section name header

Info


A. Pathology [1,54,63] navigator

  1. Deposits of cholesterol (Chol) in subendothelial region are major pathology [61]
    1. Deposits are called atherosclerotic plaques, or atheromata
    2. Plaques are most often found on outer edges of blood vessel bifurcations
    3. Inflamed endothelium is site for initial plaque deposition
    4. Intima with "fatty streaks" is probably site for initiation of plaque
  2. Composition of Plaques
    1. Low density lipoprotein (LDL), oxidized LDL, other lipids, and other components
    2. Lipid-laden macrophages (M_) called "foamy histiocytes" or foam cells
    3. Activated T lymphocytes infiltrate young lesions, cause inflammation
    4. Platelet products and fibrin, particularly in "young" plaques
    5. Fibroblasts and collagen found mainly in mature plaques
  3. Plaque Histology [75]
    1. Six types of plaques based on histology have been defined
    2. Type I - very early lesion with isolated M_ foam cells
    3. Type II - multiple foam cell layers
    4. Type III - isolated extracellular lipids
    5. Type IV - advanced lesion with confluent extracellular lipid pools ("atheroma")
    6. Type Va - advanced lesion with fibromuscular tissue layers and atheroma
    7. Type Vb - advanced lesions with calcificiations
    8. Type Vc - advanced lesions with fibrous tissue
    9. Type VI - complicated plaques with surface defects, hemorrhage, or thrombus deposition
  4. Mature Plaques
    1. More stable and show endothelial erosion (rather than rupture)
    2. Often asymptomatic, but contribute to large thrombus formation in ~25% of cases
    3. Gradual increase in size of plaques may lead to angina, claudication
    4. Presence of plaques in one part of body is risk for other parts
    5. Stable plaques are richer in M_, smooth muscle, lower in lipids, than unstable
    6. Gradual growth of plaques causing increasing stenosis can increase exertional angina, but rarely causes MI
  5. Early ("Young") Plaques [3]
    1. Plaque rupture is the most frequent cause of coronary thromboses (~65%)
    2. Endothelial cell erosion causes ~20% of coronary thromboses
    3. Younger plaques are unstable, predisposed to rupture compared with older, mature plaques
    4. These plaques which typically have dense cellular infiltrates
    5. Cells include M_ and high numbers of T lymphocytes
    6. Inflammatory components are prominant, with Th1 type cytokines (see below)
    7. Younger plaques also have fibrous cap of acellular lipid
    8. Early plaques also have high levels of tissue factor (TF), highly thrombogenic
    9. Plaque rupture exposes thrombogenic material: phospholipids, TF, platelet-adhesive matrix molecules
  6. Risks for Plaque Rupture [1,63,75]
    1. Plaques with large, eccentric lipid pools and foam cells are most likely to rupture
    2. These plaques tend to be younger, have thin fibrous caps and reduced collagen content
    3. High levels of tissue factor (TF) expression, which is very thrombogenic
    4. Chronic inflammation: IFNg expressing T cells, activated M_, mast cells
    5. Increased neovascularization
    6. Reduced density of smooth muscle cells
    7. Expression of cell adhesion molecules and leukocyte activation markers
    8. Matrix metalloproteinase expression
    9. Rupture prone plaques have plaque surface irregularities [62]
    10. Plaque surface irregularities have a 1.8X increased risk of MI than those with smooth plaques (in carotid arteries) [62]
    11. Presence of multiple complex coronary plaques on angiography associated with more severe MI and requirement for bypass surgery [70]
  7. Plaque Rupture and Thrombus Formation [75]
    1. Most plaques rupture at sites of mechanical stress: junction of plaque cap and intima
    2. Exposed ruptured surface forms nidis for platelet aggregation and clot formation
    3. Plaque rupture and clot formation contribute to about 75% of acute ischemic syndromes
    4. In addition, there is potential for downstream embolization of ruptured plaque material
    5. Plaque rupture associated with release of myeloperoxidase (MPO) [4]
  8. Plaque Composition and Restenosis [38]
    1. Large lipid core (>40%) had odds ratio 0.4 of developing >50% restenosis versus <10% lipid
    2. Marked M_ infiltration had odds ratio of 0.43 of developing >50% restenosis compared with minor macrophage infiltration

B. Pathophysiology of Atheromata [60] navigator

  1. Role of Endothelium
    1. Endothelial inflammation and damage from various causes is central to atherosclerosis
    2. LDL, particularly oxidized form, is toxic to endothelial cells, likely carried by Lp(a) [5]
    3. Lp(a), a form of LDL with plasminogen homology, competes for plasminogen receptors on endothelium and leads to a prothrombotic state
    4. Triglycerides and other fats also have acute effects on endothelium
    5. Hypertriglyceridemia and low HDL much more common in patients with atherosclerosis than are elevations in total and LDL chol [84]
    6. All of these lipids cause chronic irritation and inflammation of blood vessel wall
    7. Superoxide and other toxic oxygen metabolites also damage endothelium
    8. Endothelial cells which overly plaques do not function normally
    9. Smoking impairs endothelial dilation and probably damages endothelium [48]
    10. Hyperglycemia and insulin resistance cause marked endothelial dysfunction [15]
    11. Oxidized phospholipids are an independent risk coronary artery disase (CAD) factor, particularly in age <60 years [5]
  2. Endothelium and Shear Stress [61]
    1. Shear stress is caused by friction due to blood flow across vessel wall
    2. Stress is proportional to blood viscosity and the flow rate parallel to the wall
    3. Stress is inversely proportional to the third power of the vessel internal radius
    4. Shear stress is thought to play a major role in controlling plaque formation
    5. Shear (laminar) stress inhibits plaque formation (stimulates nitric oxide)
    6. Reduction in shear stress (including turbulent flow) stimulates plaque formation
    7. Slow blood flow stimulates endothelial proliferation, adhesion molecules, vasoconstrictors
    8. Slow blood flow also leads to reduced anti-oxidants (reduced superoxide dismutase)
  3. Response to Endothelial Damage: Inflammation
    1. Endothelial damage and inflammation stimulates repair mechanisms
    2. Both M_ and T cells are recruited
  4. Macrophages (M_) [69]
    1. Damaged vascular intima secretes macrophage colony stimulating factor (M-CSF)
    2. Recruited to the area to aide in healing the damage [46]
    3. The M_ often express activation markers and secrete cytokines
    4. M_ express scavenger receptors, which take up oxidized LDL
    5. M_ uptake of oxidized LDL is not regulated
    6. This is in contrast to uptake of normal LDL by M_ LDL receptor (regulated)
    7. Foam cells are M_ engourged with oxidized LDL
    8. Antioxidant vitamins may inhibit LDL oxidation
  5. T Lymphocytes
    1. Recruited in early lesions, and appear to stimulate M_ activation
    2. CD4+ helper T cells respond to oxidized LDL and produce "Th1" cytokines
    3. Interferon gamma (IFNg) is increased, and further activates M_
    4. Specific infectious agents have been implicated in promoting plaques, but no good data
  6. Factors which increase plaque growth also exacerbate endothelial damage
    1. Hypertension (HTN)
    2. High total Chol and low HDL Chol
    3. Diabetes mellitus
    4. Smoking - primary and second hand smoke
    5. Smoking, HTN, diabetes synergistically accellerate atherosclerosis
    6. Subclinical hypothyroidism is a ~2X risk factor for atherosclerosis in women >60 [66]
    7. Overt, chronic hypothyroidism is a known risk factor for atherosclerosis
    8. Turbulent blood flow (or lack of laminar flow)
    9. Low serum folate levels may increase vascular events (likely high homocysteine)
    10. Elevated homocysteine levels are associated with increased atherogenesis [45]
    11. Vessel damage - angioplasty, stenting
    12. Various infectious agents such as chlamydia (and CMV) have been implicated in plaques
    13. Inflammatory mediators (cytokines, chemokines) active in plaque development [13,46]
    14. Elevated serum C-reactive protein (CRP) levels are a risk factor for CAD and death [39,67,90]
    15. Angiotensin II stimulates IL6 and PAK-1 production by endothelium
    16. Statins reduce CRP levels and risk of acute cardiac events even with normal lipids [82]
    17. Diabetics with known CAD have increased levels of serum inflammation markers [68]
    18. Inflammatory T cells with Th1 cytokines are often found [2,46]
    19. Renal failure (CRF) increases CRP, homocysteine, LDL, Lp(a), HTN, fibrinogen; worsens vasodilatory function, and reduces ApoA1 levels [12,77]
    20. Cocaine induces damage to endothelium alone and is synergistic with smoking [83]
  7. Factors which reduce plaque growth lead to endothelial cell stimulation
    1. Treatment with HMG-CoA reductase inhibitors (even if normal Chol) [40]
    2. HMG-CoA reductase inhibitors indicated for primary and secondary prevention [14]
    3. Elevated HDL or ApoA1 Levels
    4. Anti-inflammatory agents - increasing evidence for efficacy of aspirin
    5. Nitric oxide production by endothelial cells inhibits plaque growth
    6. Estrogen replacement (ERT) increases nitric oxide and reduces endothelin action [16]
    7. Vitamin E may inhibit plaque growth as well
    8. Folate, Vit B6 and B12 reduce homocysteine levels and atherosclerosis (see below) [64]
    9. High intake of omega-3 fatty acids (fish oil) modestly slows plaque progression [47]
    10. Omega-3 fatty acids incorporate into plaques, reduce inflammation, promote stability [96]
    11. High fish oil intake associated with increased arrhythmias in patients with implantable cardioverter defibrillators [9]

C. Lipids and Cholesterol (Chol) [2,54,60]
[Figure] "Cholesterol Transport" navigator

  1. LDL Chol are a major predisposing factor to atherosclerosis
  2. Oxidized LDL is the major pathologic entity [76]
    1. Small LDL (B) particles are more susceptible to oxidation and atherogenesis
    2. Intermediate density lipoproteins (IDL) are precursors of LDL B and are easily oxidized
    3. LDL B are more likely to deposit in subendothelial space than other lipids
    4. These particles are easily oxidized, particularly in anti-oxidant poor subendothelial area
    5. Oxidation and inflammation can stimulate formation of "fatty streaks"
    6. Oxidized LDL binds to scavenger receptor on M_, stimulates foam cell formation
    7. Oxidized phospholipids likely carried by Lp(a) in serum [5]
  3. Subendothelial Deposition of LDL B
    1. Impairs endothelial dependent vasodilation
    2. Inhibits nitric oxide synthetase activaty (increases membrane inhibitor caveolin)
    3. Induces apoptosis in human endothelial cells
    4. Stimulates an inflammatory response
    5. Increases expression of adhesion molecules on endothelium
    6. Modifies response of vascular smooth muscle cells
    7. Increases thrombogenicity of platelets
    8. ERT has no effect on progression of atherosclerosis in women [99]
  4. Lp(a) - Lipoprotein(a) [5,25]
    1. Similar to LDL, but with Apo(a) (apoplipoprotein a) covalently linked to LDL particle
    2. Contains homology to plasminogen which binds endothelium and is prothrombotic
    3. Lp(a) elevation is a 1.5X risk factor for MI in middle aged men [74]
    4. Lp(a) elevation associated with 2-3X increased stroke, vascular death, all cause death [29]
    5. Likely carries oxidized phospholipids, elevated with vascular inflammation
  5. Trans Fatty Acids (TFA) [8]
    1. Appear to be most atherogenic of all dietary lipids
    2. Ingestion of TFA increases LDL and VLDL and reduces HDL
    3. Also stimulates vascular inflammation, endothelial dysfunction
    4. Strongly associated with atherogenesis
    5. Commonly found in fast foods due to margerine, vegetable shortening, hydrogenation
    6. Dietary TFA should be reduced to <1% of daily energy intake
    7. Estimated that reduced TFA could reduce cardiovascular events by 6-19%
  6. Other Atherogenic Lipids
    1. Chylomicron remnants
    2. Very Low Density lipoprotein (VLDL) remnants
    3. IDL
    4. LDL - includes LDL A, LDL B (highly atherogenic)
    5. Triglycerides and VLDL appear to have direct endothelial toxic effects [6]
  7. Anti-Atherogenic Lipids
    1. High Density Lipoproteins (HDL) subclasses (HDL2 and 3)
    2. HDL carries chol away from arterial wall back to liver
    3. Raising HDL reduces progression of cardiovascular disease, prevents cardiac events [104]
    4. Torcetrapib, which raises HDL levels ~63% by inhibiting CTEP, has no effect on carotid or intracoronary atheromata thickness [34,35]
  8. Insulin and Lipid Markers
    1. Fasting mature insulin level elevation often occurs with elevated lipids
    2. Fasting insulin levels also found with increased Apolipoprotein B and small LDL levels
    3. Elevations in these three risk factors increases risk of ischemic heart diseases ~18 fold
    4. These markers appear more biologically relevant molecules than standard lipid tests
    5. Insulin elevations may be compensatory for abnormal lipid metabolism
  9. Low fat diets improve endothelial function in hypercholesterolemic men [81]
  10. Statins reduce plaque growth [41], CV events [14,40,103] and mortality [91]

D. Vascular Inflammation [1,46] navigator

  1. Vascular Inflammation and CRP [3,13,37,68]
    1. Systemic inflammation correlates with ~2 fold increased risk of CAD
    2. High sensitivity CRP detection likely best inflammation marker
    3. Normal CRP levels <1mg/L, moderate risk 1-3mg/L, high risk 3-10mg/L
    4. High CRP (>3mg/dL) has 1.5-2.3X increased risk independent of Chol [67]
    5. CRP polymorphisms associated with elevated CRP levels and atherosclerosis [7]
    6. CRP, induced mainly by IL6 and made by liver, is pro-inflammatory and atherogenic [37]
    7. CRP reduces survival differentiation and function of endothelial progenitors [11]
    8. CRP and total chol to HDL ratio are most important independent risks [80]
    9. Elevated serum IL6 levels [86] stimulate CRP production [94]
    10. Troponin C and C-Reactive Protein levels are prognostic for death within 3 years after an acute coronary syndrome (ACS) [72]
    11. CRP levels >10mg/L are associated with acute inflammatory disease
    12. Aggressive statin therapy reduces chol and CRP and causes plaque regression [18,19,41]
    13. Higher levels of D-dimer, SAA, and CRP associated with 1.2X higher all cause mortality at up to 2 years after measurement in patients with lower extremity PAD [21]
    14. These markers also predicted cardiovascular mortality within 2 years of measurement [21]
  2. Other Marker of Systemic Inflammation [1]
    1. Elevated fibrinogen, Factor VII, Factor VIII, von Willebrand activity, soluble CD40 ligand
    2. Fibrinogen levels associated with increased risk for ACS, but not independently [72]
    3. Oxidized LDL stimulate local vascular inflammation
    4. Elevated MPO levels [4,87,92]
    5. Inflammation with elevated neutrophil or plasma MPO found in MI [4], unstable angina [92]
    6. Activated M_ stimulate local inflammation, promote plaque progression, correlate with lesion appearance on angiography [98]
    7. IL-6 levels are prognostic for recurrent ACS, independent of CRP and other markers
    8. Lipoprotein associated phospholipase A2 (LP-PLA2) levels associated with MI risk [73]
    9. Toll-like receptor 4 (TLR4) activation stimulates IL6 and other cytokine production
    10. TRL4 down-regulating polymorphism Asp299Gly associated with reduced atherosclerosis [93]
    11. Systemic lupus (SLE) associated with >4X increased risk of atherosclerosis [73,74]
    12. SLE with accelerated coronary calcification, hypertriglyceridemia, homocysteine [101]
    13. Reduced red cell glutathione peroxidase (GPO) predicts long term CAD events [6]
  3. Cell Adhesion Molecules (CAMs) and Atherogenesis [52]
    1. Vascular inflammation leads to expression of CAMs
    2. CAMs are key molecules in endothelial inflammation and repair of endothelial damage
    3. Damaged endothelium is induced to express various CAMs
    4. CAM expression permits leukocyte adhesion and transudation
    5. CRP induces ICAM-1 expression and M_ activation [37]
    6. In addition, denuded enthelium exposes extracellular matrix (ECM) proteins
    7. Activated lymphocytes and other leukocytes can bind to exposed ECM
    8. L- and P-selectin (carbohydrate binding proteins) involved in capture and tethering
    9. E-selectin involved in rolling; firm adhesion by integrins and ICAM, VCAM
    10. Intercellular CAM (ICAM) and platelet endothelial CAM (PECAM) for transmigration
    11. Soluble adhesion molecules (ICAM, VCAM, P- and E-selectins) levels do not provide risk information beyond CRP and standard risk factors [85]

E. Homocysteine (HC) [17,45,53,55] navigator

  1. HC is an amino acid derived from methionine
  2. Risks of Elevated HC [55,56]
    [Figure] "Plasma HC and Mortality"
    1. Associated with 2X increased vascular disease risk [50,56]
    2. Plasma HC levels correlate well with cardiovascular disease and mortality [50,56,65]
    3. Also a risk factor for fatal and nonfatal cerebral events, peripheral vascular disease, venous thromboembolic disease, as well as Alzheimer's Disease [89]
    4. Increased risk for diabetic retinopathy and nephropathy
    5. Increased risk for stroke (1.4-2.0 fold) in elderly persons [59]
  3. Causes of Elevated HC
    1. HC Metabolic Enzyme deficiencies
    2. Deficiencies in folic acid, Vitamin B6 or Vitamin B12
    3. Smoking
    4. Renal Dysfunction [77]
    5. Psoriasis (severe)
    6. Systemic Lupus Erythematosus
    7. Solid organ transplantation
    8. Malignant Neoplasm
    9. Hypothyroidism [58]
    10. Malignant neoplasms
    11. Drugs: methotrexate, nicotinic acid, phenytoin, carbamazepine, thiazide diuretics
    12. Reduced physical activity and increasing age also associated with elevated HC
  4. Reduction in Plasma HC Levels [22]
    1. Vitamins B6 + B12 + folate reduce HC levels
    2. Supplemental folate + vitamin B6 improves exercise electrocardiography in patients at high risk for CAD [64]
    3. Randomized, prospective trials of HC reduction with vitamins have shown no benefit in primary reduction in clinical events or mortality [23,24,33,55]
    4. Vitamin supplements to reduce HC are not recommended at this time [22,33]

F. Diabetes Mellitus [15,68] navigator

  1. Hyperglycemia increases platelet (and monocyte) adhesiveness and aggregation
  2. Hyperglycemia increases platelet generation of vasoconstrictors
  3. Reduces platelet generation of prostacyclin
  4. Increases plasma levels of VLDL, LDL, and Lp(a); reduces HDL
  5. Increases plasma triglycerides, lipoprotein oxidation and glycation
  6. Reduces lipoprotein lipase activity
  7. Increases fibrinogen and plasminogen activator inhibitor 1 levels
  8. Increases AT-III, protein C and S levels
  9. Decreases nitric oxide production and responsiveness
  10. Increases endothelin-1 release
  11. Diminishes prostacyclin release
  12. Increases adhesion molecule expression (platelet and monocyte)
  13. Increases endothelial cell procoagulant activity
  14. Associated with elevated systemic levels of inflammatory and procoagulant proteins [68]
  15. Diabetes effects exacerbated in patients with renal failure [77]

G. Sudden Cardiac Death (SCD) navigator

  1. Atherogenesis is associated with SCD
    1. Acute ischemia imposed on susceptible tissue is probable underlying mechanism
    2. Both partial and total coronary occlusions are associated with SCD
  2. Dyslipidemias are all associated with systemic inflammation
    1. Platelet activation, leucocytosis are common
    2. TNF alpha, IL-1, IL-6 and IL-8 are expressed
    3. Fibrinogen, plasminogen activator inhibitor (PAI) and Factor VII increased
    4. Proinflammatory and prothrombotic factors exert pro-arrhythmic effects
  3. Pathophysiology
    1. Peroxisome proliferator activated receptor (PPAR) alpha pathway upregulated by lipids
    2. Platelet activating factor (PAF) may be released in response to oxidized-LDL
    3. In addition, hepatocytes and M_ exposed to high Chol greatly increase their synthesis of of choline phospholipids
  4. Suggested Pathways for Suppressing SCD [27]
    1. Likely that agents which reduce harmful lipids and/or inflammation will reduce SCD
    2. Reduction in Chol with HMG-CoA Reductase Inhibitors (statins)
    3. ß-adrenergic blockers clearly reduce risk of SCD post-MI (and reduce plaque) [10]
    4. ACE inhibitors may reduce the risk of SCD
    5. PPAR alpha modulators such as leukotriene antagonists
    6. Cyclooxygenase (prostaglandin synthetase) inhibitors such as aspirin
    7. PAF-receptor antagonists
    8. Cytokine antagonists - note that glucocorticoids can suppress plaque formation

H. Genetic Atherosclerotic Predisposition navigator

  1. Genetic polymorphisms may contribute to premature atherosclerosis
  2. However, genetic risk factors have not been shown to be independent for ACS risk [20]
  3. Polymorphisms in Chol Regulatory Proteins and Atherosclerosis
    1. LDL Receptor Polymorphisms
    2. Chol Ester Transport Protein (CETP) [28]
    3. Hepatic lipase and other factors may play a role in controlling HDL levels
  4. 5-lipoxygenase (5-LO) promoter (regulates inflammation) polymorphism associated with atherosclerosis [102]
  5. Mutations in HC metabolizing enzymes leading to hyperhomocysteinemia (see above)
  6. Other genes such as Factor VII play a role in thrombus formation, possibly atheromata
  7. Hereditary Cerebral Arteriopathy (CADASIL) [30]
    1. Cerebral autosomal dominant arteriopathy, subcortical infarcts, leukoencephalopathy
    2. Mutations in the Notch3 gene (chr 19), codes large transmembrane receptor
    3. Typically presents as early onset (mean 45 years) dementia with lacunar infarcts
    4. MRI changes precede symptoms
    5. Other symptoms include migraine, transient ischemic attacks, mood changes, dementia

I. Assessment of Atherosclerosis navigator
J. Treatment of Atherosclerotic Disease navigator

  1. Acute therapies focus on revascularization
    1. Angioplasty
    2. Bypass surgery
  2. Subacute Therapies in Development
    1. A variety of vascular growth factors can stimulate collateral blood vessel formation
    2. VEGF, FGF, and others are in human trials for atherosclerotic diseases
    3. Local gene therapy implants can provide geographically appropriate vascular stimuli
  3. Chronic Therapies
    1. Focus on prevention of plaque rupture
    2. Reduction of LDL levels and LDL oxidation
    3. Inhibition of thrombus formation
    4. Inhibition of inflammatory cytokine expression
  4. Cholesterol Lowering Agents
    1. The statins (see below) are clearly the most effective and best tolerated
    2. Statins reduce Chol, atherogenesis, atheroma, acute thromboembolic events [14,31,41]
    3. Reduction of Chol to <120mg/dL with statins causes regression of plaques [31,44]
    4. Reduction of LDL Chol to ~60mg/dL with high dose rosuvastatin (Crestor®) leads to significant reduction in coronary [26] and carotid [41] atherosclerosis at 2 years
    5. Statins have additional anti-inflammatory properties and prevent acute vascular events [95]
    6. Niacin, especially as slow release, is fairly well tolerated and effective as well
    7. Other older agents are generally not recommended
  5. Antiplatelet Agents
    1. Aspirin clearly reduces the risk of atherosclerotic cardiac disease
    2. Clopidigrel reduces risk of recurrent stroke
    3. Anti-gpIIb/IIIa inhibitors reduce risk of acute thromboembolic events
  6. Angiotensin Converting Enzyme Inhibitors (ACE-I)
    1. Indicated for all patients with HTN and CHF, diabetes, renal disease, unless contraindicated
    2. Reduce serious vascular events in patients with atherosclerosis and normal systolic function [106]
  7. ß-adrenergic receptor blockers reduce progression and cause regression of plaque [10]
  8. Recombinant ApoA-I Milano [100]
    1. ApoA-I Milano -phospholipid complex ETC-216
    2. These complexes rapidly mobilize cholesterol and thereby can reduce plaque burden
    3. Five doses given once weekly intravenously to patients recovering from ACS
    4. Significantly reduced atheroma volume at week 6 compared with placebo
  9. An acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitor did not block progression of coronary atherosclerosis over 18 months [105]
  10. Omega-3 fatty acids reduce inflammation and promote plaque stability [96]
  11. ERT does not provide any overall cardiovascular benefit [36,42]

References navigator

  1. Hansson GK. 2005. NEJM. 352(16):1685 abstract
  2. Corti R, Farkouh ME, Badimon JJ. 2002. Am J Med. 113(8):668 abstract
  3. Forrester JS. 2002. Ann Intern Med. 137(10):823 abstract
  4. Brennan ML, Penn MS, Van Lente F, et al. 2003. NEJM. 349(17):1595 abstract
  5. Tsimikas S, Brilakis ES, Miller ER, et al. 2005. NEJM. 353(1):46 abstract
  6. Blankenberg S, Rupprecht HJ, Bickel C, et al. 2003. NEJM. 349(17):1605 abstract
  7. Lange LA, Carlson CS, Hindorff LA, et al. 2006. JAMA. 296(22):2703 abstract
  8. Mozaffarian D, Katan MB, Ascherio A, et al. 2006. NEJM. 354(15):1601 abstract
  9. Rait MH, Connor WE, Morris C, et al. 2005. JAMA. 293(23):2884
  10. Sipahi I, Tuzcu EM, Wolski KE, et al. 2007. Ann Intern Med. 147(1):10 abstract
  11. Sjoholm A and Nystrom T. 2005. Lancet. 365(9459):610 abstract
  12. Muntner P, Hamm LL, Kusek JW, et al. 2004. Ann Intern Med. 140(1):9 abstract
  13. Danesh J, Collins R, Appleby P, Peto R. 1998. JAMA. 279(18):1477 abstract
  14. Downs JR, Clearfield M, Weis S, et al. 1998. JAMA. 279(20):1615 abstract
  15. Hurst RT and Lee RW. 2003. Ann Intern Med. 139(10):824 abstract
  16. Best PJM, Berger PB, Miller VM, Lerman A. 1998. Ann Intern Med. 128(4):285 abstract
  17. Mangoni AA and Jackson SHD. 2002. Am J Med. 112(7):556 abstract
  18. Ridker PM, Cannon CP, Morrow D, et al. 2005. NEJM. 352(1):20 abstract
  19. Nissen SE, Tuzcu EM, Schoenhagen P, et al. 2005. NEJM. 352(1):29 abstract
  20. Morgan TM, Krumholz HM, Lifton RP, Spertus JA. 2007. JAMA. 297(14):1551 abstract
  21. Vidula H, Tian L, Liu K, et al. 2008. Ann Intern Med. 148(2):85 abstract
  22. Loscalzo J. 2006. NEJM. 354(15):1629 abstract
  23. HOPE-2 Investigators. 2006. NEJM. 354(15):1567 abstract
  24. Bonaa KH, Njolstad I, Ueland PM, et al. 2006. NEJM. 354(15):1578 abstract
  25. Scanu AM. 2003. NEJM. 2003. 349(22):2089 abstract
  26. Nissen SE, Nicholls SJ, Spiahi I, et al. 2006. JAMA. 295(13):1556 abstract
  27. Henry PD and Pacifico A. 1998. Lancet. 351(9111):1276 abstract
  28. Kuivenhoven JA, Jukema JW, Zwinderman AH, et al. 1998. NEJM. 338(2):86 abstract
  29. Ariyo AA, Thach C, Tracy R. 2003. NEJM. 349(22):2108 abstract
  30. Joutel A, Vahedi K, Corpechot C, et al. 1997. Lancet. 350(9090):1511 abstract
  31. Nicholls SJ, Tuzcu EM, Sipahi I, et al 2007. JAMA. 297(5):499 abstract
  32. Hodis HN, Mack WJ, LaBree L, et al. 1998. Ann Intern Med. 128(4):262 abstract
  33. Bazzano LA, Reynolds L, Holder KN, He J. 2006. JAMA. 296(22):2720 abstract
  34. Nissen SE, Tardif JC, Nicholls SJ, et al. 2007. NEJM. 356(13):1304 abstract
  35. Bots ML, Visseren FL, Evans GW, et al. 2007. Lancet. 370(9582):153 abstract
  36. Waters DD, Alderman EL, Hsia J, et al. 2002. JAMA. 288(19):2432 abstract
  37. Labarrere CA and Zaloga GP. 2004. Am J Med. 117(7):499 abstract
  38. Hellings WE, Moll FL, De Vries JP, et al. 2008. JAMA. 299(5):547 abstract
  39. Pai JK, Pischon T, Ma J, et al. 2004. NEJM. 351(25):2599 abstract
  40. Lewis SJ, Moye LA, Sacks FM, et al. 1998. Ann Intern Med. 129(9):681 abstract
  41. Crouse JR III, Raichlen JS, Riley WA, et al. 2007. JAMA. 297(12):1344 abstract
  42. Manson JE, Hsia J, Johnson KC, et al. 2003. NEJM. 349(6):523 abstract
  43. Achenbach S, Moshage W, Ropers D, et al. 1998. NEJM. 339(27):1964 abstract
  44. Callister TQ, Raggi P, Cooil B, et al. 1998. NEJM. 339(27):1973
  45. Bots ML, Launer LJ, Lindemans J, et al. 1999. Arch Intern Med. 159(1):38 abstract
  46. Ross R. 1999. NEJM. 340(2):115 abstract
  47. von Schacky C, Angerer P, Kothny W, et al. 1999. Ann Intern Med. 130(7):554 abstract
  48. Raitakari OT, Adams MR, McCredie RJ, et al. 1999. Ann Intern Med. 130(7):578 abstract
  49. Levine M, Rumsey SC, Daruwala R, et al. 1999. JAMA. 281(15):1415 abstract
  50. Ridker PM, Manson JE, Buring JE, et al. 1999. JAMA. 281(19):1817 abstract
  51. Nappo F, De Rosa N, Marfella R, et al. 1999. JAMA. 281(22):2113 abstract
  52. Price DT and Loscalzo J. 1999. Am J Med. 107(1):85 abstract
  53. Hankey GJ and Eikelboom JW. 1999. Lancet. 354(9176):407 abstract
  54. Knopp RH. 1999. NEJM. 341(7):498 abstract
  55. Eikelboom JW, Lonn E, Genest J Jr, et al. 1999. Ann Intern Med. 131(5):363 abstract
  56. Kark JD, Selhub J, Adler B, et al. 1999. Ann Intern Med. 131(5):321 abstract
  57. Selhub J, Jacques PF, Rosenberg IH, et al. 1999. Ann Intern Med. 131(5):331 abstract
  58. Hussein WI, Green R, Jacobsen DW, Faiman C. 1999. Ann Intern Med. 131(5):348 abstract
  59. Bostom AG, Rosenberg IH, Silbershatz H, et al. 1999. Ann Intern Med. 131(5):352 abstract
  60. Vogel RA. 1999. Am J Med. 107(5):479 abstract
  61. Malek AM, Alper SL, Izumo S. 1999. JAMA. 282(21):2035 abstract
  62. Rothwell PM, Villagra R, Gibson R, et al. 2000. Lancet. 355(9197):19 abstract
  63. Yeghiazarians Y, Braunstein JB, Askari A, Stone PH. 2000. NEJM. 342(2):101 abstract
  64. Vermeulen EGJ, Stehouwer CDA, Twisk JWR, et al. 2000. Lancet. 355(9203):517
  65. Chambers JC, Obeid OA, Refsum H, et al. 2000. Lancet. 355(9203):523 abstract
  66. Hak AE, Pols HAP, Visser TJ, et al. 2000. Ann Intern Med. 132(4):270 abstract
  67. Ridker PM, Hennekens CH, Buring JE, Rifai N. 2000. NEJM. 342(12):836 abstract
  68. Saito I, Folsom AR, Brancati FL, et al. 2000. Ann Intern Med. 133(2):81 abstract
  69. Babior BM. 2000. Am J Med. 109(1):33 abstract
  70. Goldstein JA, Demetriou D, Grines CL, et al. 2000. NEJM. 343(13):915 abstract
  71. Rader DJ. 2000. NEJM. 343(16):1179 (Editorial) abstract
  72. Lindahl B, Toss H, Siegbahn A, et al. 2000. NEJM. 343(16):1139 abstract
  73. Roman MJ, Shanker BA, Davis A, et al. 2003. NEJM. 349(25):2399 abstract
  74. Seed M, Ayres KL, Humphries SE, Miller GJ. 2001. Am J Med. 110(1):22 abstract
  75. Rauch U, Osende JI, Fuster V, et al. 2001. Ann Intern Med. 134(3):224 abstract
  76. Tribble DL, Rizzo M, Chait A, et al. 2001. Am J Med. 110(2):103 abstract
  77. Kennedy R, Case C, Fathi R, et al. 2001. Am J Med. 110(3):198 abstract
  78. Navas-Nacher EL, Colangelo L, Beam C, Greenland P. 2001. Ann Intern Med. 134(6):433 abstract
  79. Ruehm SG, Goyen M, Barkhausen J, et al. 2001. Lancet. 357(9262):1086 abstract
  80. Ridker PM, Stampfer MJ, Rifai N. 2001. JAMA. 285(19):2481 abstract
  81. Fuentes F, Lopez-Miranda J, Sanchez E, et al. 2001. Ann Intern Med. 134(12):1115 abstract
  82. Ridker PM, Rifai N, Clearfield M, et al. 2001. NEJM. 344(26):1959 abstract
  83. Lange RA and Hillis LD. 2001. NEJM. 345(5):351 abstract
  84. Sniderman AD, Scantlebury T, Cianflone K. 2001. Ann Intern Med. 135(6):447 abstract
  85. Malik I, Danesh J, Whincup P, et al. 2001. Lancet. 2001. 358(9286):971 abstract
  86. Lindmark E, Diderholm E, Wallentin L, Stiegbahn A. 2001. JAMA. 286(17):2107 abstract
  87. Zhang R, Brennan ML, Fu X, et al. 2001. JAMA. 286(17):2136 abstract
  88. Halkin A and Keren G. 2002. Am J Med. 112(2):126 abstract
  89. Seshadri S, Beiser A, Selhub J, et al. 2002. NEJM. 346(7):476 abstract
  90. Rifai N, Buring JE, Lee IM, et al. 2002. Ann Intern Med. 136(7):529 abstract
  91. LIPID Study Group. 2002. Lancet. 359(9315):1379 abstract
  92. Buffon A, Biasucci LM, Liuzzo G, et al. 2002. NEJM. 347(1):5 abstract
  93. Kiechl S, Lorenz E, Reindl M, et al. 2002. NEJM. 347(3):185 abstract
  94. Pradhan AD, Manson JE, Rossouw JE, et al. 2002. JAMA. 288(8):981
  95. Shepherd J, Blauw GJ, Murphy MB, et al. 2002. Lancet. 360(9346):1623 abstract
  96. Thies F, Garry JMC, Yaqoob P, et al. 2003. Lancet. 361(9356):477 abstract
  97. Prandoni P, Bilora F, Marchiori A, et al. 2003. NEJM. 348(15):1425
  98. Meuwissen M, van der Wal AC, Koch KT, et al. 2003. Am J Med. 114(7):521 abstract
  99. Hodis HN, Mack WJ, Azen SP, et al. 2003. NEJM. 349(6):535 abstract
  100. Nissen SE, Tsunoda T, Tuzcu EM, et al. 2003. JAMA. 290(17):2292 abstract
  101. Asanuma Y, Oeser A, Shintani AK, et al. 2003. NEJM. 349(25):2407 abstract
  102. Dwyer JH, Allayee H, Dwyer KM, et al. 2004. 350(1):29 abstract
  103. Nissen SE, Tuzcu EM, Schoenhagen P, et al. 2004. JAMA. 291(9):1071 abstract
  104. Whitney EJ, Krasuski RA, Personius BE, et al. 2005. Ann Intern Med. 142(2):95 abstract
  105. Nissen SE, Tuzcu EM, Brewer HB, et al. 2006. NEJM. 354(12):1253 abstract
  106. Dagenais GR, Pogue J, Fox K, et al. 2006. Lancet. 368(9535):581 abstract