EDITORIAL COMMENT
Coronary calcium as a risk factor: role in global risk assessment*
Scott M. Grundy, MD, PhDa
a Center for Human Nutrition, Departments of Clinical Nutrition and Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
Reprint requests and correspondence: Dr. Scott M. Grundy, The Center for Human Nutrition, Departments of Clinical Nutrition and Internal Medicine, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9052
scott.grundy{at}utsouthwestern.edu
The introduction of new imaging techniques offers the opportunity for identification of the presence of subclinical atherosclerosis in asymptomatic persons. The ability to measure the extent of subclinical atherosclerosis could be of value in the selection of persons for more intensive primary prevention of coronary heart disease (CHD). Techniques are currently available for measuring subclinical atherosclerosis in peripheral arteries (ankle/brachial blood pressure index), carotid arteries (intimal medial thickness measured by B-mode sonography) and coronary arteries (coronary calcium measured by computed tomography [CT]) (1). In addition, the finding of myocardial ischemia by a variety of tests usually indicates the presence of advanced coronary atherosclerosis (1). A question of considerable importance for primary prevention is how the information attained through the identification of subclinical atherosclerosis or myocardial ischemia can be used in risk assessment and in the selection of patients for more intensive risk reduction therapy for primary prevention.
The most widely used technique for detecting subclinical coronary atherosclerosis is measurement of coronary calcium scores by electron beam computed tomography (EBCT) (2,3). Coronary calcium scores also can be measured by spiral CT, although this method is not widely employed at present. The two methods for measuring coronary calcium scores have not been adequately compared. Regardless, both autopsy and angiographic studies show that the extent of calcium accumulation in coronary arteries correlates strongly with the severity of coronary atherosclerosis (4–9). Thus, the coronary calcium score gives a fairly good estimate of the total coronary plaque burden. Follow-up studies of patients undergoing coronary angiography reveal that the coronary plaque burden also is a good predictor of future coronary events (10–12). Thus, coronary calcium scores probably carry predictive power for future major coronary events. Preliminary studies indeed provide support for predictive power of coronary calcium (13,14).
To date, however, the full predictive potential of coronary calcium for future coronary events remains unknown. Moreover, the extent to which coronary calcium predicts independently of standard risk factors—cigarette smoking, hypertension, elevated low density lipoprotein cholesterol, low high density lipoprotein (HDL) cholesterol, and family history of premature CHD—has not been resolved. According to some investigators (15), estimates of coronary calcium scores should not be used in risk assessment for selection of persons for primary prevention until their independent power has been accurately determined. Certainly the standard risk factors independently predict future coronary events and are useful in selection of persons for preventive intervention (16). Their power to predict, nevertheless, is limited; if new risk factors, such as subclinical atherosclerosis, could enhance risk prediction, selection of patients for intervention would be improved.
Some investigators take a completely different view of the utility of subclinical atherosclerosis to predict coronary events. Such a view is apparent in the article in this issue of the Journal by Hecht and Superko (17); these investigators used EBCT in asymptomatic women to detect "coronary artery disease" (CAD) or subclinical atherosclerosis. They take the position that standard risk factors are of little value in risk prediction, whereas coronary calcium is robust and should essentially replace standard risk factors in the identification of patients for medical primary prevention. In the opinion of other investigators (15), however, such a position is not founded on a solid base of scientific evidence. Because these different views of the value of coronary calcium as a risk indicator are almost diametrically opposed, it may be worthwhile to examine some of the underlying issues.
One issue has to do with the meaning of two different terms: CAD and CHD. In the cardiology world, these two terms often are used interchangeably. The result is considerable confusion that could be avoided by recognizing a distinction. Unfortunately, two different meanings are applied to CAD: 1) coronary atherosclerosis, and 2) heart disease resulting from coronary atherosclerosis. The confusion could be easily eliminated by letting CAD mean coronary atherosclerosis and allowing CHD to refer to the heart disease that is the product of coronary atherosclerosis. By this distinction, CHD can refer to manifest disease of the heart—myocardial infarction, stable and unstable angina and myocardial dysfunction.
It is also important to distinguish between obstructive coronary atherosclerosis causing angina pectoris and coronary plaque rupture producing acute coronary syndromes (unstable angina pectoris and myocardial infarction). Coronary angiography is useful for identifying the former. Conversely, coronary calcium measurements have limited utility for identifying obstructive coronary atherosclerosis, but may be useful for the latter. The prime question concerns their predictive power for acute coronary syndromes.
Hecht and Superko (17) equate coronary calcium with CAD. In essence, they transform coronary calcium into a disease that needs treatment. This concept is not far removed from current practice of many cardiologists. For example, the finding of a partially blocked coronary artery by angiography often is a call for action, that is, coronary angioplasty. More recently, in the hands of some physicians, the finding of coronary calcium likewise has been a call for action, namely, for evaluation of coronary arteries by angiography followed in some cases by coronary angioplasty. This frequently unwarranted sequence of events is what led the American College of Cardiology (ACC)/American Heart Association (AHA) (3) to warn against widespread screening of EBCT to detect CAD in asymptomatic patients.
Hecht and Superko (17) give an added twist to the story. They wisely do not propose using coronary calcium to identify patients who need coronary angiography. Nevertheless, they do equate coronary calcium with CAD and suggest that its presence calls for aggressive medical therapy for risk reduction. Presumably this would mean the use of statins and aspirin for most asymptomatic patients found to have detectable coronary calcium by EBCT.
In their report, Hecht and Superko (17) suggest that the National Cholesterol Education Program (NCEP) program is flawed in risk assessment because the standard risk factors are not robust enough to accurately predict coronary atherosclerosis (CAD). However, they fail to note that the purpose of risk assessment in NCEP is not to predict coronary atherosclerosis, but to predict CHD (particularly acute coronary syndromes). Thus, by obscuring the meanings of CAD versus CHD, they misidentify the purpose of NCEP risk assessment for selection of patients for medical intervention for primary prevention.
The limitations of risk assessment using standard risk factors are well known. These are clearly laid out in reports from the Framingham Heart Study (16) and in commentaries on it (18). However, Framingham risk scores have the advantage of providing a quantitative estimate of the probability of developing CHD. For this reason, they should not be discarded in risk assessment. Risk estimates based on standard risk factors are the most reliable and quantitative tool currently available for risk assessment. Indeed other studies (19) with EBCT show that standard risk factors do in fact have predictive power for coronary atherosclerosis, although risk factors are not used for this purpose in clinical practice.
A major question regarding coronary calcium is whether estimates add independently to risk prediction beyond the standard risk factors. Efforts to short-circuit risk assessment using only coronary calcium scores appear to be ill advised. Failure to use the Framingham approach throws away valuable predictive information. To date and to my knowledge, the ability of coronary calcium scores to predict acute coronary syndromes independently of the risk factors has not been determined. Thus, to use coronary calcium scores as the sole method for estimating risk for acute coronary syndromes cannot be justified at present. Certainly a more attractive approach is to combine the use of standard risk factors and subclinical atherosclerosis in a manner to improve risk assessment.
As noted before, some investigators (15) hold that measures of subclinical atherosclerosis should not be employed in risk assessment until more research is done to define precisely the predictive power of measurements, independent of standard risk factors. To obtain this information, it would be necessary to carry out prospective studies in which coronary calcium score is measured along with other risk factors. In other words, it has been suggested that we need a new Framingham study in which coronary calcium scores are included along with standard risk factors. Unfortunately, such a study is now unethical to carry out. The need to intervene clinically on standard risk factors is so well established that allowing them to go untreated for many years is not acceptable. Wrongly perhaps some workers believe it is unethical not to tell volunteers their coronary calcium scores in prospective studies. Regardless, for these reasons, it is not possible to carry out a Framingham study including coronary calcium in prospective studies. Other ways must be sought to integrate standard risk factors with coronary calcium scores to enhance risk assessment. Additional ways therefore might be considered.
For example, I have proposed (20) that coronary calcium scores could replace age as a risk factor in Framingham risk assessment. Age counts as a risk factor in large part because it is a reflection of coronary plaque burden. Without question, coronary atherosclerosis rises with age, and the greater the plaque burden, the greater the probability of developing an acute coronary syndrome. However, for older individuals, the severity of coronary atherosclerosis varies widely. Thus, to use age as a risk factor, as a surrogate for coronary plaque burden, applies a population trend to individual patients. In this way its use differs from that of the other risk factors where the severity of the risk factor is measured specifically for individuals. Since the coronary calcium score "individualizes" the age factor, the score could replace age in Framingham equations. Although this usage does not directly solve the problem of independent predictive power of coronary calcium, it does allow coronary calcium to be used in place of a risk factor that has definite limitations when applied to individuals. Thus, use of coronary calcium as a risk factor in the place of age essentially makes use of the "lesser of two evils" in risk prediction.
Another approach is to combine coronary calcium scores with standard risk factors to enhance predictive power. This possibility was explored recently in the AHA’s Prevention V conference (1). This conference sought to evaluate the role of measures of subclinical atherosclerosis in clinical risk prediction. One of the more creative outcomes of this conference was the recognition that clinical risk assessment can separate patients into three general risk categories—high, intermediate and low. Patients with high risk are those with CHD and CHD risk equivalents (21). Patients with established CHD have a risk for developing hard coronary end points (myocardial infarction + coronary death) of  2% per year (21). If patients without CHD could be identified who have a similar risk, they could be called risk equivalents. These patients might then be entered into a risk reduction regimen now reserved for patients with established CHD. Framingham risk prediction, in fact, can be used to identify patients with a risk for hard CHD of 2% per year (21).
Theoretically, there would be no need to measure coronary calcium level in a patient whose risk for hard CHD is 2% per year. An exception might be for older patients in whom age per se is limited in its ability to predict future coronary events in older persons (18). In older persons (e.g., 60 years), coronary calcium measurements might usefully refine risk assessment by replacing age as a risk factor, as described before.
Regardless, the main utility of coronary calcium scores would be for patients who are at intermediate risk. This category can include patients with multiple risk factors who have a risk <2% per year. If coronary calcium scores are high, a patient at intermediate risk might be elevated to a high risk status and thus be deserving of more aggressive risk reduction therapy. To date and to my knowledge, there are three prospective studies (22–24) with EBCT that have recruited patients at intermediate risk. They reveal that in such patients, the absolute risk for CHD is near to or greater than 2% per year when coronary calcium scores are in the highest category for age and gender (Table 1). In other words, the finding of a high calcium score in a patient with multiple risk factors at intermediate risk strongly suggests that such a patient can be elevated to a high risk category. This patient would then be a candidate for more aggressive risk reduction therapy. Although more prospective studies are needed, the findings in Table 1 suggest one way in which coronary calcium scores might be combined with standard risk factors in risk assessment.
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Table 1 Annualized Rate of Coronary Heart Disease in Multiple Risk Factor Patients in the Highest Category of Coronary Calcium Scores
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Another potential use of coronary calcium is to assist with risk assessment in patients at uncertain risk. Examples include young adults and postmenopausal women with isolated hypercholesterolemia (elevated LDL cholesterol), isolated low HDL cholesterol, elevated homocysteine or other single risk factors that are present in severe form. Although to my knowledge there are no prospective studies to show the predictive power of coronary calcium scores in such individuals, the finding of high scores would favor a more aggressive risk reduction intervention.
These targeted approaches contrast to a more generalized "screening" of the general public for coronary calcium measurements. Both the AHA Prevention V report (1,2) and the AHA/ACC report (3) on EBCT warned against the generalized screening approach. There were two major concerns. First, there is the potential for creating unnecessary concern on the part of the patient and physician, leading to inappropriate invasive testing on coronary arteries. Second, failure to integrate coronary calcium scores into global risk assessment with standard risk factors could lead to unnecessarily aggressive treatment of risk factors in the absence of an accurate prediction of risk. Thus, whereas measurement of coronary calcium score has the potential of providing useful information in risk assessment, the potential also exists for its misuse. For this reason, the use of coronary calcium scores in clinical practice should not go far beyond their evidence base.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the author and do not necessarily represent the views of JACC or the American College of Cardiology. 
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