Lifestyle and obesity contribute mainly (if not entirely) through diet, diabetes, high blood pressure.

In dyslipidemia, subendothelial uptake and oxidation of LDL increases; oxidized lipids stimulate production of adhesion molecules and inflammatory cytokines and may be antigenic, inciting T cell-mediated immune response and inflammation in the arterial wall.   HDL protects against atherosclerosis via reverse cholesterol transport (see p. 1295); it may protect by transporting antioxidant enzymes, which can break down and neutralize oxidized lipids. 

The role of Hypertriglyceridemia is complex, and whether it has an effect independent of other lipid abnormalities is unclear. 

Hypertension may lead to vascular inflammation via angiotensin II-mediated mechanisms.  Angiotensin II stimulates endothelial cells, vascular smooth muscle cells, and macrophages to produce pro-atherogenic mediators, including proinflammatory cytokines, superoxide anions, pro-thrombotic factors; growth factors; and lectin-like oxidized LDL receptors.  It also promotes increasing rigidity through fibrinoid deposits and vessel wall necrosis, and thus increases peripheral resistance, which helps to sustain the hypertension. 

Diabetes leads to the formation of advanced gylcation end products, which increase the production of pro-inflammatory cytokines from endothelial cells.  Oxidative stress and reactive oxygen radicals, generated in diabetes.  They directly injure the endothelium and promote atherogensis.  Type 1 receptors, chemo-attractant proteins and adhesion molecules.     

Tobacco smoke contains nicotine and other chemicals that are toxic to vascular endothelium.  Smoking & passivbe smoking increases platelet reactivity (possibly pro9moting platelet thrombosis) and plasma fibrinogen levels and Hct (increasing blood viscosity).  Smoking increases LDL and decreases HDL; it also promotes vasoconstriction, which is particularly dangerous in arteries already narrowed by atherosclerosis.   

Lipoprotein(a) is a modified version of LDL that has a cysteine-rich region homologous with plsaminogen.  High levels may predispose to atherothrombosis, but the mechanism is unclear.

A high level of small, dense LDL, characteristic of diabetes, is highly atherogenic.  Mechanism may include increased susceptibility to oxidation and nonspecific endothelial binding (see p. 1296)

CRP (C-reactive protein) level does not reliably predict extent of atherosclerosis but can predict likelihood of ischemic events.  It may indicate increased risk of atherosclerotic plaque rupture, ongoing ulceration or thrombosis, or increased activity of lymphocytes and macrophages. CRP may have a direct role in artherogensis through multiple mechanisms, including down-regulation of nitric oxide

C. pneumoniae infection or other infections (eg, HIV, Helicobacter pylori) may cause endothelial dysfunction through direct infection, exposure to endotoxin, or stimulation of systemic or subendothelial inflammation. 

Renal insufficiency promotes development of atherosclerosis via several pathways including worsening hypertension and insulin resistance.

Pro-thrombotic states increase likelihood of atherothrombosis (see p. 1080 Merck).

Although arteries are not typically studied microscopically, two plaque types can be distinguished[1]:

1. The fibro-lipid (fibro-fatty) plaque is characterized by an accumulation of lipid-laden cells underneath the intima of the arteries, typically without narrowing the lumen due to compensatory expansion of the bounding muscular layer of the artery wall. Beneath the endothelium there is a "fibrous cap" covering the atheromatous "core" of the plaque. The core consists of lipid-laden cells (macrophages and smooth muscle cells) with elevated tissue cholesterol and cholesterol ester content, fibrin, proteoglycans, collagen, elastin, and cellular debris. In advanced plaques, the central core of the plaque usually contains extracellular cholesterol deposits (released from dead cells), which form areas of cholesterol crystals with empty, needle-like clefts. At the periphery of the plaque are younger "foamy" cells and capillaries. These plaques usually produce the most damage to the individual when they rupture.
2. The fibrous plaque is also localized under the intima, within the wall of the artery resulting in thickening and expansion of the wall and, sometimes, spotty localized narrowing of the lumen with some atrophy of the muscular layer. The fibrous plaque contains collagen fibers (eosinophilic), precipitates of calcium (hematoxylinophilic) and, rarely, lipid-laden cells.

In effect, the muscular portion of the artery wall forms small aneurysms just large enough to hold the atheroma.  Though the exterior of this aneurysm is strong, the vessel wall is often soft and fragile with little elasticity.  In addition as atherosclerosis progress it leads to a loss of elasticity and stiffening of the artery as a whole. 

Repeated plaque ruptures, ones not resulting in total lumen closure, combined with the clot patch over the rupture and healing response to stabilize the clot, is the process that produces most stenoses over time. The stenotic areas tend to become more stable, despite increased flow velocities at these narrowings. Most major blood-flow-stopping events occur at large plaques, which, prior to their rupture, produced very little if any stenosis.  From clinical trials, 20% is the average stenosis at plaques that subsequently rupture with resulting complete artery closure. Most severe clinical events do not occur at plaques that produce high-grade stenosis. From clinical trials, only 14% of heart attacks occur from artery closure at plaques producing a 75% or greater stenosis prior to the vessel closing.  [In other words, most stunts done preventively only manage angina]. The Merck:  “although imaging studies such as electron beam or multidector row (CT, MRI and ultrasoudn) can detect atherosclerotic plaque, they probably do not improve prediction of ischemic events over assessment of risk factors or established prediction tools (eg, Framingham risk index) and are not routinely recommended” at p 624.   

If the fibrous cap separating a soft atheroma from the bloodstream within the artery ruptures, tissue fragments are exposed and released, and blood enters the atheroma within the wall and sometimes results in a sudden expansion of the atheroma size. Tissue fragments are very clot-promoting.  The resulting formation of a thrombus (blood clot) overlying the atheroma, which osbstructs boold flow acutely.  This can result in agina, or myocardial infraction. 

Areas of severe narrowing, stenosis, detectable by angiography, and to a lesser extent "stress testing  have long been the focus of human diagnostic techniques for cardiovascular disease, in general. However, these methods focus on detecting only severe narrowing, not the underlying atherosclerosis disease. As demonstrated by human clinical studies, most severe events occur in locations with heavy plaque, yet little or no lumen narrowing present before debilitating events suddenly occur. Plaque rupture can lead to artery lumen occlusion within seconds to minutes, and potential permanent debility and sometimes sudden death.  Angiography misses most of the risk factor.  Other methods have been developed, such as (1) coronary calcium scoring by CT; (2) carotid IMT (intimal medium thickness) measurement by ultrasound; and (3) IVUS. 

Small decreases in fat intake do not appear to lessen or stablize atherosclerosis.  Effective change requires limiting fat intake to 20g/day, consisting of 6-10 g of polyunsaturated fat and less than 2 g of saturated fat.  Trans fatty acids, which are highly atherogenic, should be avoided.  Increasing carbohydrates in the diet to compensate reluts in increased triglyceride levels and seduces HDL levels.  Thus instead protein and unsaturated fats should should make up for caloric deficiency.  Alcohol increases HDL, has antioxidant, and anitinflammatory properties.  These effects appear to be the same for wine, beer, and hard liquor.  One oz 5 times a week protects against coronary atherosclerosis.  .  The rate is lowest for men who consumer >14 drinks per week, and women >9.  Other than fish oil dietary supplementation has not been shown to reduce risk.  Regular physical activity reduces incidence by reducing risk factors of diabetes, hypertension, dyslipidemia, and coronary artery disease. 

Oral antiplatelet drugs are essential because most complicatioins result from plaque fissure or rupture with platelet activation and thrombosis.  While low doses of aspirin are used, optimal dose and duration is not known, and for patients with poorly controlled risk factors, 325 mg is proven.  In 10-20 of patient taking asprin for secondary prevention, ischemic events recur.  The reason may be aspiring resistance.  Assays to detect lack of thromboxane suppression are being studied.  Some evidence suggests that ibupofen can interfere with aspirin’s antithrombotic effect, so other NSAIDs are recommended for patients taking aspirins for prevention.