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Risk Factors: Why You Get Atherosclerosis |
Traditional risk factors for the development of atherosclerotic disease include smoking, diabetes, high blood pressure, left ventricular hypertrophy (thickened heart muscle), high cholesterol and a family history of premature heart attack or stroke (under age 60). These conditions make atherosclerosis accelerate over time and make it more likely that you will have a heart attack, stroke or other arterial vascular problem.
However, traditional risk factors are not present in 50% of those who develop atherosclerotic problems.1 These individuals appear to have other genetic disorders or abnormal blood clotting, chronic inflammation of arteries or as yet unknown problems. At best we can identify about 70% of probable causes based on our current knowledge.
A growing list of blood tests is being done to identify people who have these other disorders. It is important to identify them because new therapeutic approaches are appropriate and effective. These new blood tests are a part of Global Risk Assessment. They can be functionally divided into a search for established genetic factors, blood clotting disorders, and chronic inflammation or infection of arteries. |
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Earlier Diagnosis of Asymptomatic Atherosclerosis |
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Recent studies of arterial ultrasound imaging and coronary artery calcification have made it possible to diagnose the presence of atherosclerosis long before symptoms appear. These simple, non-invasive studies allow more precise selection of patients for treatment before disease has appeared. Not all people with risk factors will develop early atherosclerotic diseases such as stroke or heart attack. Identifying the presence of mild disease which is less than 50% obstructive in the coronary arteries, provides the opportunity for appropriate, earlier primary prevention in the most appropriate patients.
Electron Beam CT Scanning (EBCT and also called UltraFast CT Scanning) is an easy, relatively inexpensive means of finding atherosclerosis in the coronary arteries. Duplex imaging of carotid or other arteries can reveal atherosclerotic plaquing non-invasively as well. These two tests are discussed below. |
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A family history of premature atherosclerotic disease is the most powerful risk anyone can have in predicting future heart attack, stroke or vascular disease. While elevated LDL cholesterol or low HDL cholesterol can run in families, other disorders are now being diagnosed and treated.
This list includes Lp (a) ("Lipoprotein a"), homocysteine, LDL Subclass or particle size, HDL subtype, fibrinogen level and even insulin levels. L p(a) is elevated in 33% of patients with coronary artery atherosclerosis.2 In asymptomatic individuals, it increases the risk of future atherosclerotic disease three fold. It is also found in persons with severe vascular disease in the carotid arteries and lower extremities.3
The combination of a low HDL and high Lp(a) is commonly found in younger men with coronary artery disease and a strong family history of heart attack early in life. The combination of an elevated LDL and Lp(a) greatly increases risk as well. However, an elevated Lp(a) alone seems to pose only a minimal increase in risk for atherosclerosis.
It is an unusual substance present to some extent in all of us. An abnormal protein called (a) is attached to an LDL particle. This protein is suspected of interfering with normal mechanisms of removing small clots on the arterial wall.4
At the present time, the most important reason for identifying high Lp(a) levels is that standard cholesterol medicines have no effect on it. Only oral estrogen therapy and niacin have been shown to reduce elevated levels.5,6
LDL Subclass. 50% of patients with coronary atherosclerotic disease have dense LDL particles (also called LDL pattern B, small LDL trait, atherogenic Lp profile, or ALP).1 When present, dense LDL increases the risk of coronary disease by 300%.1 It is the most common lipid disorder not routinely tested.
Recently its importance has grown regarding progression and regression of atherosclerotic coronary disease. Three important studies using standard cholesterol treatment have shown that the benefit occurred primarily in people who had dense LDL pattern B.7 Those with LDL pattern A had much less benefit. Importantly, these were studies of future events as well as findings on coronary angiograms in the populations treated. Lowering the LDL pattern B level and shifting particle size to pattern A provides great benefit.
As with Lp (a), the standard cholesterol drugs do not accomplish this. Dietary change, and the drugs niacin and gemfibrozil are the only interventions which provide benefit.8
Homocysteine (Hc) elevation is found in 30% of patients with coronary heart disease and 40% of patients with cerebrovascular disease (carotid atherosclerosis or stroke).9 It increases future risk by 200%. It is found in younger patients with unexplained atherosclerotic disease.
Homocysteine is a sulfa-containing amino acid and a byproduct of methionine metabolism. Genetic defects in methionine breakdown cause severe elevation and a metabolic disorder resulting in early death. One prominent feature is clots in veins and severe atherosclerosis in arteries. Fortunately this severe problem is rare. Partial defects in homocysteine metabolism result in milder elevations found in some people with premature atherosclerosis.10
How homocysteine damages the wall of arteries is uncertain. A number of mechanisms are proposed including direct damage to the protective endothelial lining of the artery, allowing cholesterol to enter the wall and inflammation to develop. It may also cause clotting problems and platelet dysfunction which could contribute to plaque growth.11
This metabolic process is vitamin dependent. Folic acid, vitamin B6, and vitamin B12 are important co-factors. It has been shown that many patients with elevated homocysteine levels are mildly deficient in one or more of these vitamins. Supplementation can result in a significant fall in the blood level of this protein.
HDL Subtype. HDL is the so-called "good cholesterol" but not all HDL is equally beneficial. An abundance of subclass IIb reflects good reverse cholesterol transport and possible benefit. A proponderance of other types such as Type III is not useful. A low HDL IIb can be corrected by specific therapy. |
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Small blood clots are a powerful influence on the growth of atherosclerotic plaque. A clot adhering to an active plaque secretes substances making the plaque grow further. If a small plaque ruptures, a clot can occlude the artery causing heart attack or stroke.
The body has a system which makes clots and one that dissolves them. An overactive clotting mechanism or an underachieving clot dissolving system could both cause problems. So far only a few abnormalities of these complex systems have been studied in relationship to atherosclerosis. Only abnormal levels of fibrinogen have been correlated with atherosclerosis.
Fibrinogen. Fibrinogen is a precursor of fibrin, a necessary building block of all blood clots. Elevated levels of fibrinogen have been found in patients with coronary artery disease in a variety of circumstances: angina patients, those with unstable angina, and those having had prior heart attack. Elevated levels are predictive of a higher likelihood of future events.12
Fibrinogen can be quite variable in blood, going up or down in response to other health problems. In addition, studies done so far are quite small. No study has shown a protective effect of directly dealing with elevated fibrinogen levels.
However, other recent studies suggest a protective effect of interfering with other parts of the clotting mechanism such as platelet "stickiness" and normal levels of coagulation proteins. Aspirin and other newer drugs affect platelet function and reduce the incidence of heart attack and stroke.13 Warfarin (Coumadin) lowers clotting proteins and may reduce second heart attack in preliminary research studies.
At present there are no recommendations for treatment based on elevated fibrinogen levels in the face of other risk factors or a prior atherosclerotic event. |
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Chronic Inflammation or Infection |
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Recent pathologic studies of atherosclerotic plaque have focused attention on inflammatory white blood cells which are very prevalent in young, active and growing plaque.13 It has been postulated that chronic inflammation or certain chronic infections may themselves be a stimulus to plaque growth.14 It is also speculated that the benefit of common anticholesterol drugs may in part be due to antiflammatory effects.15 A small number of blood tests are being explored which may indicate this process to be part of the problem.
C-Reactive Protein. This test has been used for decades to indicate the activity of arthritis and certain bacterial infections. It is well known that the level is also affected by other conditions such as malignancies, recent surgery and heart attack.
Recent preliminary data have suggested that patients with coronary artery disease may have chronically elevated levels of C-Reactive Protein (CRP) due to chronic inflammation or infection of their arteries.16 They seem to have more episodes of coronary artery disease progression such as heart attack or the need for procedures. The implication is that these patients need further investigation with such things as antibody titers and possibly treatment if a hidden infection is suspected. New information is rapidly accumulating and at present there are no firm recommendations based on abnormal levels of CRP.
Recent pathologic studies of atherosclerotic plaque have focused attention on inflammatory white blood cells which are very prevalent in young, active and growing plaque.13 It has been postulated that chronic inflammation or certain chronic infections may themselves be a stimulus to plaque growth.14 It is also speculated that the benefit of common anticholesterol drugs may in part be due to antiflammatory effects.15 A small number of blood tests are being explored which may indicate this process to be part of the problem.
C-Reactive Protein. This test has been used for decades to indicate the activity of arthritis and certain bacterial infections. It is well known that the level is also affected by other conditions such as malignancies, recent surgery and heart attack.
Antibody Titers. Certain infectious agents are capable of persistent existence inside cells with periodic emergence to infect and inflame surrounding tissues. Recently, three of these have been indirectly identified in human atherosclerotic plaque. These are chlamydia pneumoniae, cytomegalovirus (CMV) and herpes simplex. A conclusion that these common pathogens cause atherosclerosis is not yet warranted as the data are too preliminary.17
Antibody titers to some of these organisms are easily obtained. The significance of the titers in a given clinical circumstance (angina, heart attack, etc.) is yet to be determined. It is still too early to suggest antibiotic or antiviral treatment. |
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Atherosclerotic Plaque Imaging |
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Two non-invasive techniques are available for identifying the presence of atherosclerotic plaque. This is particularly useful for primary prevention of coronary heart disease and stroke in asymptomatic individuals with numerous risk factors placing them in a high risk category. Abnormalities discovered in younger people provide the benefit of treatment long before disease has progressed to a symptomatic stage.
Ultrasound Duplex Vascular Imaging. Vascular duplex imaging can identify atherosclerotic plaque in large arteries near the skin surface. This has primarily been done in the carotid artery although the femoral artery is also available for imaging. Asymptomatic plaques resulting in up to 70% obstruction of the carotid artery can be present before prophylactic surgery is needed to prevent stroke. 18 However, identification of smaller plaques in asymptomatic persons leads to aggressive treatment to prevent progression.
Electron Beam CT Scanning. Electron Beam CT Scanning is a simple tomographic x-ray technique which has been around for many years. More recent follow-up studies have validated its utility in predicting subsequent coronary events such as heart attack, sudden death or the need for angioplasty or surgery. Simply put, it images the presence of specs of calcium in older, scarred atherosclerotic plaque. It does not image the younger more dangerous plaque which is not yet calcified. In addition, the location of heart attacks is not usually where arteries are calcified but rather in other areas where younger, invisible plaque is located.
Nonetheless, the presence of abnormally high levels of older, calcified plaque in a younger person indicates a higher risk for future coronary events. The higher the "score" of calcium throughout the coronary arteries, the more likely one will have future problems.19 Thus, an abnormal calcium score for age and gender is an additional risk factor which can result in a recommendation for an aggressive risk reduction program. |
1. Superko, H R. Lipid Disorders Contributing to Coronary Heart Disease - An Update. Current Problems in Cardiology. 1996; 21: 733-780.
2. Colbaert, C et al. Modulation of Lipoprotein (a) Atherogenicity by High Denisty Lipoprotein Cholesterol Levels in Middle Aged Men with Symptomatic Coronary Artery Disease and Normal to Moderately Elevated Cholesterol. J Am Coll Cardiol. 1997; 30: 1491-1499.
3. Valentine, R J et al. Lp(a) Lipoprotein is an Independent, Discriminating Risk Factor for Premature Peripheral Atherosclerosis Among White Men. Arch Int Med. 1994; 154: 801-806.
4. Miles, L A et al. Interaction of Lp(a) with Plasminogen Binding Sites on Cells. Thromb Haemost. 771995; 73: 458-465.
5. Scanu, A. Lipoprotein (a). JAMA 1992; 267: 3326-3329.
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7. Superko, H R. What Can We Learn About Dense LDL and Lipoprotein Particles From Clinical Trials? Current Opinion in Lipidology. 1996; 7:363-368.
8. Superko, H R and Kos Investigators. Effect of Nicotinic Acid on LDL Subclass Patterns. Circ. 1994; 90:I-504.
9. Stein, J H et al. Hyperhomocysteinemia and Atherosclerotic Vascular Disease. Arch Int Med. 1998; 158:1301-1306.
10. Malinow, M R. Plasma Homocysteine: A Risk Factor for Arterial Occlusive Diseases. J. Nutr. 1996; 126: 1238S-1243S.
11. Moghadasian, M et al. Homocysteine and Coronary Artery Disease. Clinical Evidence and Genetic and Metabolic Background. Arch Int Med. 1997; 157: 2299-2308.
12. 13. Ridker, P M et al. Inflammation, Aspirin and the Risk of Cardiovascular Disease in Apparently Healthy Young Men. NEJM. 1997; 336: 973-979.
14. Cohchi, K et al. Significance of Adventitial Inflammation of the Coronary Artery in Patients With Unstable Angina: Results at Autopsy. Circ. 1985; 71: 709-716.
15. Mehta, J L et al. Interactive Role of Infection, Inflammation and Traditional Risk Factors In Atherosclerosis and Coronary Artery Disease. J Am Coll Cardiol. 1998; 31: 1217-25.
16. Rosenson, R S et al. Antiatherothrombotic Properties of Statins. JAMA. 1998; 279: 1643-1650.
17. Mendall, M A et al. C Reactive Protein and its Relation to Cardiovascular Risk Factors: A Population Based Cross Sectional Study. BMJ 1996; 312: 1061-1065.
18. O'Leary, DH et al. Carotid-Artery Intima and Media Thickness as a Risk Factor for Myocardial Infarction and Stroke in Older Adults. NEJM 1999; 340: 14-22.
19. Rumberger, JA et al. Electron Beam Computed Tomographic Coronary Calcium Scanning: A Review and Guidelines for use in Asymptomatic Persons. Mayo Clin Proc 1999; 74: 243-252. |
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