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Risk Factors Athereosclerosis

Risk assessment



SOURCES:  2002 Conn’s Current Therapy, Goodman and Gilman 11th Edition (2006), Britannica 2002 Expanded Edition, Merck Manual 11th Edition (2006),,  Goodman and Gilman references are noted as G&G.


Risk factors:  age, family history, male sex, certain dyslipidemias (high LDL with low HDL), very high triglycerides, high levels of small, clumped LDL, certain chronic infections, tobacco smoking; diabetes mellitus, hypertension, C reactive proteins.


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.      

JK’s skepticism about statins:  Statins reduce mortality by about 25%; however, how much is the result of lowering VLDL and how much is the result of reducing thrombosis is not known.  Aspirin’s prevention of thrombosis reduces overall mortaility of between 22-32% from MI (4 mega studies).  The degree of usefullness of statins, other than psychological, is unclear.  Those who take statins already have life-threatening atherosclerosis.  Statins cannot reverse this condition, and there effect upon its progression is probably minimal.  Minimal because the plaque formation is mediated by a leucocyte mechanism in response to certain blood borne chemicals such as nicotine and carbon monoxide.  The association between elevated LDL and disease is probably one of acceleration rather than causal.  Mortality figures on intervention for fabric acidsMoreover, it is not the LDL, but rather the clumps of VLDL (a thing not measured except for research) that is more predictive of continued progression of atherosclorisis.  For these reasons, I would recommend 325 mg of aspirin, weight reduction, vigorus exercise, and a change in diet—in that order.   Statins should be reserved for those with very high levels of LDL.  The alternative fibric acids, exetimbe, bile-acid sequestrants, and nician are more natural interventions.  (Aspirin reduces major cancers over 20%)

This skepticism is supported by a series of Scandinavian studies (only one has shown evidence of atherosclerotic regression—slight). Wikipedia:  “Scandinavian Simvastatin Survival Study (4S) [16] with over 15 more extending through the more recent ASTEROID [17] trial published in 2006. The first primary prevention comparative treatment trial was AFCAPS/TexCAPS [18] with multiple later comparative statin/placebo treatment trials including EXCEL.[19], ASCOT [20] and SPARCL.[21] [22] While the statin trials have all been clearly favorable for improved human outcomes, only ASTEROID showed evidence of atherosclerotic regression (slight). For both human and animal trials, those which have shown evidence of disease regression had all utilized more aggressive combination agent treatment strategies, nearly always including niacin.”[6]

There is further skepticism about the role of diet.  People who do well over-report good diet, and those with corinary disease over-report bad diet—shopping for causal explanations.  Secondly most of the cholesterol is produced in the body.  As wikipedia notes:  “Dietary changes to achieve benefit have been more controversial, generally far less effective and less widely adhered to with success. One key reason for this is that most cholesterol, typically 80-90%, within the body is created and controlled by internal production by all cells in the body (true of all animals), with typically slighly greater relative production by hepatic/liver cells. (Cell structure relies on fat membranes to separate and organize intracellular water, proteins and nucleic acids and cholesterol is one of the components of all animal cell membranes.)  While the absolute production quantities vary with the individual, group averages for total human body content of cholesterol within the U.S. population commonly run about ~35,000 mg (assuming lean build; varies with body weight and build) and ~1,000 mg/day ongoing production. Dietary intake plays a smaller role, 200-300 mg/day being common values; for pure vegetarians, essentially 0 mg/day, but this typically does not change the situation very much because internal production increases to largely compensate for the reduced intake.

Both skepticism about diet and statins is supported by the role of tabacco.  A person who smokes at least pack a day is 2.09 (in one very well controlled study) more likely to die from a heart attack in any given year than a non-smoker.  The effect of second had smoke adds further crediance.  This has little to do with cholesterol and LDL and a lot to do with carbon monoxide and other reactive chemicals in tobacco smoke, and the mechanism by which the white blood cells repond to those chemical—initiating the plaque producing mechanism. Several studies published on the site are on point. and risk factor of tobacco;, COX-2 inhibitors and the mechanism for atherosclerosis.      


A number of bio-makers have been found to be associated with coronary artery disease.  The measure of calcium provides a way to measure the progression of coronary artery disease.  The article below looks into the association of coronary calcium with coronary disease. 


Journal of the American College of Cardiology, Vol. 31, Issue 6, May 1998, 1267-73


Calcium level in plaque measurement thereof is comparable to selective coronary angiography for risk of MI.


Complete article at


Measuring the Effect of Risk Factors on Coronary Atherosclerosis: Coronary Calcium Score Versus Angiographic Disease Severity

Axel Schmermund MDA, C, *, Dietrich Baumgart MDA, Günter Görge MDA, Dietrich Grönemeyer MDB, Rainer Seibel MDB, Kent R. Bailey PhDC, John A. Rumberger PhD, MD, FACCC, Dietrich Paar MDA and Raimund Erbel MD, FACCA

A Department of Cardiology and Department of Clinical Chemistry and Laboratory Diagnostics, University Clinic Essen, Essen, Germany;

B Department of Radiology and Microtherapy and Institute for Diagnostic and Interventional Radiology, University Witten/Herdecke, Mülheim an der Ruhr, Germany;

C Division of Cardiovascular Diseases and Internal Medicine and Section of Biostatistics, Mayo Clinic and Foundation, Rochester, Minnesota, USA.

21 October 1997;

revised 16 January 1998;

accepted 26 January 1998.

Available online 8 March 1999.



Objectives. This study sought to determine whether noninvasive quantification of coronary calcium is comparable to selective coronary angiography in measuring the effect of cardiovascular risk factors on coronary atherosclerosis.

Background. Electron beam computed tomography (EBCT) allows the delineation of anatomic coronary atherosclerotic disease and may be useful for noninvasively defining the role of established and new cardiovascular risk factors in selected patient groups.

Methods. A total of 211 consecutive patients, 26 to 79 years old, referred for evaluation of suspected or recently diagnosed coronary artery disease were examined. Selective coronary angiography was used to define five angiographic disease categories: normal coronary arteries, nonobstructive disease and one-, two- or three-vessel disease. EBCT was used to calculate coronary calcium scores, and cardiovascular risk, including lipid variables and fibrinogen levels, was assessed.

Results. Coronary calcium score and angiographic disease severity categories were largely predicted by identical risk factors (i.e., age, male gender, total/high density lipoprotein cholesterol ratio, fibrinogen) and, to a lesser degree, hypertension. Only smoking predicted angiographic disease severity but not calcium scores. The risk factors together explained a comparable proportion of the variability in angiographic disease categories and in calcium score quintiles (33% vs. 41%, p = 0.16 by bootstrap analysis). An overall risk score composed of these risk factors separated angiographic disease categories and calcium score quintiles with a similar area under the receiver operating characteristic curve ([mean ± SE] 0.81 ± 0.03 vs. 0.83 ± 0.03, p = NS).

Conclusions. Quantification of coronary calcium is comparable to selective coronary angiography in measuring the effect of established cardiovascular risk factors on coronary atherosclerosis. Thus, EBCT may be useful for the noninvasive evaluation of the relations between conventional or developing cardiovascular risk factors and coronary atherosclerosis



From the complete article: 

Coronary Calcium and atherosclerosis


Several mechanisms link arterial calcification to atherosclerosis.  Cholesterol and its oxidation products accelerate coronary calcification.  Smaller amounts of calcium have been shown to be present in noncomplex, lipid-rich fibromuscular plaques and in coronary lesions seen in young adults (type iii lesion).  More advanced type Vb/Vii plaques regularly contain calcium deposits.  Although calcium quantitites are best correlated with overall coronary plaque area, a positive correlation with stenosis severity is also seen, establishing the potential for noninvasive diagnosis or coronary stenosis.  In contrast, even severe stenosis are occasionally non-calcified as assessed by EBCT.  Coronary angiography very reliably detects flow-limiting stenoses.  Overall plaque burden may be underestimated because of mechanisms such as arterial remodeling, a diffuse distribution of atherosclerotic disease and eccentric lesion formation.  In this respect, sophisticated angiographic scoring methods seem to offer only limited incremental value. 


Smoking was independently associated with angiographic disease but not with coronary calcium score. Smoking is a risk factor for coronary arterial thrombosis irrespective of plaque morphology, and it may lead to clinical symptoms at earlier stages of coronary artery disease than in nonsmokers. Accordingly, smokers with a comparably low coronary plaque burden and little or no calcification may become symptomatic.


An interesting finding in our study group was the strong independent predictive value of fibrinogen levels with respect to both calcium scores and angiographic disease categories. It has been previously shown that elevated fibrinogen levels independently predict cardiovascular events.  Its role as an indicator of inflammation notwithstanding, elevated fibrinogen levels can be considered a major cardiovascular risk factor.


Recent reports have suggested that chronic infection with agents such as Chlamydia pneumoniae may play a role in vascular endothelial damage and atherogenesis.  Homocystein  concentrations have been associated with premature coronary artery disease and myocardial infraction. EBCT may allow noninvasive evaluation of the relation between conventional or developing cardiovascular risk factors and coronary atherosclerosis.


Those who have a financial interest in the outcome manipulate the results, Major study finds that all 37 journal articles positive effects over stated; the average was 32%. Statins cause erectile dysfunction, cognitive imparement, and cancer.  

Lipitor (2011) lifetime sales $131 billion, tops all drugs.  Plavix at $60 billion is second.



52% short term


LA Times, Health section, July 21, 2008  --  excerpts

Vytorin, the combination drug (simvastatin (better known by its commercial name Zocor) and ezetimibe--known as Zetia) prescribed to lower cholesterol, sustained another blow today, when the author of a major clinical trial announced that the medication had failed to drive down hospitalization and death due to heart failure in patients with narrowing of the aortic valve. In the process, researchers in Norway detected a significant blip in cancers in the 1,800 subjects they followed

Today's findings suggested something more ominous: the incidence of cancer -- and of dying of cancer -- was significantly higher in the patients taking Vytorin. Altogether, 67 patients on placebo developed cancer during the trial. Among subjects on Vytorin, 102 developed cancers of various kinds.*  This is the second adverse press—the first being in March 08, when the ENHANCE trial found that Vytorin fared no better than a placebo at reducing plaque buildup on the walls of patients' arteries.* *

Comments by jk

Simvastatin (Zocor) is off patent.  Thus in a scramble for profits a combination drug (on patent) was introduced.  Direct to consumer market cost $155 in 07—mainly TV ads. 

*  The pressing issue is that since the development  of Statins, the very first animal studies in the 60s it has been known that Statins increase the incidents of cancer.  However, nearly all studies done thereafter have not included cancer. 

*  Several studies have failed to find a reduction in the build of plaque, even thought the statins including Zocor, reduce LDL and cholesterol.  Few studies include the principle reason for taking a statin, namely a reduction in the death rate.  Claims for such reduction probably entail a failure to control the contravening variable, aspirin usage.  Given a pile of evidence, including the very mechanism of plaque formation, which involves inflammation process, I must conclude that the use of statins is highly suspect.  Given the harm done including cognitive impairment, weakness, and cancer, if my skepticism is born out, the harm done by statins as a course of treatment will far surpass that of VIOXX which killed over 200,000 people world wide by accelerating atherosclerosis.