Home | 2-PAGE SUMMATION ON STATINS | Understanding Atherosclerosis & its MI Link--jk | understanding heart attack | lipids, lipoproteins, the basics | ABOUT Cholesterol | Tables of Risk Factors plus STATS | Niacin prevents MI 25% | Statins, inflammation & atherogenesis--their failure | inflammation, obesity and atherosclerosis | Risk Factors Athereosclerosis | High Cholesterol and treatments | STATINS, lowering cholesterol doesn't prolong life | MMP role in atherogenesis and statins | COX-2 Suppression and statins | High HDL not Prophylactic | Other Markers for Cardiovascular Disease | $70,000 standard heart treatment per year following a MI | Why improving cholesterol profile with statins has little effect | Statins side effects | Statins over prescribed | Recommendation for your heart | New Major Study Pans Statins | STATIN COMBO STUDY, NO BENEFITS | C-Reactive Protein and Statins | Ozone & cholesterol combine to cause heart disease | Calcium score and coronary disease--a review | Serious cognitive impairment from bypass operation, Scientific American | ARRHYTHMIA, sudden early death and prevention for relatives | STEM CELLS GROW HEART MUSCLE | BYPASS & STENTS over sold
Calcium score and coronary disease--a review

The value of calcium score, a measure of coronary artery disease, is discussed below in a careful review by the American Heart Association.  The relationship between score and prognosis is modest, and a high score is used as a way to push drugs whose life extending effects are minimal.  We have taken a skeptical view of the use of statins, and will be publishing articles exposing the fact that in most cases a stent and bypass surgery are grossly oversold--jk.  


Early detection is critical in order to implement early lifestyle changes and early therapies to prevent major adverse coronary events. The most commonly used screening method for coronary disease is CT based coronary artery calcium quantification based on Agatston Method, which was developed by Arthur Agatston. The Agatston Score development was based upon the quantification of total coronary artery calcium in the entire heart for purposes of early detection and risk assessment.  The whole-heart Agatston Score has been shown to be independent to traditional risk factors; however, the overall predictive accuracy is relatively modest as it does not take into consideration the spatial distribution and regional characteristics of individual calcified lesions. Furthermore, because it lacks spatial distribution information it cannot distinguish between plaque located in high risk areas versus low risk areas. .

Circulation. 1996;94:1175-1192, doi: 10.1161/01.CIR.94.5.1175, (Circulation. 1996;94:1175-1192.), 1996 American Heart Association, Inc. 


Coronary Artery Calcification: Pathophysiology, Epidemiology, Imaging Methods, and Clinical Implications

A Statement for Health Professionals From the American Heart Association


Coronary Artery Calcification: Pathophysiology, Epidemiology, Imaging Methods, and Clinical Implications" was approved by the American Heart Association Science Advisory and Coordinating Committee on June 20, 1996.

Executive Summary

Atherosclerotic calcification is an organized, regulated process similar to bone formation that occurs only when other aspects of atherosclerosis are also present. Nonhepatic Gla-containing proteins like osteocalcin, which are actively involved in the transport of calcium out of vessel walls, are suspected to have key roles in the pathogenesis of coronary calcification. Osteopontin and its mRNA, known to be involved in bone mineralization, have been identified in calcified atherosclerotic lesions. Calcified human atherosclerotic plaque also contains mRNA for bone morphogenetic protein-2a, a potent factor for osteoblastic differentiation, and cells that are capable of osteoblastic differentiation. These cells may be the ones from which vascular calcifying cells are derived. These and other recent findings indicate that calcification is an active process and not simply a passive precipitation of calcium phosphate crystals, as once thought.

Although calcification is found more frequently in advanced lesions, it may also occur in small amounts in earlier lesions that appear in the second and third decades of life. Histopathological investigation has shown that plaques with microscopic evidence of mineralization are larger and associated with larger coronary arteries than are plaques or arteries without calcification. The relation of arterial calcification to the probability of plaque rupture is unknown. Although the amount of coronary calcium correlates with the amount of atherosclerosis in different individuals and to a lesser extent in segments of the coronary tree in the same individuals, it is not known if the quantity of calcification tracks the quantity of atherosclerosis over time in the same individuals. Further research is needed to better elucidate the relation of calcification to the pathogenesis of both atherosclerosis and plaque rupture.

In vivo epidemiological evidence and postmortem studies show that the prevalence of coronary calcium deposits in a given decade of life is 10 to 100 times higher than the expected 10-year incidence of coronary heart disease events for individuals of the same age. This disparity is less evident in the elderly and symptomatic than in the young and asymptomatic. Realization of this fact has generated the need to determine clinically useful threshold levels of coronary calcium content (such as the calcium score determined by electron beam computed tomography [EBCT]) in order to make appropriate management decisions. The limited available evidence linking radiographically detectable coronary calcium to future coronary heart disease events of death and infarction suggests that this link is strongest in symptomatic and very high-risk subjects. The results of ongoing epidemiological studies will be needed to further elucidate this connection.

Fluoroscopy, electron beam, and helical computed tomography can identify calcific deposits; EBCT and, to a lesser extent, double-helical CT have the enhanced capability to localize coronary calcification and detect smaller and less dense calcific deposits. Only EBCT can quantitate the amount or volume of calcium. The absence of calcific deposits on an EBCT scan implies the absence of significant angiographic coronary narrowing; however, it does not imply the absence of atherosclerosis, including unstable plaque. Similarly, calcification may frequently be seen in the absence of significant angiographic narrowing and before there has been sufficient plaque build-up to narrow the vessel to the extent that ischemia would be apparent on stress electrocardiograms or stress-thallium determinations.

According to the available evidence, a negative EBCT coronary calcium study, when no calcium is detected, does not absolutely rule out the presence of atherosclerotic plaque, including unstable plaque, but does imply a very low likelihood of significant luminal obstruction. The majority of patients who have had angiographically normal coronary arteries have negative EBCT scans and a low risk of a cardiovascular event within the next 2 to 5 years. Women tend to have low scores or negative scans before menopause.

On the other hand, a positive scan, that is, one in which some calcium is detected in at least one vessel, confirms the presence of atherosclerotic plaque. The greater the amount of calcification, the greater the likelihood of obstructive disease, but there is not a one-to-one relation, and the findings are not site specific. A high calcium score may be consistent with a moderate to high risk of a cardiovascular event within the next 2 to 5 years.

Unless the calcific area is greater than 2 mm, the reproducibility of coronary calcium detection with EBCT appears to be insufficient for serial assessment of coronary calcium levels in individual patients. However, because EBCT has been shown to be sufficiently accurate for predicting the presence of angiographic stenoses somewhere in the coronary arteries and for predicting the likelihood of clinical end points in symptomatic patients, it can be used as part of a cardiological examination done under the supervision of a physician knowledgeable about the significance of scan results and the management of coronary heart disease. Presently the data are insufficient to recommend coronary artery calcium screening in lieu of stress testing for most patients with chest pain, except in those with atypical chest pain, for whom a negative study may be useful by itself or in addition to exercise testing. The role of EBCT as a screening tool in asymptomatic patients with conventional risk factors is not yet clearly defined. It can be anticipated, however, that identifying the presence of premorbid coronary artery disease would influence the aggressiveness with which risk factor modification is approached. There is no role at present for application of the test to screen populations of young (less than 40 years old), healthy individuals with no risk factors. The importance of calcification in such individuals will have to await event data that are currently being obtained.


The ability to detect and quantify coronary artery calcium using currently available imaging methods has created significant interest in developing appropriate applications for various clinical settings. This statement describes the pathophysiology of coronary artery atherosclerosis and calcification, the available epidemiological information related to coronary calcification, various diagnostic methods for detecting coronary calcification and, once identified, its significance and prognostic value. The statement concludes with potential practical applications for detecting coronary calcium in specific patient subgroups and comments on screening for coronary calcium, based on available epidemiological data and current understanding of the pathophysiology of coronary artery disease.

Pathophysiology of Coronary Artery Disease

Viewpoints on the pathophysiology of coronary atherosclerosis have dramatically changed in the last few years. The mechanisms of progression of coronary atherosclerosis and plaque instability and rupture in acute coronary syndromes are now more completely understood.1 2 3 4

Lesions of Atherosclerosis
A new classification has been proposed to characterize atherosclerotic plaque progression into five phases, from fatty streak to the advanced complicated lesion.
2 5 The American Heart Association Committee on Vascular Lesions defined each of these phases by lesion morphological characteristics.6 This classification system relates the clinical phases of plaque evolution to the types of lesions seen pathologically so that clinicians and investigators alike may share a common language and understanding of these processes.

Vulnerable Lipid-Rich Plaque and Acute Coronary Syndrome
Plaque Disruption
In the process of atherogenesis, lipid accumulation, cell proliferation, and extracellular matrix synthesis may be expected to be linear with time. However, angiographic studies show that the progression of coronary artery disease in humans is neither linear nor predictable.
2 4 Indeed, recently it has become apparent that arteriographically mild coronary lesions may undergo significant progression to severe stenosis or total occlusion over a period of a few months.7 8These lesions, which are often found in concert with more advanced atherosclerotic lesions, may account for as many as two thirds of patients in whom unstable angina or other acute coronary syndromes develop.2 9 This unpredictable and episodic progression is likely caused by plaque disruption with subsequent thrombus formation that changes plaque geometry, leading to plaque growth and acute occlusive coronary syndromes.10 11 Angioscopic studies performed in vivo have supported this theory.12

Recent pathological studies have shown that atherosclerotic plaques prone to rupture are commonly composed of a crescentic mass of lipids separated from the vessel lumen by a fibrous cap.13 In addition to a rather passive phenomenon of plaque disruption, the concept of an active phenomenon related to macrophage activity is evolving.14 Extracts from human and rabbit atherosclerotic plaques revealed macrophages and expression of metalloproteinases that induced an increase in the breakdown of extracellular matrix, suggesting that macrophages could be responsible for an active phenomenon of plaque disruption.3 15 16

Disruption of a vulnerable or unstable plaque with a subsequent change in plaque geometry and thrombosis may result in acute occlusion with unstable angina or other acute coronary syndromes. Histopathologically, plaque fissuring occurs in various shapes and sizes. The tear may be small, allowing blood to enter, expand, and uproot the plaque but not necessarily resulting in thrombus formation in the arterial lumen. If the tear is large, a subsequent, usually platelet-rich thrombus may form within the lumen and occlude the vessel
17 ; such a thrombus may be either partially lysed or become replaced in the process of organization by the vascular repair response.2 5 Of interest, an acute occlusive thrombus may be permeated by several channels and appear partially open at angiography.

Calcium Deposition in Coronary Artery Disease
Lesions of Atherosclerosis and Calcium Deposition
Atherosclerotic calcification begins as early as the second decade of life, just after fatty streak formation.
18 With refined microscopic methods,19 the lesions of younger adults have revealed small aggregates of crystalline calcium among the lipid particles of lipid cores.6 18 Calcific deposits are found more frequently and in greater amounts in elderly individuals and more advanced lesions.19 In most advanced lesions, when mineralization dominates the picture, components such as lipid deposits and increased fibrous tissue may also be present.

Calcium phosphate (hydroxyapatite, Ca3[-PO4]2-xCa[OH]2), which contains 40% calcium by weight, precipitates in diseased coronary arteries by a mechanism similar to that found in active bone formation and remodeling.20 Electron microscopic evidence supports the theory by which hydroxyapatite, the predominant crystalline form in calcium deposits,19 21 is formed primarily in vesicles that pinch off from arterial wall cells, analogous to the way matrix vesicles pinch off from chondrocytes in developing bone.22 23 24 It has been postulated that vesicles, derived from dead foam and smooth muscle cell debris and contained within extracellular lipid-rich accumulations, may also serve as the sites of small calcium deposits.5 6 A very close spatial association between cholesterol deposits and hydroxyapatite has also been demonstrated.25Accordingly there may be various mechanisms of calcium deposition in atherosclerosis.

Although the biochemical sequence of events leading to atherosclerotic calcification is not well understood, recent attention has focused on a unique class of proteins known as Gla-containing proteins, which have a very high affinity for hydroxyapatite. Gla (gamma carboxyglutamate) is an unusual amino acid residue whose only known function is to bind calcium.26 27 Indeed, it has been suggested that Gla proteins may be actively related to atherosclerotic calcification. They do not interfere with normal calcium homeostasis because they are not calcium chelators, but if precipitationof calcium occurs, available Gla-containing proteins would be expected to bind to the precipitate.19Decarboxylation of Gla residues to glutamyl residues greatly diminishes the affinity of Gla-containing proteins for hydroxyapatite.26 27

Although passive absorption of Gla-containing proteins from serum cannot be entirely excluded, this seems unlikely19 because coronary arterial calcification seems to occur exclusively in atherosclerotic arteries and is absent in normal vessel wall.28 There may be a mechanistic link between pathological processes leading to calcification and those leading to atherosclerosis. It is conceivable, for example, that atherosclerotic processes inhibit the synthesis and/or activity of γ-glutamate carboxylase, thus perhaps explaining why atherosclerotic arteries contain only about 30% of the carboxylase activity found in normal arterial segments.29 Alternatively, it is also conceivable that cells in atherosclerotic lesions synthesize less carboxylase.

Overall, present findings lend credence to the idea that atherosclerotic calcification is not merely passive adsorption but instead is an organized, regulated process similar in many respects to bone formation. Recently, clear differences in the occurrence of arterial wall calcification were observed among genetically distinct inbred mouse strains,30 indicating for the first time that there is a genetic component in this clinically significant trait.

Molecular Basis for Calcification
Fitzpatrick et al
31 used in situ hybridization to identify mRNA of matrix proteins associated with mineralization in coronary artery specimens. Using undecalcified sections of postmortem coronary arteries, they found mineralization to be diffuse, rather than solely confined to the intima, and present in all atherosclerotic plaques. Specifically they identified a cell attachment protein (osteopontin), a protein associated with calcium (osteonectin), and a γ-carboxylated protein that regulates mineralization (osteocalcin). The traditional sectioning methodology, which uses decalcification, may miss a significant amount of mineralization. Indeed, hydroxyapatite was not detected in any coronary sections deemed normal by traditional light microscopy.

Osteopontin is a phosphorylated glycoprotein, regulated by local cytokines, with known involvement in the formation and calcification of bone. Immunohistochemistry of the specimens examined by Fitzpatrick for osteopontin demonstrated intense, highly specific staining in the outer margins of all diseased segments at each calcification front, although staining was evident throughout the entire plaque.31 Other studies showed that osteopontin can be seen in tissue demonstrating atherosclerotic involvement20 and appeared to be present only in sites of concomitant coronary atherosclerotic disease.32 33 Hirota et al34demonstrated with Northern blotting that osteopontin mRNA expression is related to severity of atherosclerosis. On the other hand, osteonectin expression of mRNA decreased with development of atherosclerosis, suggesting a counterregulatory role. Shanahan et al35 and Ikeda et al32 independently demonstrated that the predominant cell type in the areas associated with this ectopic bone protein expression are macrophage-derived foam cells, although some smooth muscle cells could also be identified.

Giachelli and associates,36 using immunochemistry and in situ hybridization, demonstrated that medial smooth muscle cells in uninjured arteries contain very low levels of osteopontin and mRNA. However, injury to either the adult rat aorta or carotid artery initiated a time-dependent increase in both osteopontin protein and mRNA within the arterial smooth muscle cells, suggesting a possible role for osteopontin in the proliferative and migratory phases of arterial injury. They also showed that basic fibroblast growth factor, transforming growth factor-, and angiotensin II, all proteins implicated in the arterial injury response, elevated osteopontin expression in confluent vascular smooth muscle cells in vitro.

Finally, Bostrom et al20 recently identified bone morphogenetic protein-2a, a potent factor for osteoblastic differentiation, in calcified human atherosclerotic plaque. Cells cultured from the vascular wall formed calcified nodules similar to those found in bone cell cultures and responded to transforming growth factor .37 The predominant cells in these nodules had immunocytochemical features characteristic of microvascular pericytes, which are capable of osteoblastic differentiation. These findings provide additional evidence that arterial calcium in atherosclerosis is a regulated process similar to bone formation rather than a passive precipitation of calcium phosphate crystals.

Role of Calcium in Remodeling
The role of mineralization in the pathogenesis and fate of the coronary plaque is unknown. Although coronary calcification has in the past been regarded as a passive process of adsorption or precipitation, evidence reviewed here suggests that this may not be the case.
19 If it is true that coronary calcification is an organized, regulated process, then to what end is this organization and regulation directed? That is, does calcification serve some functional role?

Teleologically, it can be speculated that coronary arterial calcification may, in a manner analogous to collateral formation, represent an attempt to protect threatened myocardium by strengthening weakened atherosclerotic plaque prone to rupture. Calcified lesions and fibrotic hypocellular lesions are much stiffer than cellular lesions,38 and biomechanical data suggest that calcified areas are unlikely to be associated with sites of plaque rupture.39 Demer40 has shown that the presence of calcification alters the mechanical properties of the plaque. In vivo evidence of the relative stability of calcified lesions has been obtained with intravascular ultrasound (IVUS).41 Thus, coronary calcification might represent an attempt by the arterial wall to stabilize itself, thereby minimizing the risk of plaque rupture. For example, if a plaque develops a heavily calcified cap, it is about five times stiffer than a cellular lesion or normal vessel wall and very resistant to rupture.13 38 Over the short term this may lead to increased stress near the junction of the cap and the adjacent intima, and it is here, at the interface between a calcified and noncalcified atherosclerotic section, that plaque rupture often occurs. Although the dissection that follows angioplasty is not a model for natural plaque disruption, focal calcification is a major reason for dissection after balloon angioplasty, and it may influence the length and severity of balloon angioplasty–induced dissections.42 43 One theory is that with more extensive calcification and fibrosis of the vessel, these weak points may be eliminated and the risk of rupture correspondingly decreased. It can be speculated that the vessel is rendered less vulnerable to rupture only when extensive calcification has occurred, whereas the early or intermediate stages of calcification may actually enhance plaque vulnerability. This may help explain why calcification alone is not an ideal prognostic indicator for plaque rupture in heterogeneous populations13and is compatible with the high frequency of calcification found in older populations,44 45 46 who tend to have the largest plaque burden.

Coronary remodeling associated with the development and progression of atherosclerotic disease is a recently described phenomenon47 whereby the luminal cross-sectional area and/or external vessel dimensions become enlarged to compensate for increasing areas of mural plaque.48 Coronary artery calcium is an intimate component of some plaques. In a histopathological investigation, Clarkson et al49 have shown that plaques with microscopic evidence of mineralization were much larger and were associated with much larger coronary arteries than sections without microscopic evidence of calcification; this was true in both humans and nonhuman primates. The compensatory enlargement of atherosclerotic coronary segments may explain why coronary angiography frequently underestimates the severity of coronary disease as compared with histopathological studies. Studies attempting to correlate the site and amount of coronary calcium with percent luminal narrowing at the same anatomic site have shown a positive but nonlinear relation with large confidence limits.50 51 However, coronary plaque and its associated coronary calcification may have only a poor correlation with the extent of histopathological stenosis.49 52 In situ coronary calcium, on the other hand, appears to be closely associated with plaque size.52

A recent study by Rumberger et al53 emphasized that the total area of coronary artery calcification, determined by EBCT, is correlated in a linear fashion with the total area of coronary artery plaque on a segmental, individual coronary artery and whole coronary artery system basis. However, the areas of coronary calcification were approximately one fifth that of the associated coronary plaque. In addition there were clear areas of plaque without associated coronary calcium. These data suggest that one size of coronary plaque is most commonly associated with coronary calcium, but in smaller plaques the calcium is either not present or is undetectable with currently available imaging modalities. Thus, mild coronary plaque may be present without detectable coronary calcium at that same anatomic site.

Coronary Mineralization and Acute Coronary Artery Syndromes
Although calcification is a consistent finding in areas of significant focal coronary artery narrowing,28 its presence also has implications in coronary thrombotic syndromes and coronary dissection after angioplasty. Some believe that mildly or moderately stenotic plaque is more likely to rupture and lead to coronary syndromes.
2 Hangartner et al54 have shown in pathological examination of the hearts of 54 men who had stable angina that, for stenoses of more than 50% diameter narrowing, 48% were caused by concentric fibrous (hard) plaques, 28% by lipid-rich (soft) plaques, 12% by eccentric fibrous plaques, and 12% by eccentric lipid rich plaques. Forty-four percent of plaques causing stenoses of 30% to 50% were eccentric and were often in series with segments of higher-grade stenoses. Most patients had mixtures of all plaque types in varying proportions, but in the mean, two thirds were fibrotic and one third were lipid rich. These observations underlie the apparent paradox that the more extensive the coronary calcification, the more likely that a coronary event may occur. Calcification can be detected in some mildly or moderately stenotic plaques, which some believe to be the type more likely to rupture and lead to coronary syndromes,2 while Cheng et al39suggest that a calcified plaque itself is less, not more, likely to rupture. Rather, the presence of calcified plaque implies the likely association of lipid-rich and possibly unstable plaque. There are additional implications for predisposition to plaque rupture and myocardial infarction.42 55 56 Van der Wal et al57demonstrated that the site of intimal rupture or erosion of thrombosed coronary plaques is characterized by an inflammatory process, regardless of the dominant plaque morphology. Demer et al58 have argued that the presence of a soft plaque, with a point of weakness induced by inflammation adjacent to an area of calcification, predisposes the plaque to rupture because of the presence of a tissue interface of differing physical properties that is subjected to the pulsatile changes of arterial pressure.

In Vivo Imaging Methods

Coronary artery calcification is potentially detectable in vivo by the following methods: plain film roentgenography; coronary arteriography; fluoroscopy, including digital subtraction fluoroscopy; cinefluorography; conventional, helical, and electron beam computed tomography; intravascular ultrasound; magnetic resonance imaging; and transthoracic and transesophageal echocardiography. In current practice, fluoroscopy and EBCT are most commonly used to detect coronary calcification noninvasively, while cinefluorography and IVUS are used by coronary interventionalists to evaluate calcification in specific lesions before angioplasty.

Plain Chest Radiographs
Coronary calcification is not easily detected on chest radiographs. Accuracy is only 42%, compared with fluoroscopy, which in itself is not extremely sensitive.
59The chest film, while readily available and inexpensive, has low sensitivity for detecting coronary calcification.60

Fluoroscopy has frequently been used to detect calcification in coronary arteries. Table 1
Description: Down, adapted from Detrano and Froelicher,61 summarizes seven studies examining fluoroscopic detection of coronary calcification in 2670 patients undergoing coronary arteriography.62 63 64 65 66 67 68 Sensitivity in detecting significant stenoses (greater than 50% diameter obstructions) ranged from 40% to 79%, with specificity ranging from 52% to 95%.


Table 1. Correlation of Fluoroscopic Detection of Coronary Calcification With Presence of Significant* Angiographic Narrowing  {not copied because of low relevance}

In a fluoroscopic study of 613 asymptomatic male aircrew members who underwent coronary arteriography because of one or more abnormal screening tests,69 coronary artery calcification had a 66.3% sensitivity and a 77.6% specificity in determining angiographically significant coronary stenosis (greater than 50% diameter narrowing). The positive predictive value was 37.7% and negative predictive value was 91.9%; for disease with greater than 10% stenosis, sensitivity was 60.6% and specificity 85.9%. The authors concluded that a fluoroscopically negative calcification test indicated a low likelihood of significant coronary artery disease, whereas a positive calcification test substantially increased the likelihood of angiographically significant coronary artery disease.

Although fluoroscopy can detect moderate to large calcifications, its ability to identify small calcific deposits is low. In one study70 only 52% of calcific deposits seen on high-resolution EBCT images could be detected fluoroscopically (P<.001). The mean calcium density in lesions detected by EBCT was +99 HU, whereas for lesions detected by fluoroscopy it was +546 HU, signifying that only larger, more highly calcified plaques are detectable with fluoroscopy as compared with CT. This may explain why calcification detected by EBCT is more sensitive but less specific than fluoroscopy, as discussed below.

Fluoroscopy is widely available in both inpatient and outpatient settings and is relatively inexpensive, but it has several disadvantages. In addition to only a low to moderate sensitivity, fluoroscopic detection of calcium is dependent on the skill and experience of the operator as well as the number of views studied. Other important factors include variability of fluoroscopic equipment, the patient's body habitus, overlying anatomic structures, and overlying calcifications in structures such as vertebrae and valve annuli. With fluoroscopy, quantification of calcium is not possible, and film documentation is not commonly obtained.

Conventional Computed Tomography
Because calcium attenuates the x-ray beam, computed tomography (CT) is extremely sensitive in detecting vascular calcification. In a study evaluating CT detection of calcium as a marker of significant angiographic stenosis,71sensitivities of 16% to 78% were found, depending on which vessel included the calcified plaque. Specificities were 78% to 100% and positive predictive values 83% to 100%, suggesting that significant coronary artery disease was likely to be present when coronary calcification was seen on CT.

Computed tomography, fluoroscopy, and angiography were compared in a study of 47 patients with a mean age of 57 years.72 The CT scans showed calcification in 62% of vessels with significant lesions on angiography, whereas fluoroscopy showed calcium in only 35%. In a group without angina, coronary calcification was found by CT in only 4%, and no patient had significant stenosis on coronary arteriography. In this study CT detected calcification in all patients in whom fluoroscopy showed calcification and in all patients in whom angiography showed stenosis. Overall, CT showed calcification in 50% more vessels than did fluoroscopy.

Another study of suspected coronary artery disease patients73 found that 90% of a group of 108 patients with calcification detected by conventional CT had significant stenosis (greater than 75% narrowing), whereas, of 121 patients with significant stenosis on angiography, 80% had calcification on CT. Sensitivity was 65%, specificity, 87%.

Therefore, while conventional CT appears to have better capability than fluoroscopy to detect coronary artery calcification, its limitations are slow scan times resulting in motion artifacts, volume averaging, breathing misregistration, and inability to quantify amount of plaque.

Helical or Spiral Computed Tomography
Helical CT has considerably faster scan times than conventional CT—on the order of 1 second—but imaging as fast as 0.6 second is possible. Overlapping sections also improve calcium detection. Shemesh et al
74 reported coronary calcium imaging by helical CT as having a sensitivity of 91% and a specificity of 52% when compared with angiographically significant coronary obstructive disease. Double helical CT was useful in predicting the absence of coronary artery disease in elderly women in the absence of calcification.75 However, other preliminary data have shown that even at these accelerated scan times, and especially with single helical CT, calcific deposits are blurred due to cardiac motion, and small calcifications may not be seen.76 Still, helical CT remains superior to fluoroscopy and conventional CT in detecting calcification. Double-helix CT scanners appear to be more sensitive than single-helix scanners in detection of coronary calcification because of their higher resolution and thinner slice capabilities.

Electron Beam Computed Tomography
General Description
Electron beam computed tomography uses an electron gun and a stationary tungsten "target" rather than a standard x-ray tube to generate x-rays, permitting very rapid scanning times. Originally referred to as 
cine or ultrafast CT, the termEBCT is now used to distinguish it from standard CT scans because modern spiral scanners are also achieving subsecond scanning times. For purposes of detecting coronary calcium, EBCT images are obtained in 100 ms with a scan slice thickness of 3 mm. Thirty to 40 adjacent axial scans are obtained by table incrementation. The scans, which are usually acquired during one or two separate breath-holding sequences, are triggered by the electrocardiographic signal at 80% of the RR interval, near the end of diastole and before atrial contraction, to minimize the effect of cardiac motion. The rapid image acquisition time virtually eliminates motion artifact related to cardiac contraction. The unopacified coronary arteries are easily identified by EBCT because the lower CT density of periarterial fat produces marked contrast to blood in the coronary arteries, while the mural calcium is evident because of its high CT density relative to blood. Additionally, the scanner software allows quantification of calcium area and density. An arbitrary scoring system has been devised based on the x-ray attenuation coefficient, or CT number measured in Hounsfield units, and the area of calcified deposits.77 A screening study for coronary calcium can be completed within 10 or 15 minutes, requiring only a few seconds of scanning time. Electron beam CT scanners are more expensive than conventional or spiral CT scanners and are available in relatively fewer sites.

Tanenbaum et al
78 were the first to report use of EBCT for detecting calcific deposits in the coronary arteries. The amount of calcification detected on 50 ms scans with 1.5 mm2 pixel size was compared with coronary arteriography in 54 patients. Stenosis of the coronary arteries was considered significant when luminal narrowing was 70%; in the left main coronary artery the accepted significant stenosis was 50%. In this series angiograms showed significant coronary artery disease in 43 patients; 88% of these had detectable calcium in at least one coronary artery. Specificity for significant stenosis in this study was 100%. The scans were confined to examination of the proximal 76 mm of the coronary arteries and not distal vascular sections.

In 1992 Agatston et al70 reported the first large clinical series in which EBCT was used to detect calcification of the coronary arteries. Five hundred eighty-four consecutive patients with a mean age of 48 years underwent 100 ms EBCT scans with 3 mm thick slices (0.46 mm2 pixel size); 50 also underwent fluoroscopic examination. One hundred nine patients had coronary artery disease established by a history of myocardial infarction (22) or angiographic evidence of greater than 50% diameter narrowing on coronary angiography (87). The remaining 475 patients had no history of coronary disease. Patients with a history of coronary artery disease consistently had more calcium than patients of comparable age with no history of coronary artery disease (P<.0001). A total calcium score of 50 (a weighted sum of x-ray density and total calcium area) resulted in a sensitivity of 71% and specificity of 91% for patients in the 40- to 49-year-old age group with at least 50% stenosis. A total calcium score of 300 in the 60- to 69-year-old age group with similar severity of stenosis had a sensitivity of 74% and a specificity of 81%. The negative predictive value of a zero calcification score was 98% (age 40 to 49), 94% (age 50 to 59), and 100% (age 60 to 69). Electron beam CT showed calcium in 90%, and fluoroscopy showed it in 52% of patients with established coronary artery disease, although only 87 patients had angiographic documentation. The authors concluded that EBCT appeared to be an excellent technique for detecting and quantifying calcification of coronary arteries. The study additionally showed that the mean total calcium score increased with age.

Breen et al79 studied 100 patients aged 23 to 59 years who underwent EBCT and angiography. Significant obstruction was defined as greater than 50% narrowing of the vessel diameter on the angiogram. Sensitivity of detecting any calcium (ie, calcium score greater than 0) in individuals with significant angiographic stenosis was 100%; specificity was 47%. In patients whose angiograms showed stenosis greater than 10%, sensitivity for detecting any calcium by EBCT was 94%, and specificity was 72%. In this series eight patients with calcification had no angiographic evidence of coronary artery disease, and 28 patients with calcification had mild or moderate coronary artery disease.

Fallavollita et al80 compared EBCT detection of calcium with coronary angiography in 106 patients under the age of 50 and found an 85% sensitivity and 45% specificity in patients with significant stenosis, defined as greater than 50% diameter narrowing on angiography. For multivessel disease, sensitivity was 94%, while in single-vessel disease it was 75%. Positive predictive value was 66%. Because negative predictive value was only 70%, the authors emphasized that the absence of EBCT calcium may not exclude significant coronary disease in this younger patient group. However, it should be emphasized that only 20 3-mm EBCT sections were examined, as opposed to 30 to 40 sections in most other angiographic comparison studies, and distal calcification, commonly seen in the right coronary artery,50 may have been missed in the analysis. Thus, the negative predictive value in single-vessel disease may have been underestimated.

A larger multicenter study81 that looked at coronary calcification as an indicator of significant stenosis involved 431 patients with symptoms of coronary artery disease (CAD) (251 men and 180 women; mean age 56 years). In this group, sensitivity of any detectable calcification by EBCT as an indicator of significant stenosis (greater than 50% narrowing) was 92% and specificity 43%. When these CT images were reinterpreted in a blinded and standardized manner, however, specificity was only 31%.82

In a more recent multicenter study51 of 710 enrolled patients, 427 had significant angiographic disease, and coronary calcification was detected in 404, yielding a sensitivity of 95%. Of the 23 patients without calcification, 83% had single-vessel disease on angiography. Of the 283 patients without angiographically significant disease, 124 had negative EBCT studies.

Although EBCT is very sensitive in defining coronary vascular calcification, the extent and site of calcification does not equate with site-specific stenosis. Bormann et al83 found that calcium scores were not predictive of a significant stenosis at the calcification site and that no receiver-operator characteristic curve could be found that would suggest a clinically useful calcium score as an indicator of more than 70% stenosis at the same anatomic site. In this study, however, only one patient had significant stenosis in the absence of calcification. In a series of 150 patients from two institutions undergoing EBCT scans and coronary arteriography, Stanford et al84 found only one patient who had greater than 50% narrowing in the absence of calcification.

The presence and amount of calcium detected in a coronary artery by EBCT indicates the presence and amount of associated atherosclerotic plaque.53Additionally, in a recent review, Rumberger et al85 suggested that the magnitude of the calcium score can be used to a high specificity in predicting associated stenosis somewhere within the epicardial coronary system, but the extent of calcification at a given anatomic site may be less useful in predicting luminal narrowing identified at angiography. Table 2Description: Down provides a summary of seven studies relating EBCT calcification to significant coronary stenosis.50 51 79 80 8687 88 In these studies the absence of calcification indicated a low likelihood of significant luminal obstruction. Except for the Fallavollita study,80 which did not use the same imaging protocol as the others, the negative predictive values ranged from 84% to 100%. Predictive values are based on prior probability; because most patients in these studies had indications for angiography, these predictive values would not apply to asymptomatic patient groups or populations.


Table 2. Calcium Detected by Electron Beam Computed Tomography (EBCT) as an Indicator of Significant Angiographic Stenosis*   {Not included because of low relevance}

Reproducibility of Results
Reproducibility of the calcium measurement or calcium score is essential to assess progression, stabilization, and/or regression of disease in individual patients and to conduct longitudinal studies based on a change in coronary calcium determination. Janowitz et al
89 evaluated calcific plaque in 25 symptomatic and asymptomatic patients 406 days apart. Subjects with proven obstructive coronary artery disease on angiography had a 48% increase in calcium score compared with 22% in asymptomatic subjects. Patients with obstructive coronary artery disease had 55 new calcific deposits on the follow-up study versus 18 in the asymptomatic group. Although Janowitz et al concluded that EBCT may be useful for studying both the natural history of coronary disease and the effects of intervention, they did not consider that interscan differences might result from interscan measurement error.

Several studies have shown a variability in repeated measures of coronary calcium by EBCT; therefore, use of serial EBCT scans in individual patients to track the progression or regression of calcium is problematic. Bielak et al86 studied 256 patients who had EBCT evaluation of calcium and coronary angiography. A repeat EBCT scan was done immediately after the initial scan but after the patient had gotten off the scanner table and walked briefly around the room. These investigators found that segmental areas with small amounts of calcification (less than 2 mm2) were seen at a second examination only 50% of the time (P<.0001). Other investigators90 91 92 have suggested that a large increase in calcium score is needed before a change in calcium score can be attributed to progression of pathology rather than measurement error. Thus, although calculation of the total calcium score using EBCT is quantitative50 51 53 77 79 82 88 93 94 and operator independent,95 reproducibility varies from excellent96 to moderate,91 depending on the laboratory and, most likely, the actual magnitude of the calcium score. Therefore, the conclusions of Janowitz et al can most probably be applied to investigations in which large groups of patients are studied but not necessarily to individual patients undergoing routine clinical follow-up. The variability in repetitive measurements of calcium score is largely related to scan misregistration secondary to patient motion. Preliminary application of 6 mm thick slice scanning92 rather than the traditional 3 mm EBCT scanning has been suggested to halve interscan variability. Further improvements in electrocardiographic triggering algorithms and shorter total scan time have recently been implemented and should further reduce interscan variability. Also, careful patient instruction about breath holding can reduce respiratory misregistration.


Costs and Risks of Scanning
Assessment of coronary calcification by EBCT can be done in virtually any subject and provides anatomic rather than physiological information. Thus, no preparation or discontinuation of medications is required before testing, which is totally noninvasive, involves minimal patient cooperation, and produces results available for qualitative evaluation on an immediate basis. Quantitative review of calcium scoring using EBCT requires additional analysis but is available generally within 10 to 20 minutes. The current total charge for an EBCT examination (limited CT of the chest) and interpretation is approximately the same as the charge for a routine nurse-monitored treadmill test. Charges vary in different parts of the United States but average between $300 and $400. This is roughly one half the charge for a stress echocardiogram and one third the charge for a stress radionuclide examination. Radiation dosimetry for a single screening EBCT scan for coronary calcium has an effective (integrated over thorax) radiation dose of 82 mrem for males and approximately 150 mrem for females (accounting for breast irradiation).88 97 Although it is difficult to make direct comparisons due to differences in dose delivery and localization, a posteroanterior and lateral chest x-ray combination involves approximately 10 mrem and a screening two-view mammogram about 35 mrem. A thallium scan delivers a highly localized dose of approximately 1 rem to the thorax and abdomen98 ; conventional coronary arteriography results in radiation doses two to three orders of magnitude or greater than that from an EBCT coronary calcium scan.99 However, even though the EBCT radiation dose is minimal, indiscriminate use or mass screening is not condoned. At present the AHA recommends that it be done only at the request of a physician and for specific clinical indications as outlined above.

Intravascular Ultrasound
Intravascular ultrasound is a newer method for detecting coronary atherosclerosis.
100 By using transducers with rotating reflectors mounted on the tips of catheters, it is possible to obtain cross-sectional images of the coronary arteries during cardiac catheterization. The sonograms provide information not only about the lumen of the artery but also about the thickness and tissue characteristics of the arterial wall. Calcification is seen as a hyperechoic area with shadowing: fibrotic noncalcified plaques are seen as hyperechoic areas without shadowing.101 Friedrich and colleagues102 reported on the ability of IVUS to detect the histological extent of in situ coronary calcium. Examining 50 fresh human coronary artery vessel segments and using histological confirmation, the sensitivity of IVUS for dense, coherent calcification was 90%, with a specificity of 100%. However, for small accumulations of microcalcification and/or scattered calcification (areas less than 0.05 mm2), sensitivity was only 64%, although high specificity was preserved.

Rickenbacher et al,103 using IVUS, found that although intimal hyperplasia was seen early after cardiac transplantation, coronary calcification developed more slowly and was detected in 2% to 12% of patients within 5 years, increasing to 24% 6 to 10 years after transplantation.

Mintz et al41 compared IVUS to angiography and found that angiography was significantly less sensitive than IVUS in detecting calcification at the site of a target lesion. This finding was confirmed by Tuzcu et al,104 who also found calcium by angiography at another site in the coronary tree in two thirds of patients without calcium at the target site.

The disadvantages in use of IVUS, as opposed to other imaging modalities, are that it is invasive and currently performed only in conjunction with selective coronary angiography, and it visualizes only a limited portion of the coronary tree. Thus, it has no role in screening for coronary artery disease. Although invasive, the technique is clinically important because it can show atherosclerotic involvement in patients with normal findings on coronary arteriograms102 104 105106 and helps define the morphological characteristics of stenotic lesions before balloon angioplasty and selection of atherectomy devices.42 104

Magnetic Resonance Imaging
The ability to detect coronary calcification with magnetic resonance imaging (MRI) is limited. Calcium is almost always characterized by low signal intensity on both T1- and T2-weighted spin-echo (static dark blood) images primarily as a result of the low density of mobile protons in calcified lesions.
107 In addition, because of the sensitivity of MRI to the heterogeneous magnetic susceptibility found in calcified tissue, gradient-echo magnitude (static or dynamic bright blood) images also typically depict calcified lesions as discreet areas of reduced signal intensity.108 However, the theory is more complex for particulate calcium, as T1 relaxation may be enhanced by surface relaxation mechanisms, and this may result in a hyperintense signal.109 Experimental studies have shown that calcium particles with greater surface area create greater T1 relaxivity, thus negating the decreases in signal intensity caused by reductions in both proton density and T2. For concentrations of calcium particulate of up to 30% by weight, the intensity on standard T1-weighted images increases but then subsequently decreases with increasing concentrations.109 Because microcalcifications do not substantially alter the signal intensity of voxels that contain a large amount of soft tissue, the net contrast in such calcium collections is low. Therefore, MRI detection of small quantities of calcification is difficult, and there are no reports or expected roles for MRI in detection of coronary artery calcification.

Transthoracic and Transesophageal Echocardiography
Transthoracic (surface) echocardiography is exquisitely sensitive to detection of mitral and aortic valvular calcification; however, visualization of the coronary arteries has been documented only on rare occasions, because of the limited available external acoustic windows. Thus, there are no practical applications for transthoracic echocardiographic localization of coronary artery calcifications. Transesophageal echocardiography is a widely available methodology that often can visualize the proximal coronary arteries.
110 111 However, neither of these methods has sufficient density, resolution, or available acoustic windows to reliably define in situ coronary artery calcium.

Epidemiological Considerations

In 1961 Blankenhorn112 summarized the evidence that coronary artery calcification occurred only in sites involved with atherosclerosis. This observation has been confirmed by several investigators. Because it is now accepted that the initial response of the artery to atherosclerosis is adaptive (arterial enlargement associated with atherosclerosis), and that, for most people, extensive atherosclerosis is not associated with coronary symptoms,47 48 49 it is additionally important to know the prevalence of calcification in atherosclerotic lesions. Few publications have addressed this question, partly because methods to determine the presence of atherosclerotic plaque and calcification in vivo are imprecise. Furthermore, the definition of coronary artery disease may be based on clinical symptomatology or angiography, whereas descriptions of atherosclerosis may come from autopsy studies, IVUS, or other imaging methods. Nevertheless, the literature reviewed suggests atherosclerotic plaque is present in 50% of individuals aged 20 to 29 years, rising to 80% in individuals aged 30 to 39.113Calcification is present in 50% of individuals aged 40 to 49 and 80% of individuals aged 60 to 69,55 113 114 115 116 whereas significant stenosis is present in only 30% of individuals aged 60 to 69.113 For individuals aged 30 to 39 with symptomatic coronary artery disease, calcification may be present in 72%55 115116 and stenosis in 60%.117

In autopsy studies a modest correlation has been observed between percent coronary stenosis and extent of calcification.28 Mautner et al118 observed that 54% of coronary segments with greater than 75% stenosis had coronary calcification on directed EBCT scanning, but calcification was present in only 41%, 23%, and 6% of those with stenosis of 51% to 75%, 26% to 50%, and 1% to 25%, respectively. Overall, more calcified sites were associated with nonstenotic disease (632) than stenotic disease (368). In another analysis of these data,118 93% of coronary arteries with at least one stenosis greater than 75% had calcification, whereas only 20% of arteries with less than 50% stenosis and only 4% of those arteries with less than 25% stenosis contained calcific deposits. Data were not presented for the group with 50% to 75% stenosis. These studies both relied on histology to define percent stenosis as an area of plaque per area within the internal elastic lamina rather than using percent stenosis determined by reduction in luminal diameter as seen on two-dimensional projections of angiographic images. Because area varies by the square of the radius, histologically estimated coronary stenosis is considerably greater than that provided by coronary angiography119 ; thus, 50% and 75% area stenosis on histopathology may correlate with 15% and 30% to 50% diameter stenosis by angiography, respectively.

A summary of the literature relating coronary calcification to clinical disease is complicated by the evolution of technology for identifying calcification (vide supra). Thus, in an early study using fluoroscopy,120 prevalence of calcium in patients with and without symptoms was, respectively, 28% and 2% in persons aged 30 to 40 years and 95% and 56% in persons aged 60 to 70. On the other hand, a more recent study using EBCT77 showed prevalences of 100% and 25% in younger persons and 100% and 74% in older persons with and without symptoms.

This dilemma is further confounded by the fact that while only a minority of patients undergoing catheterization have nonobstructive disease, this population likely represents the vast majority of apparently healthy middle-aged adults. Furthermore, recent clinical studies suggest that patients with mild coronary artery disease (less than 50% stenosis) may be at relatively high risk of developing clinical events,121 that the angiographic degree of stenosis is a poor predictor of subsequent culprit lesions, and that angiography cannot differentiate stable from unstable lesions with a substantial degree of confidence.2

Risk Factors for Coronary Calcification
Age and gender are the most important risk factors for coronary calcification, ranging from 14% for men and women less than 40, to 93% to 100% for men older than 70, and 77% to 100% for women older than 70.122 123 124 125

The Framingham study126 puts the 8-year risk of coronary heart disease for the average middle-aged person at between 1% and 5%, depending on age and risk factors, with an expected 8-year incidence of events ranging from less than 1% to 15% for persons younger than 40 to older than 80 years. Comparing these figures with the prevalence of calcification described above, it is evident that prevalence of calcification is much higher than risk of events. Thus, only a small proportion of persons with atherosclerosis and detectable coronary calcium will eventually develop clinical coronary events, and effective risk stratification will require a threshold calcium volume (at present undefined), score, or distribution pattern of calcification to define a high risk versus low or intermediate coronary calcium screen.127

Several investigators have studied risk factors for their association with coronary artery calcifications.46 123 128 129 130 131 Elevated plasma cholesterol has most consistently been shown to be associated with coronary calcification.45 122 125128 129 130 131 Diminished HDL,129 130 cigarette smoking,46 123 130 elevated blood pressure,123 130 obesity,129 130 number of risk factors,123 131 diabetes,46and elevated triglycerides129 have all been shown to be associated with coronary calcification in one or more studies in one or more patient groups.

Coronary Calcification and Clinical Outcomes
Although the presence or absence of calcification is related to overall atherosclerotic plaque burden, it is event data (angina, myocardial infarction, necessity for percutaneous transluminal coronary angioplasty [PTCA], or coronary artery bypass surgery) that are important in determining the clinical significance of coronary artery calcification. Little et al
121 have shown that acute occlusions resulting in myocardial infarction often occurred in vessels with less than 50% angiographically determined stenosis, but it is also important to note that these patients frequently had concomitant severe angiographic stenoses. This study, however, did not assess calcification. Brundage et al132 reviewed several series reporting the 5-year mortality and incidence of myocardial infarction. In this review there was a 7% 5-year mortality in 1275 patients with less than 50% angiographic stenosis versus a 3% mortality in 4250 persons with normal arteriograms. The 5-year incidence of myocardial infarction was 5% in 188 patients with mild stenosis versus 1% in the 573 persons with normal arteriograms. Brundage concluded that infarction and death were two to three times more common in persons with mild plaque than in those without plaque.

It is important to study not only event data but also the progression or possible regression of disease, because Waters et al133 have shown coronary atherosclerotic progression is a strong independent predictor of future coronary events.

Margolis and colleagues66 studied 800 patients referred for cardiac catheterization predominantly for angina pectoris (90%). They observed that symptomatic patients with calcification demonstrated on conventional fluoroscopy had a 5-year survival rate of 58% versus 87% in those without detectable calcium. Furthermore, the prognostic significance of coronary artery calcification appeared to be independent of age, gender, and angiographically diseased vessels. In addition, calcification was independent of exercise and left ventricular function tests. On the other hand, a smaller study by Hudson and Walker134 of 78 patients without cardiac symptoms concluded that there was no difference in 5-year survival whether or not calcium was present. Although they suggested that coronary calcium may have a different significance in symptomatic and asymptomatic populations, both studies66 134 suffered from methodological problems regarding selection and measurement bias.

Detrano et al135 studied survival in asymptomatic, high-risk subjects with coronary artery calcification detected on fluoroscopy. These investigators followed 1461 subjects with a greater than 10% risk of having a coronary event within 8 years. (A coronary event was defined as angina, documented myocardial infarction, myocardial revascularization, or death from coronary heart disease.) Events at 1 year occurred in 5.4% of 691 subjects with coronary calcification versus 2.1% of the 768 subjects without fluoroscopic calcium (P=<.001). One-vessel calcification incurred an event risk of 5.4%; two-vessel, 5.6%; and three-vessel, 6.2%. Detrano et al found that radiographically detectable calcium was associated with a risk for having an event 2.7 times greater compared with the group with no calcification. They also found that the presence of calcification was an independent predictor of at least one coronary event when controlled for age, gender, and other risk factors. However, it should be emphasized that three deaths due to coronary heart disease and two nonfatal myocardial infarctions occurred in subjects without detectable coronary calcium. Their conclusions were that the presence of coronary calcium detected fluoroscopically identified an increased risk of a cardiac event in asymptomatic high-risk subjects at 1 year, and this increased risk was independent of that incurred by standard risk factors.

There are limited data available on the prognostic significance of coronary calcium detected by conventional x-ray computed tomography. Naito and colleagues136followed a group of 241 older individuals (136 men, 105 women) for an average of 4 years. Among 82 patients with coronary calcium, 4.9% developed myocardial infarction, whereas none of the 159 patients without coronary calcium experienced infarction. However, mortality (all causes) was no different between the two groups. In women overall mortality was 26% (3.7% due to infarction) in the calcium group and 9% (0% due to infarction) in the noncalcium group. In men total mortality was 13% (5.5% due to infarction) in the calcium group and 12% (0% due to infarction) in the noncalcium group. However, the mean age of these persons was 61 years, and there were no data for younger individuals.

Investigators in a recently published multicenter EBCT calcium study82 looked at event data in 501 symptomatic patients who were studied with both EBCT for calcium and coronary angiography. The majority of these patients had symptoms of coronary artery disease. In this group 1.8% died and 1.2% had nonfatal myocardial infarctions during a mean follow-up period of 31 months. A threshold of 100 or greater in the calcium score was shown to be highly predictive in separating patients with cardiac events at follow-up from those without events and calcium scores of less than 100. In this study, logistic regression, which included, in addition to calcium score, age, gender, and coronary angiographic findings as independent variables, showed that only log calcium score predicted events.

Mautner et al50 looked at the amount of calcification detected on EBCT examinations and the percent blockage determined histomorphometrically. In the 1426 segments from coronary arteries of patients with histories of symptomatic coronary artery disease, calcium was present on EBCT in 41%. In the 1535 segments from asymptomatic coronary artery disease patients, EBCT detected calcium in 24%, whereas in normal control subjects, only 4% had calcium. EBCT had a sensitivity of 94% for detecting calcium in a coronary artery versus a specificity of 76%. The positive predictive value was 84%; the negative predictive value was 90%. Mautner et al concluded that the EBCT calcium score appeared to be an effective predictor of coronary artery disease. In this study the symptomatic CAD group was defined as having a history of angina or myocardial infarction and a narrowing greater than 75% in at least one section of a coronary artery. The asymptomatic CAD group had at least one segmental narrowing greater than 75% but no symptoms. The control group had no symptoms and no narrowing greater than 75%.

Arad et al137 followed 1173 initially asymptomatic patients for an average of 19 months. Nineteen patients had 27 cardiovascular events, including one death, seven myocardial infarctions, and one nonhemorrhagic stroke. In addition 18 patients developed symptoms requiring coronary bypass surgery (8) or PTCA (10). Electron beam CT coronary calcium scores were correlated with subsequent events, depending on the threshold for the lower limit of calcium score. For coronary artery calcium score thresholds of 100, 160, and 680, EBCT had sensitivities of 89%, 89%, and 53%, and specificities of 77%, 82%, and 95%, respectively. Negative predictive values were greater than 99%, and odds ratios ranged from 22.2 to 35.6:1 (P<.00001) for these thresholds. Other risk factors, such as presence of hypercholesterolemia, low HDL cholesterol, hypertension, diabetes, and family history failed to predict subsequent events. Extrapolation of the results of this study to other asymptomatic populations must be done with caution, because there were only eight major coronary events (death or myocardial infarction), and patients were self-selected for entry into the study.

Although these correlative studies indicate that patients with greater amounts of coronary calcification are more likely to suffer a clinical event compared with patients without calcification or lesser amounts, it is important to note that they do not address the relation of calcification to the process or likelihood of plaque rupture.138 These studies evaluated calcium in the entire coronary vasculature, and it is not known whether events were a consequence of ruptured plaques that were or were not calcified.

In addition to the rationale that detection of coronary artery calcium is useful in identifying those at risk for acute coronary events, early detection of mild coronary atherosclerosis is of potential value also, particularly if the process can be slowed, arrested, or reversed. There are substantial data to indicate that lowering serum cholesterol in patients with known coronary artery disease (secondary prevention) reduces the incidence of nonfatal infarction, fatal infarction, cardiovascular mortality, and all-cause mortality.139 Although some have questioned the wisdom of routine cholesterol screening in asymptomatic populations,140 there is mounting evidence that risk reduction and lipid lowering in patients with elevated cholesterol without clinical disease (ie, high-risk, asymptomatic individuals) is efficacious.141 142 143


Practical Applications of Coronary Calcium Detection

Based on the prior discussion, clinical application of information about coronary artery calcification is predicated on its noninvasive detection and quantification as a surrogate measure of atherosclerotic plaque. This limits imaging to conventional and digital fluoroscopy and x-ray computed tomography. Of these methods, only EBCT presently has the capability to quantify coronary artery calcification.

Potential uses for coronary calcium assessments, based on this information, fall into three broad categories that reflect common clinical practice dilemmas or decision paradigms:

1. Evaluation of patients with chest pain: results used in the decision to perform adjunctive or additional noninvasive stress testing, a coronary angiogram, or proceed with medical therapy for angina pectoris, etc.

2. Screening of asymptomatic subjects: goals include identifying subjects for aggressive risk factor management, further diagnostic workup with exercise testing and angiography, and exclusion from high-risk occupations (airline pilot, etc).

3. Following progression of coronary atherosclerosis: scan results at follow-up intervals help determine efficacy of pharmacological or nutritional intervention (eg, lipid-lowering agents, antioxidants, or other therapies) for retarding progression of atherosclerosis.

The following section reviews the data supporting or contesting the validity of each of these potential applications.

Evaluation of Patients With Chest Pain
Patients with chest pain of an indeterminate nature, particularly if coronary status is unknown (no prior infarction, angiogram, or other definitive diagnostic result), frequently require further investigations before a decision can be made regarding the proper course of treatment. In ambulatory subjects, electrocardiographic exercise testing, with or without cardiac imaging, is commonly used. If the results are markedly abnormal, the patient is frequently referred for a coronary angiogram to obtain information about the need for revascularization. If the results are completely normal, the patient may be reassured or referred for further evaluations directed at noncardiac causes of chest pain. In the case of equivocal results, the decision to administer medical therapy, perform an alternative form of stress testing, implement aggressive risk factor management, or perform coronary angiography will depend on other aspects of the patient's symptoms and wishes as well as the physician's judgment. The physician's decision on the need for further testing and/or responses to the results of initial testing should consider the specificity and sensitivity of exercise test results, along with the pretest probability based on symptoms, risk factors, etc, in estimating the postexercise test probability of not only angiographically severe disease but also morbid events.
144 Specific results are more important when they are present and sensitive results when they are absent.

Numerous studies62 63 64 67 77 87 116 145 146 147 148 149 150 have shown that coronary calcium assessment using fluoroscopy or EBCT has a sensitivity for significant angiographic stenoses comparable to that of exercise tests when used with symptomatic patients, although specificity is lower. Moreover, three of these studies have shown that symptomatic patients with coronary calcium have at least a fourfold increased risk of death or infarction when compared with those with less or no calcification.68 82 86 151 The fluoroscopic finding of at least one definitely calcified coronary vessel66 or the EBCT finding of a coronary calcium score exceeding 100 (or calcium phosphate mass exceeding 20 mg82 ) has been shown to be highly predictive of the presence of advanced coronary plaque and stenosis. This can be helpful in decisions to proceed with additional noninvasive stress testing or even to proceed to angiography in this patient subset with chest pain of uncertain origin. In general, greater degrees of calcification are consistent with greater amounts of atherosclerotic plaque and more advanced associated coronary luminal narrowing.85 93

There are four published studies of sensitivities and specificities with regard to angiography that involved comparisons of radiographic coronary calcifications and exercise testing results in the same symptomatic subjects.67 135 152 153 They are listed in Table 3Description: Down. In addition to these studies, Spadaro and colleagues154 have published an abstract reporting the results of a comparison of EBCT with exercise thallium scintigraphy in 150 patients. These authors did not report sensitivity and specificity but did report an overall accuracy of 79% for EBCT compared with 63% for thallium scintigraphy. Detrano et al,68 using multivariate techniques, have shown that fluoroscopic coronary calcium adds independent information for predicting angiographic stenosis when both fluoroscopy and exercise thallium scintigraphy are done before angiography. The advantage of using an assessment of coronary artery calcification under these circumstances is that it can be done regardless of the patient's ability to exercise to a maximum workload and regardless of the presence of resting electrocardiographic abnormalities. Additionally, noninvasive assessment of coronary artery calcium, an anatomic and nonphysiological evaluation of the coronary arteries, is not influenced by concomitant use of various cardiotonic and vasoactive drugs that may confound performance and/or interpretation of an exercise test. However, conventional stress testing provides a physiological basis for the chest pain syndromes and valuable guidance on subsequent pharmacological therapy of angina if the test is deemed positive. Also, there is general consensus as to the interpretation of stress testing, with and without imaging of the myocardium. On the other hand, there is no consensus on the proper threshold of calcium score for a positive versus a negative EBCT scan.


Table 3. Comparisons of Radiographic Coronary Artery Calcifications and Exercise Testing Results in Symptomatic Subjects*  {table not reproduced for lack of relevant information}


Perhaps the most valuable finding in the symptomatic patient is a negative EBCT scan for coronary calcium. As discussed earlier, the negative predictive value of an EBCT calcium scan for significant (ie, 50% or greater diameter stenosis in any major coronary vessel) is greater than 90% and perhaps closer to 95% in some circumstances. Electron beam CT scanning may then be an appropriate first test in individuals with atypical cardiac symptoms, in whom the pretest likelihood for ischemic disease is considered low by the clinician. Persons in this group are likely to have a negative or minimal calcium score. Those with a zero or very low calcium score (generally less than 10) could be reassured and further testing directed at noncardiac sources of chest pain. Conversely, if the calcium score is consistent with moderate or severe atherosclerotic plaque development, then additional cardiac evaluation, including formal stress testing, may be an appropriate next step.

Thus, there are insufficient data to recommend coronary artery calcium scanning in lieu of stress testing as a broad generalization in patients with chest pain. However, there are sufficient data to suggest that coronary calcium evaluation, especially with EBCT, is ready for clinical application in the de novo patient with chest pain, particularly with an "atypical" chest pain presentation, and that this anatomic evaluation may be useful by itself or in addition to exercise testing.85

Screening of Asymptomatic Subjects
Asymptomatic subjects differ from symptomatic subjects (patients) in two regards. First, according to the data obtained from the Framingham study, asymptomatic subjects have a relatively low risk of morbid coronary events.
155Risk is plotted against age in the FigureDescription: Down, using data from Anderson et al,155which also depicts the prevalence of coronary calcification in another group of asymptomatic men of the same ages. The risk of events is seen to be lower than the prevalence of calcification at all ages and is particularly lower in younger patients. Second, because a major objective of both medical and invasive therapy is to relieve symptoms, which asymptomatic subjects lack, there is less incentive to screen such subjects.



Figure 1. Coronary artery calcium prevalence, 10-year event risk, and prevalence/risk ratio in asymptomatic men (see text for risk profile).155 Event risk and calcium prevalence are plotted against right axis, and prevalence/risk ratio is plotted against left axis. Prevalence/risk curve decreases with age, suggesting that although serious over-prediction will occur in the young, over-prediction will be only moderate in the elderly.

However, if a threshold for fluoroscopic or EBCT scan results could be determined that effectively stratifies asymptomatic subjects into very high- versus very low-risk groups, aggressive risk factor modification could be selectively applied to the high-risk group. This presumes that such thresholds exist and that they can be determined; that is, that one knows how much calcium separates very low from very high risk. However, if risk increases with the amount of calcium in a continuous graded manner without a sudden, discrete step at a certain score or mass level, and the slope of this risk versus mass curve is sufficiently steep, evaluation of coronary calcium mass may still be an effective method of selecting those who could benefit most from aggressive risk factor management. Such an approach to the use of the exercise electrocardiogram has been proposed by some to screen asymptomatic individuals156 but, by and large, has not been accepted by the medical community as cost-effective.157 158

Clinical follow-up studies of asymptomatic subjects undergoing coronary calcium screening are under way, and some results are available.134 135 137 159 160 161Three of these studies137 159 161 involved self-referred subjects who underwent scanning as part of commercial, media-advertised heart evaluation programs. Two are studies of the South Bay Heart Watch cohort consisting of 1461 asymptomatic adult Los Angeles residents with very high coronary risk who underwent fluoroscopy between 1990 and 1992135 and then EBCT between 1993 and 1994.160 One report concerns a cohort of 153 subjects undergoing upper GI fluoroscopy, during which assessment of coronary calcification was performed.134Table 4Description: Down summarizes the results of these six studies. From these limited data obtained from asymptomatic patients, it appears that the presence of coronary calcium is predictive of future revascularization, based on the results of the one published report by Arad et al.137 However, the use of revascularization and angina as end points has been criticized61 because the reporting of chest pain and subsequent evaluation and invasive intervention can occur partly because of psychological concerns or economic motivation generated when an anxious patient reports a high coronary calcium score to his or her physician. The high ratio (3.2:1) of the number of these revascularizations to the number of coronary deaths and infarctions from the commercially recruited cohorts of Balogh159 and Arad137 suggest that this referral bias may have been present.


Table 4. Coronary Heart Disease Events in Asymptomatic Subjects Followed After Coronary Calcium Studies*

{not reproduced for lack of relevance}

Second, the presence of coronary calcium in asymptomatic subjects is probably predictive of future nonfatal myocardial infarctions, because 86% (32 of 37 total) of those who suffered nonfatal infarctions had coronary calcium in four of the studies. And third, in the two studies reporting coronary heart disease death, only 12 of 16 subjects suffering this event had radiographically detectable coronary calcium. One of these studies involved 15 coronary deaths135 and the other only one coronary death.137 Eleven of the 15 deaths in the first cohort occurred in subjects with coronary calcium (P=.07). Although these results are suggestive, the paucity of data in asymptomatic patients supporting an association between coronary calcification and hard events, particularly coronary heart disease death, is evident, and more data are needed before a conclusion regarding the predictive value for coronary death can be made.

In summary, there are insufficient data to determine whether the relation between coronary calcium and coronary heart disease risk warrants the use of calcium screening in low-risk, asymptomatic subjects. The widespread proliferation of screening programs for coronary calcium as a single, isolated diagnostic modality in such persons should be discouraged. The manifest relation between calcification and atherosclerosis suggests that EBCT may have a role in establishing susceptibility (as opposed to merely quantitating risk) for coronary disease. The role of EBCT as a screening tool in asymptomatic patients with conventional risk factors is not yet clearly defined. It can be anticipated, however, that identifying the presence of premorbid coronary artery disease would influence the aggressiveness with which risk factor modification is approached.

Following Progression of Coronary Atherosclerosis
The mechanism of coronary atherosclerosis progression involves changes in plaque volume and composition.
6 Because the effects of these changes on coronary lumen morphology is variable, the use of coronary angiography to follow disease progression has been criticized.162

Intracoronary ultrasound163 shares with coronary angiography the problems of invasiveness and high cost but provides a much truer assessment of atherosclerotic volume and composition. However, because of its high cost, invasiveness, and difficulty in accessing the entire coronary tree, intracoronary ultrasound cannot be used for routine serial assessments in clinical situations.

Because EBCT coronary calcium scanning results in quantitative evaluations of coronary calcium, the concept of using this technique for serial assessments of atherosclerosis is attractive.164 To be applicable, however, coronary calcium measurements should accurately track atherosclerotic volume and have sufficient interstudy reliability so that differences over time cannot be attributed to measurement error. Unfortunately, neither of these conditions has been sufficiently satisfied. There have been no studies in animals or humans showing that coronary calcium mass correlates over time with the volume of atherosclerosis in individual subjects. The reproducibility studies done to date8691 165 166 show that changes in calcium score of as much as 50% may be necessary to be certain that a real change has taken place. This wide margin is largely caused by misregistration due to respiratory and cardiac motion during the 2- to 3-second intervals between the acquisition of image slices. (Recent modifications in EBCT scanners have reduced misregistration artifacts by shortening the intervals between scans to less than 1 second.)

Because neither the theoretical tenet on which this would be based nor the necessary reliability of the EBCT image acquisition process has been proved, there are insufficient data at this time to recommend the use of coronary calcium studies in assessing progression of coronary atherosclerosis.

Other Potential Indications
Other potential indications for coronary calcium assessments that have received little discussion and even less scientific validation include the screening of heart transplant donors and evaluation of children with familial hyperlipidemias
166 and patients with Kawasaki disease.167 Recommendations regarding these indications cannot be made at this time due to the lack of supporting data.


Atherosclerotic calcification is an organized, regulated process similar to bone formation that occurs only when other aspects of atherosclerosis are also present. Nonhepatic Gla-containing proteins like osteocalcin, which are actively involved in the transport of calcium out of vessel walls, are suspected to have key roles in the pathogenesis of coronary calcification. Osteopontin and its mRNA, known to be involved in bone mineralization, have been identified in calcified atherosclerotic lesions. Calcified human atherosclerotic plaque also contains mRNA for bone morphogenetic protein-2a, a potent factor for osteoblastic differentiation, and cells that are capable of osteoblastic differentiation. These cells may be those from which vascular calcifying cells are derived. These and other recent findings indicate that calcification is an active process and not simply a passive precipitation of calcium phosphate crystals, as once thought.

Although calcification is found more frequently in advanced lesions, it may also occur in small amounts in earlier lesions, which appear in the second and third decades of life. Histopathological investigation has shown that plaques with microscopic evidence of mineralization are larger and associated with larger coronary arteries than plaques or arteries without calcification. The relation of arterial calcification to the probability of plaque rupture is unknown. Although the amount of coronary calcium correlates with the amount of atherosclerosis in different individuals and to a lesser extent in segments of the coronary tree in the same individuals, it is not known if the quantity of calcification tracks the quantity of atherosclerosis over time in the same individuals. Further research is needed to better elucidate the relation of calcification to the pathogenesis of both atherosclerosis and plaque rupture.

Epidemiological evidence and postmortem studies show that the prevalence of coronary calcium deposits in a given decade of life is 10 to 100 times higher than the expected 10-year incidence of coronary heart disease events for individuals of the same age. This disparity is less evident in the elderly and symptomatic than in the young and asymptomatic. Realization of this fact has generated the need for determination of clinically useful threshold levels of coronary calcium content (such as the calcium score determined by EBCT) to make appropriate management decisions. The limited available evidence linking radiographically detectable coronary calcium to future coronary heart disease events of death and infarction suggests that this link is strongest in symptomatic and very high-risk subjects. The results of ongoing epidemiological studies will be needed to further elucidate this connection.

Fluoroscopy, electron beam, and helical computed tomography can identify calcific deposits. Electron beam CT and, to a lesser extent, double-helical CT have the enhanced capability to localize coronary calcification and detect smaller and less dense calcific deposits. Only EBCT can quantitate the amount or volume of calcium. The absence of calcific deposits on an EBCT scan implies the absence of significant angiographic coronary narrowing; however, it does not imply the absence of atherosclerosis, including unstable plaque. Similarly, calcification may frequently be seen in the absence of significant angiographic narrowing and before there has been sufficient plaque build-up to narrow the vessel to the extent that ischemia would be apparent on stress electrocardiograms or stress thallium determinations.

Table 5Description: Down summarizes the conclusions that can be drawn from a negative EBCT coronary calcium study, based on the available evidence, when no calcium is detected. Similarly, Table 6Description: Down provides guidelines for interpreting the results of a positive scan, with some calcium detected in at least one vessel.

Table 5. Absence of Detectable Coronary Artery Calcification Using Electron Beam Computed Tomography (Negative Test)

Table 6. Presence of Detectable Coronary Artery Calcification Using Electron Beam Computed Tomography (Positive Test)

Unless the calcific area is greater than 2 mm, reproducibility of coronary calcium detection with EBCT appears to be insufficient for serial assessment of coronary calcium levels in individual patients. However, EBCT has been shown to be sufficiently accurate for predicting the presence of angiographic stenoses somewhere in the coronary arteries and for predicting the likelihood of clinical end points in symptomatic patients. This evaluation should be done under the supervision of a physician knowledgeable about the significance of scan results and in management of coronary heart disease. There is no role at present for use of the test to screen populations of young (less than 40 years old), healthy individuals with no risk factors. The importance of calcification in such individuals will have to await event data that are currently being obtained.


The authors thank Richard Cohen, MD, and James Willerson, MD, for their helpful comments during the preparation of this manuscript. We also thank Jeanette Allison for her superb secretarial assistance.


Requests for reprints should be sent to the Office of Scientific Affairs, American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231-4596.


1. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s.Nature.. 1993;362:801-809.[Medline] [Order article via Infotrieve]


2. Fuster V. Lewis A. Connor Memorial Lecture—Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation.. 1994;90:2126-2146. Erratum. Circulation. 1995;91:256.[Abstract/Free Full Text]

3. Libby P. Molecular bases of the acute coronary syndromes. Circulation..1995;91:2844-2850.[Free Full Text]

4. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation..1995;92:657-671.[Free Full Text]

5. Stary HC. Composition and classification of human atherosclerotic lesions.Virchows Arch A Pathol Anat Histopathol.. 1992;421:277-290.[Medline] [Order article via Infotrieve]

6. Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr, Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation.. 1995;92:1355-1374.[Abstract/Free Full Text]

7. Ambrose JA, Tannenbaum MA, Alexopoulos D, Hjemdahl-Monsen CE, Leavy J, Weiss M, Borrico S, Gorlin R, Fuster V. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol..1988;12:56-62.[Abstract]

8. Little WC, Constantinescu M, Applegate RJ, Kutcher MA, Burrows MT, Kahl FR, Santamore WP. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease?Circulation.. 1988;78:1157-1166.[Abstract/Free Full Text]

9. Steinberg D. Antioxidants and atherosclerosis: a current assessment.Circulation.. 1991;84:1420-1425.[Free Full Text]

10. Falk E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis: characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J.. 1983;50:127-134.[Abstract/Free Full Text]

11. Davies MJ, Richardson PD, Woolf N, Katz DR, Mann J. Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. Br Heart J.. 1993;69:377-381.[Abstract/Free Full Text]

12. Sherman CT, Litvack F, Grundfest W, Lee M, Hickey A, Chaux A, Kass R, Blanche C, Matloff J, Morganstern L, et al. Coronary angioscopy in patients with unstable angina pectoris. N Engl J Med.. 1986;315:913-919.[Medline] [Order article via Infotrieve]

13. Richardson PD, Davies MJ, Born GV. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet..1989;2:941-944.[Medline] [Order article via Infotrieve]

14. Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT. Macrophage infiltration in acute coronary syndromes: implications for plaque rupture.Circulation.. 1994;90:775-778.[Abstract/Free Full Text]

15. Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest.. 1994;94:2493-2503.

16. Galis ZS, Sukhova GK, Kranzhofer R, Clark S, Libby P. Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases.Proc Natl Acad Sci U S A.. 1995;92:402-406.[Abstract/Free Full Text]

17. DeWood MA, Spores J, Notske R, Moyser LT, Burroughs R, Golden MS, Lang HT. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med.. 1980;303:897-902.[Medline] [Order article via Infotrieve]

18. Stary HC. The sequence of cell and matrix changes in atherosclerotic lesions of coronary arteries in the first forty years of life. Eur Heart J. 1990;11(suppl E):3-19.

19. Doherty TM, Detrano RC. Coronary arterial calcification as an active process: a new perspective on an old problem. Calcif Tissue Int.. 1994;54:224-230.[Medline][Order article via Infotrieve]

20. Bostrom K, Watson KE, Horn S, Wortham C, Herman IM, Demer LL. Bone morphogenetic protein expression in human atherosclerotic lesions. J Clin Invest..1993;91:1800-1809.

21. Schmid K, McSharry WO, Pameijer CH, Binette JP. Chemical and physicochemical studies on the mineral deposits of the human atherosclerotic aorta. Atherosclerosis.. 1980;37:199-210.[Medline] [Order article via Infotrieve]

22. Anderson HC. Mechanism of mineral formation in bone. Lab Invest..1989;60:320-330.[Medline] [Order article via Infotrieve]

23. Tanimura A, McGregor DH, Anderson HC. Calcification in atherosclerosis, I: human studies. J Exp Pathol.. 1986;2:261-273.[Medline] [Order article via Infotrieve]

24. Tanimura A, McGregor DH, Anderson HC. Calcification in atherosclerosis, II: animal studies. J Exp Pathol.. 1986;2:275-297.[Medline] [Order article via Infotrieve]

25. Hirsch D, Azoury R, Sarig S, Kruth HS. Colocalization of cholesterol and hydroxyapatite in human atherosclerotic lesions. Calcif Tissue Int.. 1993;52:94-98.[Medline] [Order article via Infotrieve]

26. Vermeer C. Gamma-carboxyglutamate-containing proteins and the vitamin K-dependent carboxylase. Biochem J.. 1990;266:625-636.[Medline] [Order article via Infotrieve]

27. Price PA. Gla-containing proteins of bone. Connect Tissue Res.. 1989;21:51-60.[Medline] [Order article via Infotrieve]

28. Simons DB, Schwartz RS, Edwards WD, Sheedy PF, Breen JF, Rumberger JA. Noninvasive definition of anatomic coronary artery disease by ultrafast computed tomographic scanning: a quantitative pathologic comparison study. J Am Coll Cardiol.. 1992;20:1118-1126.[Abstract]

29. Deboervanderberg MAG, Van Haarlem LJM, Vermeer C. Vitamin-K-dependent carboxylase in human vessel wall. Thromb Res. 1986;(S6):134.

30. Qiao J-H, Xie P-Z, Fishbein MC, Kreuzer J, Drake TA, Demer LL, Lusis AJ. Pathology of atheromatous lesions in inbred and genetically engineered mice: genetic determination of arterial calcification. Arterioscler Thromb..1994;14:1480-1497.[Abstract/Free Full Text]

31. Fitzpatrick LA, Severson A, Edwards WD, Ingram RT. Diffuse calcification in human coronary arteries: association of osteopontin with atherosclerosis. J Clin Invest.. 1994;94:1597-1604.

32. Ikeda T, Shirasawa T, Esaki Y, Yoshiki S, Hirokawa K. Osteopontin mRNA is expressed by smooth muscle-derived foam cells in human atherosclerotic lesions of the aorta. J Clin Invest.. 1993;92:2814-2820.

33. Ingram RT, Fitzpatrick LA, Edwards WD, Frye RL, Fisher LW, Schwartz RS. Calcification in human coronary atherosclerosis is specifically associated with osteopontin, a bone matrix protein. J Am Coll Cardiol.. 1993;21:363A. Abstract.

34. Hirota S, Imakita M, Kohri K, Ito A, Morii E, Adachi S, Kim HM, Kitamura Y, Yutani C, Nomura S. Expression of osteopontin messenger RNA by macrophages in atherosclerotic plaques: a possible association with calcification. Am J Pathol..1993;143:1003-1008.[Abstract]

35. Shanahan CM, Cary NR, Metcalfe JC, Weissberg PL. High expression of genes for calcification-regulating proteins in human atherosclerotic plaques. J Clin Invest.. 1994;93:2393-2402.

36. Giachelli CM, Bae N, Almeida M, Denhardt DT, Alpers CE, Schwartz SM. Osteopontin is elevated during neointima formation in rat arteries and is a novel component of human atherosclerotic plaques. J Clin Invest.. 1993;92:1686-1696.

37. Watson KE, Bostrom K, Ravindranath R, Lam T, Norton B, Demer LL. TGF-beta 1 and 25-hydroxycholesterol stimulate osteoblast-like vascular cells to calcify. J Clin Invest.. 1994;93:2106-2113.

38. Lee RT, Grodzinsky AJ, Frank EH, Kamm RD, Schoen FJ. Structure-dependent dynamic mechanical behavior of fibrous caps from human atherosclerotic plaques.Circulation.. 1991;83:1764-1770.[Abstract/Free Full Text]

39. Cheng GC, Loree HM, Kamm RD, Fishbein MC, Lee RT. Distribution of circumferential stress in ruptured and stable atherosclerotic lesions: a structural analysis with histopathological correlation. Circulation.. 1993;87:1179-1187.[Abstract/Free Full Text]

40. Demer LL. Effect of calcification on in vivo mechanical response of rabbit arteries to balloon dilation. Circulation.. 1991;83:2083-2093.[Abstract/Free Full Text]

41. Mintz GS, Popma JJ, Pichard AD, Kent KM, Satler LF, Chuang YC, Ditrano CJ, Leon MB. Patterns of calcification in coronary artery disease: a statistical analysis of intravascular ultrasound and coronary angiography in 1155 lesions.Circulation.. 1995;91:1959-1965.[Abstract/Free Full Text]

42. Hodgson JM, Reddy KG, Suneja R, Nair RN, Lesnefsky EJ, Sheehan HM. Intracoronary ultrasound imaging: correlation of plaque morphology with angiography, clinical syndrome and procedural results in patients undergoing coronary angioplasty. J Am Coll Cardiol.. 1993;21:35-44.[Abstract]

43. Fitzgerald PJ, Ports TA, Yock PG. Contribution of localized calcium deposits to dissection after angioplasty: an observational study using intravascular ultrasound. Circulation.. 1992;86:64-70.[Abstract/Free Full Text]

44. Detrano R, Wong N, French WJ, Georgiou D, Young EK, Brezden O, Brundage B. Prevalence of coronary calcific deposits in 1,000 high risk, asymptomatic individuals. Eur Heart J.. 1993;13:P1065. Abstract.

45. Lie JT, Hammond PI. Pathology of the senescent heart: anatomic observations on 237 autopsy studies of patients 90 to 105 years old. Mayo Clin Proc..1988;63:552-564.[Medline] [Order article via Infotrieve]

46. Detrano RC, Wong ND, French WJ, Tang W, Georgiou D, Young E, Brezden OS, Doherty T, Brundage BH. Prevalence of fluoroscopic coronary calcific deposits in high-risk asymptomatic persons. Am Heart J.. 1994;127:1526-1532.[Medline][Order article via Infotrieve]

47. Gibbons GH, Dzau VJ. The emerging concept of vascular remodeling. N Engl J Med.. 1994;330:1431-1438.[Medline] [Order article via Infotrieve]

48. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med.. 1987;316:1371-1375.[Medline] [Order article via Infotrieve]

49. Clarkson TB, Prichard RW, Morgan TM, Petrick GS, Klein KP. Remodeling of coronary arteries in human and nonhuman primates. JAMA.. 1994;271:289-294.[Abstract/Free Full Text]

50. Mautner SL, Mautner GC, Froehlich J, Feuerstein IM, Proschan MA, Roberts WC, Doppman JL. Coronary artery disease: prediction with in vitro electron beam CT.Radiology.. 1994;192:625-630.[Abstract/Free Full Text]

51. Budhoff MJ, Georgiou D, Brody A, Agatston AS, Kennedy J, Wolfkiel C, Stanford W, Shields P, Lewis RJ, Janowitz WR, Rich S, Brundage BH. Ultrafast computed tomography as a diagnostic modality in the detection of coronary artery disease: a multicenter study. Circulation.. 1996;93:898-904.[Abstract/Free Full Text]

52. Sangiorgi G, Srivatsa SS, Staab M, Rumberger JA, Kaufman R, Peyser P, Fitzpatrick LA, Schwartz RS. Total coronary calcified volume is highly correlated with total plaque volume: a histologic study of 723 segments. J Am Coll Cardiol.1995;25:386A. Abstract.

53. Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwartz RS. Coronary artery calcium areas by electron beam computed tomography and coronary atherosclerotic plaque area: a histopathologic correlative study. Circulation..1995;92:2157-2162.[Abstract/Free Full Text]

54. Hangartner JR, Charleston AJ, Davies MJ, Thomas AC. Morphological characteristics of clinically significant coronary artery stenosis in stable angina. Br Heart J. 1986;56:501-508.[Abstract/Free Full Text]

55. Beadenkopf WG, Daoud AS, Love BM. Calcification in the coronary arteries and its relationship to arteriosclerosis and myocardial infarction. Am J Roentgenol..1964;92:865-871.

56. Kragel AH, Reddy SG, Wittes JT, Roberts WC. Morphometric analysis of the composition of atherosclerotic plaques in the four major epicardial coronary arteries in acute myocardial infarction and in sudden coronary death. Circulation..1989;80:1747-1756.[Abstract/Free Full Text]

57. van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology.Circulation.. 1994;89:36-44.[Abstract/Free Full Text]

58. Demer LL, Watson KE, Bostrom K. Mechanism of calcification in atherosclerosis. Trends Cardiovasc Med.. 1994;4:45-49.[Medline] [Order article via Infotrieve]

59. Souza AS, Bream PR, Elliott LP. Chest film detection of coronary artery calcification: the value of the CAC triangle. Radiology.. 1978;129:7-10.[Abstract/Free Full Text]

60. Kelley MJ, Newell JD. Chest radiography and cardiac fluoroscopy in coronary artery disease. Cardiol Clin.. 1983;1:575-595.[Medline] [Order article via Infotrieve]

61. Detrano R, Froelicher V. A logical approach to screening for coronary artery disease. Ann Intern Med.. 1987;106:846-852.

62. Bartel AG, Chen JT, Peter RH, Behar VS, Kong Y, Lester RG. The significance of coronary calcification detected by fluoroscopy: a report of 360 patients.Circulation.. 1974;49:1247-1253.[Abstract/Free Full Text]

63. Hamby RI, Tabrah F, Wisoff BG, Hartstein ML. Coronary artery calcification: clinical implications and angiographic correlates. Am Heart J.. 1974;87:565-570.[Medline] [Order article via Infotrieve]

64. Bierner M, Fleck E, Dirschinger J, Klein U, Rudolph W. Significance of coronary artery calcification: relationship to localization and severity of coronary artery stenosis [in German]. Herz.. 1978;3:336-343.[Medline] [Order article via Infotrieve]

65. Aldrich RF, Brensike JF, Battaglini JW, Richardson JM, Loh IK, Stone NJ, Passamani ER, Ackerstein H, Seningen R, Borer JS, Levy RI, Epstein SE. Coronary calcifications in the detection of coronary artery disease and comparison with electrocardiographic exercise testing: results from the National Heart, Lung, and Blood Institute's type II coronary intervention study. Circulation.. 1979;59:1113-1124.[Free Full Text]

66. Margolis JR, Chen JT, Kong Y, Peter RH, Behar VS, Kisslo JA. The diagnostic and prognostic significance of coronary artery calcification: a report of 800 cases.Radiology.. 1980;137:609-616.[Abstract/Free Full Text]

67. Hung J, Chaitman BR, Lam J, Lesperance J, Dupras G, Fines P, Bourassa MG. Noninvasive diagnostic test choices for the evaluation of coronary artery disease in women: a multivariate comparison of cardiac fluoroscopy, exercise electrocardiography, and exercise thallium myocardial perfusion scintigraphy. J Am Coll Cardiol. 1984;4:8-16.[Abstract]

68. Detrano R, Salcedo EE, Hobbs RE, Yiannikas J. Cardiac cinefluoroscopy as an inexpensive aid in the diagnosis of coronary artery disease. Am J Cardiol..1986;57:1041-1046.[Medline] [Order article via Infotrieve]

69. Loecker TH, Schwartz RS, Cotta CW, Hickman JR Jr. Fluoroscopic coronary artery calcification and associated coronary disease in asymptomatic young men. J Am Coll Cardiol. 1992;19:1167-1172.[Abstract]

70. Agatston AS, Janowitz WH. Coronary calcification: detection by ultrafast computed tomography. In: Stanford W, Rumberger JA, eds. Ultrafast Computed Tomography in Cardiac Imaging: Principles and Practice. Mt Kisco, NY: Futura; 1992:77-95.

71. Timins ME, Pinsk R, Sider L, Bear G. The functional significance of calcification of coronary arteries as detected on CT. J Thorac Imaging.. 1991;7:79-82.[Medline][Order article via Infotrieve]

72. Rienmuller R, Lipton MJ. Detection of coronary artery calcification by computed tomography. Dynam Cardiovasc Imaging. 1987;1:139-145.

73. Masuda Y, Naito S, Aoyagi Y, Yamada Z, Uda T, Morooka N, Watanabe S, Inagaki Y. Coronary artery calcification detected by CT: clinical significance and angiographic correlates. Angiology.. 1990;41:1037-1047.

74. Shemesh J, Apter S, Rozenman J, Lusky A, Rath S, Itzchak Y, Motro M. Calcification of coronary arteries: detection and quantification with double-helix CT. Radiology.. 1995;197:779-783.[Abstract/Free Full Text]

75. Shemesh J, Tenenbaum A, Fisman EZ, Apter S, Rath S, Rozenman J, Itzchak Y, Motro M. Absence of coronary calcification on double-helical CT scans: predictor of angiographically normal coronary arteries in elderly women. Radiology..1996;199:665-668.[Abstract/Free Full Text]

76. Baskin KM, Stanford W, Thompson BH, Hoffman E, Tajik J, Heery SD. Comparison of electron beam and helical computed tomography in assessment of coronary artery calcification. Circulation. 1995;92(suppl I):I-651. Abstract.

77. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15:827-832.[Abstract]

78. Tanenbaum SR, Kondos GT, Veselik KE, Prendergast MR, Brundage BH, Chomka EV. Detection of calcific deposits in coronary arteries by ultrafast computed tomography and correlation with angiography. Am J Cardiol.. 1989;63:870-872.[Medline] [Order article via Infotrieve]

79. Breen JB, Sheedy PF II, Schwartz RS, Stanson AW, Kaufmann RB, Moll PP, Rumberger JA. Coronary artery calcification detected with ultrafast CT as an indication of coronary artery disease. Radiology.. 1992;185:435-439.[Abstract/Free Full Text]

80. Fallavollita JA, Brody AS, Bunnell IL, Kumar K, Canty JM Jr. Fast computed tomography detection of coronary calcification in the diagnosis of coronary artery disease: comparisons with angiography in patients <50 years old. Circulation..1994;89:285-290.[Abstract/Free Full Text]

81. Georgiou D, Budoff M, Kennedy J, Bleiweis MS, Wolfkiel C, Brody AS, Stanford W, Shields P, Brundage BH. The value of ultrafast CT coronary calcification in predicting significant coronary artery disease compared to angiography: a multicenter study. Circulation. 1993;88(suppl I):I-639. Abstract.

82. Detrano R, Hsiai T, Wang S, Puentes G, Fallavollita J, Shields P, Stanford W, Wolfkiel C, Georgiou D, Budoff M, Reed J. Prognostic value of coronary calcification and angiographic stenoses in patients undergoing coronary arteriography. J Am Coll Cardiol. 1996;27:285-290.[Abstract]

83. Bormann JL, Stanford W, Stenberg RG, Winniford MD, Berbaum KS, Talman CL, Galvin JR. Ultrafast tomographic detection of coronary artery calcification as an indicator of stenosis. Am J Card Imaging.. 1992;6:191-196.

84. Stanford W, Breen J, Thompson B, Schwartz R, Galvin J, Rumberger J, Berbaum K, Sheedy P. Can the absence of coronary calcification on ultrafast CT be used to rule out of [sic] nonsignificant coronary artery stenosis? J Am Coll Cardiol.1992;19:189A. Abstract.

85. Rumberger JA, Sheedy PF, Breen JF, Fitzpatrick LA, Schwartz RS. Electron beam computed tomography and coronary artery disease: scanning for coronary artery calcification. Mayo Clin Proc. 1996;71:369-377.[Abstract/Free Full Text]

86. Bielak LF, Kaufmann RB, Moll PP, McCollough CH, Schwartz RS, Sheedy PF II. Small lesions in the heart identified at electron beam CT: calcification or noise?Radiology.. 1994;192:631-636.[Abstract/Free Full Text]

87. Devries S, Wolfkiel C, Fusman B, Bakdash H, Ahmed A, Levy P, Chomka E, Kondos G, Zajac E, Rich S. Influence of age and gender on the presence of coronary calcium detected by ultrafast computed tomography. J Am Coll Cardiol.1995;25:76-82.[Abstract]

88. Rumberger JA, Sheedy PF III, Breen JF, Schwartz RS. Coronary calcium, as determined by electron beam computed tomography, and coronary disease on arteriogram: effect of patient's sex on diagnosis. Circulation.. 1995;91:1363-1367.[Abstract/Free Full Text]

89. Janowitz WR, Agatston AS, Viamonte M Jr. Comparison of serial quantitative evaluation of calcified coronary artery plaque by ultrafast computed tomography in persons with and without obstructive coronary artery disease. Am J Cardiol..1991;68:1-6.[Medline] [Order article via Infotrieve]

90. Detrano R, Wang S, Tang W, Bakhsheshi H, Georgiou D, Brundage B, Wong N. Progression of coronary calcification can be tracked with ultrafast computed tomography: concordance and reliability are sufficient. Am J Card Imaging.1994;8(suppl 1):6. Abstract.

91. Devries S, Wolfkiel C, Shah V, Chomka E, Rich S. Reproducibility of the measurement of coronary calcium with ultrafast computed tomography. Am J Cardiol.. 1995;75:973-975.[Medline] [Order article via Infotrieve]

92. Detrano R, Wang S, Tang W, Brundage B, Wong N. Thick slice electron beam tomographic scanning allows reproducible and accurate assessments of coronary calcific deposits. Circulation. 1995;92(suppl I):I-650. Abstract.

93. Rumberger JA, Schwartz RS, Simons DB, Sheedy PF III, Edwards WD, Fitzpatrick LA. Relation of coronary calcium determined by electron beam computed tomography and lumen narrowing determined by autopsy. Am J Cardiol..1994;73:1169-1173.[Medline] [Order article via Infotrieve]

94. Kaufmann RB, Sheedy PF II, Maher JE, Bielak LF, Breen JF, Schwartz RS, Peyser PA. Quantity of coronary artery calcium detected by electron beam computed tomography in asymptomatic subjects and angiographically studied patients.Mayo Clin Proc.. 1995;70:223-232.[Abstract/Free Full Text]

95. Kaufmann RB, Sheedy PF II, Breen JF, Kelzenberg JR, Kruger BL, Schwartz RS, Moll PP. Detection of heart calcification with electron beam CT: interobserver and intraobserver reliability for scoring quantification. Radiology.. 1994;190:347-352.[Abstract/Free Full Text]

96. Shields JP, Mielke CH Jr, Rockwood TH, Short RA, Viren FK. Reliability of electron beam computed tomography to detect coronary artery calcification. Am J Card Imaging.. 1995;9:62-66.[Medline] [Order article via Infotrieve]

97. Stanford W, Thompson BH, Weiss RM. Coronary artery calcification: clinical significance and current methods of detection. AJR Am J Roentgenol..1993;161:1139-1146.[Abstract/Free Full Text]

98. Drug Information for the Health Care Professional. Rockville, Md: United States Pharmacopeial Convention Inc; 1991:2457.

99. Cascade PN, Peterson LE, Wajszczuk WJ, Mantel J. Radiation exposure to patients undergoing percutaneous transluminal coronary angioplasty. Am J Cardiol.. 1987;59:996-997.[Medline] [Order article via Infotrieve]

100. Waller BF, Pinkerton CA, Slack JD. Intravascular ultrasound: a histological study of vessels during life—the new `gold standard' for vascular imaging.Circulation.. 1992;85:2305-2310.[Free Full Text]

101. Honye J, Mahon DJ, Tobis JM. Intravascular ultrasound imaging. Trends Cardiovasc Med. 1991;1:305-311.[Medline] [Order article via Infotrieve]

102. Friedrich GJ, Moes NY, Muhlberger VA, Gabl C, Mikuz G, Hausmann D, Fitzgerald PJ, Yock PG. Detection of intralesional calcium by intracoronary ultrasound depends on the histologic pattern. Am Heart J.. 1994;128:435-441.[Medline] [Order article via Infotrieve]

103. Rickenbacher PR, Pinto FJ, Chenzbraun A, Botas J, Lewis NP, Alderman EL, Valantine HA, Hunt SA, Schroeder JS, Popp RL, Yeung AC. Incidence and severity of transplant coronary artery disease early and up to 15 years after transplantation as detected by intravascular ultrasound. J Am Coll Cardiol. 1995;25:171-177.[Abstract]

104. Tuzcu EM, Berkalp B, De Franco AC, Ellis SG, Goormastic M, Whitlow PL, Franco I, Raymond RE, Nissen SE. The dilemma of diagnosing coronary calcification: angiography versus intravascular ultrasound. J Am Coll Cardiol.1996;27:832-838.[Abstract]

105. Tobis JM, Mallery J, Mahon D, Lehmann K, Zalesky P, Griffith J, Gessert J, Moriuchi M, McRae M, Dwyer ML, Greep M, Henry WL. Intravascular ultrasound imaging of human coronary arteries in vivo: analysis of tissue characterizations with comparison to in vitro histological specimens. Circulation.. 1991;83:913-926.[Abstract/Free Full Text]

106. Nissen SE, Gurley JC, Grines CL, Booth DC, McClure R, Berk M, Fischer C, DeMaria AN. Intravascular ultrasound assessment of lumen size and wall morphology in normal subjects and patients with coronary artery disease.Circulation.. 1991;84:1087-1099.[Abstract/Free Full Text]

107. Holland BA, Kucharczyk W, Brant-Zawadzki M, Norman D, Haas DK, Harper PS. MR imaging of calcified intracranial lesions. Radiology.. 1985;157:353-356.[Abstract/Free Full Text]

108. Atlas SW, Grossman RI, Hackney DB, Gomori JM, Campagna N, Goldberg HI, Bilaniuk LT, Zimmerman RA. Calcified intracranial lesions: detection with gradient-echo-acquisition rapid MR imaging. AJR Am J Roentgenol.. 1988;150:1383-1389.[Abstract/Free Full Text]

109. Henkelman RM, Watts JF, Kucharczyk W. High signal intensity in MR images of calcified brain tissue. Radiology.. 1991;179:199-206.[Abstract/Free Full Text]

110. Koh KK, Hwang HK, Kin PG, Lee SH, Cho SK, Kim SS, Han JJ, Lee YT, Park PW, Yoon DH. Isolated left main coronary ostial stenosis: intraoperative transesophageal echocardiography during surgical angioplasty. Int J Cardiol..1994;43:202-206.[Medline] [Order article via Infotrieve]

111. Fernandes F, Alam M, Smith S, Khaja F. The role of transesophageal echocardiography in identifying anomalous coronary arteries. Circulation..1993;88:2532-2540.[Abstract/Free Full Text]

112. Blankenhorn DH. Coronary arterial calcification: a review. Am J Med Sci..1961;242:41-49.

113. Tejada C, Strong JP, Montenegro MR, Restrepo C, Solberg LA. Distribution of coronary and aortic atherosclerosis by geographic location, race, and sex. Lab Invest.. 1968;18:509-526.[Medline] [Order article via Infotrieve]

114. Blankenhorn DH, Stern D. Calcification of the coronary arteries. Am J Roentgenol.. 1959;81:772-777.

115. Eggen DA, Strong JP, McGill HC Jr. Coronary calcification: relationship to clinically significant coronary lesions and race, sex, and topographic distribution.Circulation.. 1965;32:948-955.[Abstract/Free Full Text]

116. Frink RJ, Achor RW, Brown AL Jr, Kincaid OW, Brandenburg RO. Significance of calcification of the coronary arteries. Am J Cardiol.. 1970;26:241-247.[Medline][Order article via Infotrieve]

117. Strong JP, Solberg LA, Restrepo C. Atherosclerosis in persons with coronary heart disease. Lab Invest.. 1968;18:527-537.[Medline] [Order article via Infotrieve]

118. Mautner GC, Mautner SL, Froehlich J, Feuerstein IM, Proschan MA, Roberts WC, Doppman JL. Coronary artery calcification: assessment with electron beam CT and histomorphometric correlation. Radiology.. 1994;192:619-623.[Abstract/Free Full Text]

119. Crouse JR III, Thompson CJ. An evaluation of methods for imaging and quantifying coronary and carotid lumen stenosis and atherosclerosis. Circulation.1993;87(suppl II):II-17-II-33.

120. Oliver MF, Morley P, Samuel E, Young GB, Kapur PL. Detection of coronary artery calcification during life. Lancet.. 1964;1:891-895.[Medline] [Order article via Infotrieve]

121. Little WC, Constantinescu M, Applegate RJ, Kutcher MA, Burrows MT, Kahl FR, Santamore WP. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease?Circulation.. 1988;78:1157-1166.

122. Agatston AS, Janowitz WR, Aizawa N, Gasso J, Hildner F, Viamonte M, Prineas R. Quantification of coronary calcium reflects the angiographic extent of coronary artery disease. Circulation. 1991;84(suppl II):II-159. Abstract.

123. Goel M, Wong ND, Eisenberg H, Hagar J, Kelly K, Tobis JM. Risk factor correlates of coronary calcium as evaluated by ultrafast computed tomography.Am J Cardiol.. 1992;70:977-980.[Medline] [Order article via Infotrieve]

124. Janowitz WR, Agatston AS, Kaplan G, Viamonte M Jr. Differences in prevalence and extent of coronary artery calcium detected by ultrafast computed tomography in asymptomatic men and women. Am J Cardiol.. 1993;72:247-254.[Medline][Order article via Infotrieve]

125. Wong ND, Kouwabunpat D, Vo AN, Detrano RC, Eisenberg H, Goel M, Tobis JM. Coronary calcium and atherosclerosis by ultrafast computed tomography in asymptomatic men and women: relation to age and risk factors. Am Heart J..1994;127:422-430.[Medline] [Order article via Infotrieve]

126. National Heart, Lung, and Blood Institute. Framingham Study: an epidemiological investigation of cardiovascular disease. US Department of Commerce, National Technical Information Service.

127. Wong ND, Detrano RC, Abrahamson D, Tobis JM, Gardin JM. Coronary artery screening by electron beam computed tomography: facts, controversy, and future.Circulation.. 1995;92:632-636.[Free Full Text]

128. Hoeg JM, Feuerstein IM, Tucker EE. Detection and quantitation of calcific atherosclerosis by ultrafast computed tomography in children and young adults with homozygous familial hypercholesterolemia. Arterioscler Thromb..1994;14:1066-1074.[Abstract/Free Full Text]

129. Mahoney LT, Burns TL, Stanford W, Thompson BH, Witt JD, Rost CA, Lauer RM. Coronary risk factors measured in childhood and young adult life are associated with coronary artery calcification in young adults: the Muscatine study. J Am Coll Cardiol.. 1996;27:277-284.[Abstract]

130. Maher JE, Peyser PA, Kaufmann RB, Bielak LF, Sheedy PF, Schwartz RS. Gender-specific predictors of coronary artery calcium in asymptomatic adults. Am J Card Imaging. 1994;8(suppl 1):5. Abstract.

131. Lee DJ, Mantelle LL, Agatston AS, Gerace TA, Janowitz WR, Prineas RJ. Risk factor correlates of coronary-artery calcification. Circulation.. 1992;85:880. Abstract.

132. Brundage BH, Detrano RC, Wong N. Ultrafast computed tomography: imaging of coronary calcium in atherosclerosis. Am J Card Imaging.. 1992;6:340-345.[Medline] [Order article via Infotrieve]

133. Waters D, Craven TE, Lesperance J. Prognostic significance of progression of coronary atherosclerosis. Circulation.. 1993;87:1067-1075.[Abstract/Free Full Text]

134. Hudson NM, Walker JK. The prognostic significance of coronary artery calcification seen on fluoroscopy. Clin Radiol.. 1976;27:545-547.[Medline] [Order article via Infotrieve]

135. Detrano RC, Wong ND, Tang W, French WJ, Georgiou D, Young E, Brezden OS, Doherty TM, Narahara KA, Brundage BH. Prognostic significance of cardiac cinefluoroscopy for coronary calcific deposits in asymptomatic high risk subjects.J Am Coll Cardiol. 1994;24:354-358.[Abstract]

136. Naito S, Takasu J, Aoyagi Y, Morooka N, Watanabe S, Masuda Y, Inagaki Y. Progression to ischemic heart disease in subjects with coronary calcification as evaluated by computed tomography. J Cardiol.. 1990;20:249-258.[Medline] [Order article via Infotrieve]

137. Arad Y, Spadaro LA, Goodman K, Lledo-Perez A, Sherman S, Lerner G, Guerci AD. Predictive value of electron beam CT of the coronary arteries: 19-month follow-up of 1173 asymptomatic subjects. Circulation.. 1996;93:1951-1953.[Abstract/Free Full Text]

138. Doherty TM, Detrano RC. Coronary artery calcification. Radiology..1995;195:576-577.[Free Full Text]

139. Rossouw JE, Lewis B, Rifkind BM. The value of lowering cholesterol after myocardial infarction. N Engl J Med.. 1990;323:1112-1119.[Medline] [Order article via Infotrieve]

140. Hulley SB, Walsh JM, Newman TB. Health policy on blood cholesterol: time to change directions. Circulation.. 1992;86:1026-1029.[Free Full Text]

141. Brown BG, Zhao XQ, Sacco DE, Albers JJ. Lipid lowering and plaque regression: new insights into prevention of plaque disruption and clinical events in coronary disease. Circulation.. 1993;87:1781-1791.[Abstract/Free Full Text]

142. Blankenhorn DH, Hodis HN. George Lyman Duff Memorial Lecture: Arterial imaging and atherosclerosis reversal. Arterioscler Thromb.. 1994;14:177-192.[Abstract/Free Full Text]

143. Pedersen TR, Kjekshus J, Berg K, Haghfelt T, Faergeman O, Thorgeirsson G, Pyorala K, Miettinen T, Wilhelmsen L, Olsson AG, Wedel H. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet.. 1994;344:1383-1389.[Medline] [Order article via Infotrieve]

144. Wilson DA, Detrano RC, Narahara KA, Brundage BH, Georgiou D, French WJ, Ginzton LE, Shapiro SM, Bobbio M, Shandling A. Effects of exercise test results on physician perceptions of coronary artery disease probability using a threshold analysis. Am J Cardiol.. 1992;70:846-850.[Medline] [Order article via Infotrieve]

145. Margolis JR, Chen JT, Kong Y, Peter RH, Behar VS, Kisslo JA. The diagnostic and prognostic significance of coronary artery calcification: a report of 800 cases.Radiology.. 1980;137:609-616.

146. Gianrossi R, Detrano R, Colombo A, Froelicher V. Cardiac fluoroscopy for the diagnosis of coronary artery disease: a meta analytic review. Am Heart J..1990;120:1179-1188.[Medline] [Order article via Infotrieve]

147. Kelley MJ, Newell JD. Chest radiography and cardiac fluoroscopy in coronary artery disease. Cardiol Clin.. 1983;1:575-595.

148. Langou RA, Huang EK, Kelley MJ, Cohen LS. Predictive accuracy of coronary artery calcification and abnormal exercise test for coronary artery disease in asymptomatic men. Circulation.. 1980;62:1196-1203.[Abstract/Free Full Text]

149. Rifkin RD, Uretsky BF. Screening for latent coronary artery disease by fluoroscopic detection of calcium in the coronary arteries. Am J Cardiol..1993;71:434-436.[Medline] [Order article via Infotrieve]

150. Saltiel F, Thuot R, Bourassa MG. L'apport de la radioscopie et de la cineradiographie cardiaque a l'etude de la maladie coronarienne. L'Union Medicale Du Canada.. 1979;108:1494-1499.

151. Moore EH, Greenberg RW, Merrick SH, Miller SW, McLoud TC, Shepard JA. Coronary artery calcifications: significance of incidental detection on CT scans.Radiology.. 1989;172:711-716.[Abstract/Free Full Text]

152. Hung J, Chaitman BR, Lam J, Lesperance J, Dupras G, Fines P, Cherkaoui O, Robert P, Bourassa MG. A logistic regression analysis of multiple noninvasive tests for the prediction of the presence and extent of coronary artery disease in men.Am Heart J.. 1985;110:460-469.[Medline] [Order article via Infotrieve]

153. Kajinami K, Seki H, Takekoshi N, Mabuchi H. Noninvasive prediction of coronary atherosclerosis by quantification of coronary artery calcification using electron beam computed tomography: comparison with electrocardiographic and thallium exercise stress test results. J Am Coll Cardiol. 1995;26:1209-1221.[Abstract]

154. Spadaro LA, Sherman S, Roth M, Lerner G, Guerci AD. Comparison of thallium stress testing and electron beam tomography in the prediction of coronary artery disease. J Am Coll Cardiol. 1996;27:175A. Abstract.

155. Anderson KM, Wilson PW, Odell PM, Kannel WB. An updated coronary risk profile: a statement for health professionals. Circulation.. 1991;83:356-362.[Free Full Text]

156. Bruce RA, Fisher LD, Hossack KF. Validation of exercise-enhanced risk assessment of coronary heart disease events: longitudinal changes in incidence in Seattle community practice. J Am Coll Cardiol. 1985;5:875-881.[Abstract]

157. Sox HC Jr, Littenberg B, Garber AM. The role of exercise testing in screening for coronary artery disease. Ann Intern Med.. 1989;110:456-469.

158. Sox HC, Littenberg B, Garber A. Exercise stress testing for asymptomatic coronary artery disease. (Stanford University School of Medicine—prepared for Blue Cross/Blue Shield Association). May 1987.

159. Balogh T, Hoff J, Rich S, Wolfkiel CJ. Development of coronary artery disease in asymptomatic subjects undergoing coronary artery calcification screening by electron beam tomography. Circulation. 1995;92(suppl I):I-650. Abstract.

160. Puentes G, Detrano R, Tang W, Wong N, French W, Narahara K, Brundage B, Baksheshi H. Estimation of coronary calcium mass using electron beam computed tomography: a promising approach for predicting coronary events? Circulation.1995;92(suppl I):I-313. Abstract.

161. Wong ND, Abrahamson D, Tran H, Eisenberg H, Detrano RC. Coronary calcium quantity assessed by electron beam CT: relation to new coronary events.Circulation.. 1995;91:934. Abstract.

162. Nissen SE, Gurley JC, Grines CL, Booth DC, Fischer C, DeMaria AN. Coronary atherosclerosis is frequently present at angiographically normal sites: evidence from intravascular ultrasound in man. Circulation. 1990;82(suppl III):III-459. Abstract.

163. Mallery JA, Tobis JM, Griffith J, Gessert J, McRae M, Moussabeck O, Bessen M, Moriuchi M, Henry WL. Assessment of normal and atherosclerotic arterial wall thickness with an intravascular ultrasound imaging catheter. Am Heart J..1990;119:1392-1400.[Medline] [Order article via Infotrieve]

164. Wong ND, Teng W, Abrahamson D, Willner R, Henein N, Franklin SS, Kashyap ML, Rosenzweig B, Kukes G, Detrano RC. Noninvasive tracking of coronary atherosclerosis by electron beam computed tomography: rationale and design of the Felodipine Atherosclerosis Prevention Study (FAPS). Am J Cardiol..1995;76:1239-1242.[Medline] [Order article via Infotrieve]

165. Wang S, Detrano RC, Tang W, Doherty TM, Puentes G, Wong N, Brundage B. Detection of coronary calcification with electron beam computed tomography: evaluation of inter-examination reproducibility and comparison of three image acquisition protocols. Am Heart J. In press.

166. Hoeg JM, Feuerstein IM, Tucker EE. Detection and quantitation of calcific atherosclerosis by ultrafast computed tomography in children and young adults with homozygous familial hypercholesterolemia. Arterioscler Thromb..1994;14:1066-1074.

167. Kurosaki K, Yoshibayashi M, Suzuki A, Kamiya T, Naito H. Wall abnormality of apparently normal coronary artery after Kawasaki disease. In: Kato H, ed. Kawasaki Disease: Proceedings of the 5th International Kawasaki Disease Symposium. New York, NY: Elsevier Science; 1995:489-493.


Enter supporting content here

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.