G, Mazzone T; Adipose tissue and atherosclerosis: exploring the connection. Arterioscler Thromb Vasc Biol. 2007 May;27(5):996-1003. Epub 2007 Feb 15.
  12. van Leuven SI, Franssen R, Kastelein JJ, et al; Systemic inflammation as a risk factor for atherothrombosis. Rheumatology (Oxford). 2008 Jan;47(1):3-7. Epub 2007 Aug 16.
  13. Giovannucci E, Liu Y, Hollis BW, et al; 25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective Arch Intern Med. 2008 Jun 9;168(11):1174-80.
  14. Levy P, Pepin JL, Arnaud C, et al; Obstructive sleep apnea and atherosclerosis. Prog Cardiovasc Dis. 2009 Mar-Apr;51(5):400-10.
  15. Smulders YM, Blom HJ; The homocysteine controversy. J Inherit Metab Dis. 2010 Jun 22.
  16. Fowkes FG, Murray GD, Butcher I, et al; Ankle brachial index combined with Framingham Risk Score to predict JAMA. 2008 Jul 9;300(2):197-208.
  17. Scolari F, Ravani P; Atheroembolic renal disease. Lancet. 2010 May 8;375(9726):1650-60. Epub 2010 Apr 8.
  18. Finn AV, Kolodgie FD, Virmani R; Correlation between carotid intimal/medial thickness and atherosclerosis: a point Arterioscler Thromb Vasc Biol. 2010 Feb;30(2):177-81. Epub 2009 Aug 13.
  19. Waugh N, Black C, Walker S, et al; The effectiveness and cost-effectiveness of computed tomography screening for Health Technol Assess. 2006 Oct;10(39):iii-iv, ix-x, 1-41.
  20. Lipid modification - cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease; NICE Clinical Guideline (May 2008, amended May 2010)
  21. British National Formulary
  22. Krumholz HM, Hayward RA; Shifting views on lipid lowering therapy. BMJ. 2010 Jul 28;341:c3531. doi: 10.1136/bmj.c3531.
  23. Hausenloy DJ, Yellon DM; Targeting residual cardiovascular risk: raising high-density lipoprotein Heart. 2008 Jun;94(6):706-14.
  24. Derdemezis CS, Filippatos TD, Mikhailidis DP, et al; Review article: effects of plant sterols and stanols beyond low-density J Cardiovasc Pharmacol Ther. 2010 Jun;15(2):120-34. Epub 2010 Mar 3.
  25. Kapil V, Webb AJ, Ahluwalia A; Inorganic nitrate and the cardiovascular system. Heart. 2010 Aug 23.
  26. Riccioni G, Mancini B, Di Ilio E, et al; Protective effect of lycopene in cardiovascular disease. Eur Rev Med Pharmacol Sci. 2008 May-Jun;12(3):183-90.
  27. Curin Y, Andriantsitohaina R; Polyphenols as potential therapeutical agents against cardiovascular diseases. Pharmacol Rep. 2005;57 Suppl:97-107.
  28. Basu A, Penugonda K; Pomegranate juice: a heart-healthy fruit juice. Nutr Rev. 2009 Jan;67(1):49-56.
  29. Nettleton JA, Steffen LM, Mayer-Davis EJ, et al; Dietary patterns are associated with biochemical markers of inflammation and Am J Clin Nutr. 2006 Jun;83(6):1369-79.
  30. Lippi G, Franchini M, Favaloro EJ, et al; Moderate red wine consumption and cardiovascular disease risk: beyond the "French Semin Thromb Hemost. 2010 Feb;36(1):59-70. Epub 2010 Apr 13.

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.

Original Author:
Dr Naomi Hartree
Current Version:
Peer Reviewer:
Dr Adrian Bonsall
Document ID:
1830 (v22)
Last Checked:
23/10/2013
Next Review:
22/10/2018