REVIEWS
Coronary Calcification in the Diagnosis of Coronary Artery Disease ROBERT D. RIFKIN, MD ALFRED F. PARISI, MD, FACC EDWARD FOLLAND, MD West Roxbury, Massachusetts
Clinical, postmortem and angiographic studies ot coronary caicitication are reviewed to define the value of fluoroscopy in the diagnosis and management of coronary artery disease. Autopsy studies consistently show a unique association between calcification of the coronary arteries and atherosclerosis. The relation of coronary calcification to the presence of major stenosis is more variable but is strong enough to be of clinical value, particularly in the younger subject. The diagnostic value of fluoroscopy can be improved by attention to the detailed features of calcitication observed with the technique. Combined use of fluoroscopy and exercise testkg appears to be a valid and as yet unexploited approach to the noninvasive diagnosis bf coronary stenosis. Fluoroscopy has been a neglected method of noninvasive diagnosis and is sufficiently promising to warrant greater clinical use.
The extensive mortality and morbidity associated with ischemic heart disease in the United States have stimulated the search for noninvasive methods to assist the clinician in the diagnosis of coronary arterial stenosis. Although the fluoroscopic detection of coronary calcification has received much attention,‘-I5 fluoroscopy has been largely neglected by clinicians in evaluating patients with possible coronary disease. This neglect may be due in part to the high predictive values reported in early studies of exercise stress testing. 16-18As further experience with stress electrocardiography has accumulated, major limitations in its predictive potential have emerged. 1g~20Recognition of the diagnostic limitations inherent in electrocardiographic exercise stress testing suggests that the fluoroscopic examination for calcification of the coronary arteries deserves reevaluation. In this communication we review the diagnostic significance of coronary calcification with major emphasis on studies correlating the fluoroscopic examination with the angiographic appearance of the coronary arteries. The likelihood ratio formulation of Bayes’ theorem is used in this review to analyze data from studies comparing fluoroscopy with selective angiography. It has recently been shown that likelihood ratio analysis offers a convenient means of characterizing the diagnostic performance of a test.lg A synopsis of Bayesian analysis is presented in Appendix 1 and 2. Autopsy Studies of Coronary From the Cardiology Departments, the Lemuel Shattuck Hospital, Jamaica Plain, Massachusetts and the United States Veterans Administration Hospital, West Roxbury. Massachusetts. Manuscript received November 13, 1978; revised manuscript received January 31, 1979, accepted February 1, 1979. Address for reprints: Robert D. Rifkin, MD, Lemuel Shattuck Hospital, 170 Morton Street, Jamaica Plain, Massachusetts 02130.
Calcification
Calcification in coronary atherosclerosis versus Monckeberg’s medial sclerosis: Postmortem histologic studies of excised coronary arteries have demonstrated that discrete deposits of coronary calcium in adults are almost invariably located in areas of advanced atheroslcerotic disease.*-6T15 In contrast, in other small and medium-sized muscular arteries of the body, such as the iliac and femoral vessels, calcification may develop as a result of Monckeberg’s medial sclerosis. Involvement of the coronary arteries by Monckeberg’s medial sclerosis is exceedingly rare.15
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The distinction between these two causes of vascular calcification is important because calcification in Monckeberg’s medial sclerosis affects the media of the vessel exclusively and never results in luminal narrowing, whereas atherosclerosis involves the intima and often leads to compromise of the lumen.‘” Radiographically, it may be difficult to distinguish between vascular calcification related to Monckeberg’s medial sclerosis and that associated with atherosclerosis, although differentiation can always be made histologically. The original observation that discrete deposits of coronary calcium were uniquely associated with atherosclerosis was made in 1912 by Faber21 and later corroborated by Monckeberg.22 In reviewing coronary arterial calcification in 1961, Blankenhorn15 reported that a search of German and English studies from 1903 to 1958 revealed no definite cases of Monckeberg’s medial sclerosis of the coronary arteries. To confirm the validity of this observation in a contemporary population, Blankenhorn15 studied at autopsy the coronary arteries of 89 hearts of Los Angeles residents. Microscopic examination of 3,500 coronary arterial segments disclosed that all calcific lesions were related to atherosclerosis. This relation was additionally confirmed in 2,567 subsequent autopsy cases.1-6 However, a single ;exception was recently reported by Lachman et a1.,2” who described the necropsy findings in a 41 year old woman with extensive medial sclerosis of Monckeberg; small deposits of calcium in the media of the left anterior descending coronary artery and its diagonal branches were not associated with atherosclerotic lesions in this patient. Calcification of atherosclerotic plaques: Discrete deposits of calcium in the coronary arteries are most often found in “complicated” atherosclerotic plaques where some necrosis and hemorrhage have occurred.15 However, McCarthy and Palmer4 reported that small deposits may occasionally be observed in fibromuscular plaques close to the internal lamina in the absence of necrosis; these were associated with minimal luminal narrowing. Large deposits (greater than 0.5 cm) were accompanied by necrotic atherosclerotic changes and considerable deposition of lipid and cholesterol. Luminal narrowing of 70 percent or more was more frequently found with these lesions. Distribution of coronary calcification: This distribution was similar in all reported autopsy series. The left anterior descending coronary artery was the most frequently and most heavily calcified of the three major coronary vessels.4,g Calcification was most commonly seen in the proximal 4 cm of the coronary arteries.2*4J.g Eggen et al.” noted that the peak density of calcification occurred between 2 and 4 cm from the origin of both the right coronary artery and the left anterior descending coronary artery. However, calcification was distributed in a more uniform manner along the length of the right coronary artery. Coronary calcification and ischemic heart disease: There was agreement among investigators regarding the relation of calcification to ischemic heart disease. The prevalence of coronary calcification was 142
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greater in subjects with evidence of atherosclerotic heart disease at autopsy than among control subjects, but this difference was less pronounced in the elderly. As evidence of ischemic disease, Beadenkopf et al.’ used the presence of myocardial infarction at necropsy, whereas Eggen et a1.5 used the cause of death (atherosclerotic versus accidental). Calcification was so common at autopsy in the older subjects studied by Eggen et al. that it was necessary to quantitate the extent of calcification, in terms of percent vessel surface area calcified, to observe a difference between the accidental and atherosclerotic deaths in the elderly. Calcification, coronary stenosis and myocardial infarction: A direct relation between the extent of coronary calcification (measured as number of vessels calcified’ or percent surface area calcified” or by a scoring system2T3) and the severity of stenotic lesions or frequency of myocardial infarction was consistently observed in these autopsy series. Vessels without calcification at autopsy exhibited fewer &noses than those with calcium.2,4,” Within the group showing calcification, the more extensively the vessels were calcified the more frequent and the more severe the degree of stenosis.2-” These relations were recognized in all age groups and both sexes, but were most marked in the younger patients. Detection of Coronary Calcification in Living Patients Plain chest X-ray film and conventional fluoroscopy: These techniques are insensitive detectors of coronary calcium in the living subject and reveal calcification only when it is exceptionally heavy. Habbe and Wright24 in 1950 identified calcification in only 3 percent of patients with heart disease over age 40 years on routine cardiac fluoroscopy. Image intensifier fluoroscopy resulted in a major improvement in the detection of coronary calcification. With use of this method, coronary calcification was noted in 15 percent of an unselected population8 and in 54 percent of patients with symptoms of ischemic heart disease.” Image intensifier fluoroscopy and cinefluorography: The most accurate method of detecting calcification is optical viewing of the image intensifier tube, followed closely by cinefluorography with high resolution film.” Television relay of the image intensifier tube is an effective but somewhat inferior technique. Tomography is inadequate because of cardiac motion.” Image intensifier fluoroscopic systems currently in use allow detection of calcific deposits of 2 to 3 rnrn.6,7,9,11In the near future, commercially available image intensifiers may be capable of detecting calcium deposits as small as 1 mm in their largest diameter.7 Clinical Studies of Coronary Calcification Relation to severity of ischemic heart disease: Several clinical investigations found that the frequency of symptoms of ischemic heart disease was greater in subjects with coronary calcification than among those free of fluoroscopically detectable calcium.s-10 A direct relation between the number of vessels calcified and the prevalence of clinically evident ischemic heart disease
CORONARY CALCIFICATION-RIFKIN
was documentedlo; moreover, ischemic heart disease was more common among subjects with severe calcification than among those with lesser degrees of calcification.8 These results are consistent with the findings of autopsy studies. Clinical studies were also in accord with autopsy studies relating coronary calcification to age.8-‘l A progressive increase in the prevalence of fluoroscopitally detectable calcification with increasing age has been noted in subjects with and without symptoms and signs of ischemic heart disease. Prognostic significance: One study regarding the prognostic significance of coronary calcification has been reported. Hudson and Walker7 screened 440 consecutive patients referred for upper gastrointestinal tract X ray series with image intensifier fluoroscopy and identified 78 with coronary arterial calcification. The 5 year survival rate did not differ significantly in this group and an age- and sex-matched control group of 75 subjects who were also selected from the 440 screened patients but had no detectable coronary calcification. A serious defect in this study was the advanced age of the subjects. Eighty-five percent of both the calcification and control groups were over age 60 years and 39 percent were over 70 years. Moreover, the mortality rate was 50 percent in both groups over the 5 year follow-up period (13 percent mortality/year). Among the control subjects under age 60 years, 2 of ll(18 percent) died in the 5 year period (3.9 per cent annual mortality rate). These high mortality rates suggest that the study population was not representative of most clinical groups. Because the investigators did not analyze their data according to cause of death it is not known whether the calcification and control group8 differed with respect to mortality related to ischemic heart disease as such. Correlation with stress testing: In a recent study, Kelly et a1.25correlated the results of fluoroscopy and exercise stress testing in 108 asymptomatic men. They found that ischemic electrocardiographic exercise responses were 8.75 times more common in subjects with fluoroscopically detectable coronary calcification than in those free of calcification and, conversely, that calcification was 3.1 times more common in their subjects who exhibited a positive stress test. Coronary Angiographic Studies Calcification at fluoroscopy as a predictor of coronary stenosis: Despite considerable evidence from
clinical and postmortem investigations suggesting the diagnostic value of detecting coronary calcification, only two studies1”J4 have correlated fluoroscopic with coronary arteriographic findings. The characteristics of these study populations are summarized in Table I, and likelihood ratios calculated from the data are shown in Tables II and III.* In their study of 500 patients, Hamby et al. l3 found an overall sensitivity of 76 percent and a specificity of In both studies, fluoroscopy was performed before arteriography. A fluoroscopic finding of calcification was considered a true positive result if the subject had a major stenosis in any vessel. It was not necessary that stenosis be present in the vessel with calcium or that stenosis be located at the site of the calcium deposit. l
ET AL.
TABLE I Summary of Two Studies Comparing Fluoroscopically Detectable Coronary Calcification Wlth Coronary Anaiograohic Findinos
Patients (no.) Selection Angiographic criterion for significant disease Prevalence of disease in study population Exclusions
78 percent
Hamby et al. I3
Bartel et aLT4
500 Consecutive catheterizations At least one stenosis 250 %
360 Consecutive catheterizations At least one stenosis 370 % 0.74
0.50
Aortic valve disease
associated
None stated
with the finding
of calcium,
yielding a likelihood ratio for stenosis of only 3.52. However, likelihood ratios associated with calcification were higher in their younger subjects. In men less than age 50 years, calcification was associated with a likelihood ratio of 6, whereas among women in this age group the likelihood ratios exceeded 20. Figure 1 indicates that calcification in these men under age 50 is a moderate predictor of stenosis and among women under 50 years it is a strong predictor of major narrowing. Identification of coronary calcification in older patients is not as useful as in younger subjects since the likelihood ratios gradually approach 1 as age increases. The likelihood ratios and sensitivity levels in men under age 50 years are comparable with values associated with a “positive” exercise test. lg In such men, fluoroscopic detection of calcium can be as reliable in the diagnosis of coronary stenosis as the finding of a depressed S-T segment response to exercise. In women under age 50, both the likelihood ratio and the sensitivity of calcification exceed the values associated with a positive exercise stress test. However, the number of young women studied was small, and these findings remain to be confirmed. The absence of calcification was not useful in excluding disease in the subjects studied by Hamby et al., except possibly in men over age 50, among whom the likelihood ratio associated with a negative fluoroscopic examination was equal to 0.26 (Table II). There were insufficient data to draw any conclusions regarding the absence of coronary calcification in women. The sensitivity associated with detectable calcification among the 360 patients studied by Bartel et al. l4 was 56 percent whereas specificity was 95 percent, in-
dicating a likelihood ratio of 11.20. The higher likelihood ratio suggests a greater diagnostic reliability associated with the finding of calcification than is indicated by Hamby’s data. Although the results of these two studies appear to be inconsistent, they may merely reflect the tendency for sensitivity and specificity to vary inversely with changes in resolution or observer threshold.26 The overall likelihood ratios might be in closer accord if the resolution of the fluoroscopic systems were identical. Thus a method is needed to document resolving power at the time of each fluoroscopic examination. July 1979
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TABLE II Likelihood Ratios for al Least One Stenosis of 50 Percent or More Associated WHA the Presence or Absence of Coronary Calcification (according lo the data of Hamby et al.13)
All subjects Men
Women
All ages 30-39 yr 40-49 yr 50-59 yr yr 60-69 370 yr All ages 30-39 yr 40-49 yr 50-59 yr 60-69 yr 370 yr
Likelihood Ratios Calcium Present Calcium Absent
Sensitivity+
Soecificitvt
2501250 2191105 14116 53130 103132
0.76 0.75 0.36 0.62 0.81
0.76 0.74 0.94 0.90 0.72
3.52 2.66 6.00 6.20 2.90
0.31 0.34 0.68 0.42 0.26
43120 615 311145 2123 4138 14152 9127 215
0.86 1.00 0.84 0.50 1.00 0.79 1.00 0.50
0.55 0.00 0.81 1.00 0.95 0.81 0.59 0.21
1.90 1.oo 4:§2
O.? 0.20 0.50 0.00 0.26 0.00 2.50
20.00 4.16 2.44 0.63
D = number of subjects with major stenosis; 5 = number of subjects without major stenosis. + Sensitivity = fraction of subjects with major stenosis who exhibited coronary calcification = true positive/(true positive + false negative). Specificity = fraction of subjects free of major stenosis who were free of calcification = true negative/(true negative + false positive). + Numerator and denominator of likelihood ratio equal 0. § Denominator of likelihood ratio equals zero. l
Combined fluoroscopy and exercise testing as predictors of stenosis: Pending the results of further arteriographic studies relating stenosis to the severity
TABLE III Likelihood Ratios for al Least One Stenosis > 70% Associated With Fluoroscopically Detectable Coronary Calcification (according lo the data of Bartel et al.‘*) Sensitivity
Specificity’
0.56
0.95
l
All study subjects, any detectable calcification Detectable calcification in: 1 vessel 2 vessels 3 vessels
Likelihood Ratios Calcium Calcium Present Absent 11.20
0.46
0.19 0.20 0.17
and distribution of calcification, fluoroscopy can still be used effectively for diagnosis in middle-aged subjects in spite of only moderate likelihood ratios if it is used in conjunction with exercise stress testing. Fluoroscopy and exercise testing are complementary techniques for evaluating coronary artery disease because the finding of calcification provides anatomic evidence of atherosclerosis whereas exercise-induced S-T depression suggests hemodynamic impairment to flow.
See footnote, Table II. + Denominator of likelihood ratio equals 0. l
Similar considerations may apply to the decrease in the value of the likelihood ratio associated with calcification among older subjects in the study of Hamby et al. (Table II). Their data indicate that the specificity of calcification diminishes with age whereas sensitivity is increased. In these older subjects a more detailed classification of calcification, based on its distribution and density rather than simply on its presence or absence, may reveal subgroups in which specificity is improved and likelihood ratios are increased in exchange for a lower sensitivity level. This possibility is supported by the observations of Bartel et al. (Table III), which show that the likelihood ratio associated with coronary calcification increases with the number of vessels in which deposits can be identified. Autopsy data relating stenosis to degree of calcification provide additional supporting evidence. Thus, the diagnostic value of fluoroscopy in older subjects may not be accurately reflected by the likelihood ratios derived from the data available at this time.
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PRE-TEST
RISK
FIGURE 1. Family of curves showing the predictive value as a function of the pretest risk of disease or prevalence of disease in the population. Curves have been constructed for various values of the likelihood ratio, L, according to the likelihood ratio form of &ayes’ theorem (see Appendix 1).
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CALCIFICATION-RIFKIN
ET AL.
TABLE IV Values of the Likellhood Ratio Associated With Various Classes of the S-T Segment Response to Exercise in Men With Detectable Coronary Calcification S-T Segment Response to Exercise (mm of horizontal or downsloping depression) 2.0-2.49
1.5-1.99
1.0-1.49
31 mm Age (yr)
L+
Senr
L
Sen
L
Sen
L
Sen
30-39 40-49 50-59 60-69
44.5 46.0 21.5 14.1
0.22 0.39 0.50 0.54
14.1 14.6 8.8 4.5
0.06 0.11 0.14 0.15
56.3 58.2 27.2 17.8
0.04 0.07 0.09 0.10
127.8 132.2 61.9 40.5
0.05 0.08 0.10 0.11
Downsloping S-T* L Sen 385.8 398.7 186.5 122.2
0.16 0.28 0.38 0.39
Downsloping S-T segment with 1 mm or more J point depression. + L = likelihood ratio for the presence of at least one stenosis of 50 percent or greater associated with the finding of detectable coronary calcification and the indicated level of S-T depression. * Sen = sensitivity: the fraction of subjects with at least one stenosis of 50 percent or greater who will exhibit both the indicated level of S-T depression and detectable coronary calcification. For two independent tests the sensitivity of a combined result is equal to the product of the individual test sensitivitv levels (Aooendix 2). Thus. coronarv calcification and S-T depression of 1 mm or more in a 30 to 39 year old man has a sensitivity level of aboui0.61 x’O.‘3;s = 0.22. ’ l
Although arteriographic data for combinations of exercise stress testing and fluoroscopy have not been reported, a quantitative estimate of the diagnostic potential of this approach can be made by calculating the likelihood ratios for such combinations as the product of the likelihood ratios associated with the patient’s exercise response and fluoroscopic result. Similarly, the sensitivity or specificity of a joint result is equal to the product of the sensitivity or specificity levels, respectively, of the test results that constitute the combination (Appendix 2). For example, the prevalence of disease in subjects with chest pain atypical of ischemia is between 0.23 and 0.60.27 Ischemic S-T depression of 1.0 to 1.49 mm (likelihood ratio = 2.35)lg would increase risk to only 0.41 to 0.78. However, if fluoroscopy revealed calcification, the probability of disease in a man aged 40 to 49 years with this exercise response would reach 0.81 to 0.95 (combined likelihood ratio of 2.35 X 6 = 14.1). Conversely, if less than 0.5 mm of S-T depression were found and no calcification were present in this same subject, the probability of disease would be reduced to 0.03 to 0.15 (combined likelihood ratio of 0.12). Tables IV and V list the likelihood ratios and sensitivity levels associated with various combinations of S-Tsegment responses and fluoroscopic findings* and
can be used in conjunction with Figure 1 to determine the probability of disease associated with any set of results when the pretest risk is known (Appendix 1). It is evident from these tables that combined use of fluoroscopy and exercise stress testing may substantially enhance diagnostic reliability when test results are concordant (both test results associated with likelihood ratios greater than 1 or both associated with likelihood ratios less than 1). Discordant test results-for example, a positive exercise test and negative fluoroscopic result-will be associated with intermediate values of the likelihood ratio and, with some exceptions, will not be ’ The data of Hamby et aLi were used to calculate these combined likelihood ratios because they take into account age and sex variations, whereas the data of Sartel et al.14 do not. Values of the likelihood ratio for S-T depression were obtained from published data.lg
TABLE V Likelihood Ratios Associated With the Finding of a “Negative” Exercise Test and Absent Coronary Calcification in Men S-T Segment Response to Exercise (mm S-T depression)
Coronary Calcification in the Diagnosis of Coronary Artery Disease ROBERT D. RIFKIN, MD ALFRED F. PARISI, MD, FACC EDWARD FOLLAND, MD West Roxbury, Massachusetts
Clinical, postmortem and angiographic studies ot coronary caicitication are reviewed to define the value of fluoroscopy in the diagnosis and management of coronary artery disease. Autopsy studies consistently show a unique association between calcification of the coronary arteries and atherosclerosis. The relation of coronary calcification to the presence of major stenosis is more variable but is strong enough to be of clinical value, particularly in the younger subject. The diagnostic value of fluoroscopy can be improved by attention to the detailed features of calcitication observed with the technique. Combined use of fluoroscopy and exercise testkg appears to be a valid and as yet unexploited approach to the noninvasive diagnosis bf coronary stenosis. Fluoroscopy has been a neglected method of noninvasive diagnosis and is sufficiently promising to warrant greater clinical use.
The extensive mortality and morbidity associated with ischemic heart disease in the United States have stimulated the search for noninvasive methods to assist the clinician in the diagnosis of coronary arterial stenosis. Although the fluoroscopic detection of coronary calcification has received much attention,‘-I5 fluoroscopy has been largely neglected by clinicians in evaluating patients with possible coronary disease. This neglect may be due in part to the high predictive values reported in early studies of exercise stress testing. 16-18As further experience with stress electrocardiography has accumulated, major limitations in its predictive potential have emerged. 1g~20Recognition of the diagnostic limitations inherent in electrocardiographic exercise stress testing suggests that the fluoroscopic examination for calcification of the coronary arteries deserves reevaluation. In this communication we review the diagnostic significance of coronary calcification with major emphasis on studies correlating the fluoroscopic examination with the angiographic appearance of the coronary arteries. The likelihood ratio formulation of Bayes’ theorem is used in this review to analyze data from studies comparing fluoroscopy with selective angiography. It has recently been shown that likelihood ratio analysis offers a convenient means of characterizing the diagnostic performance of a test.lg A synopsis of Bayesian analysis is presented in Appendix 1 and 2. Autopsy Studies of Coronary From the Cardiology Departments, the Lemuel Shattuck Hospital, Jamaica Plain, Massachusetts and the United States Veterans Administration Hospital, West Roxbury. Massachusetts. Manuscript received November 13, 1978; revised manuscript received January 31, 1979, accepted February 1, 1979. Address for reprints: Robert D. Rifkin, MD, Lemuel Shattuck Hospital, 170 Morton Street, Jamaica Plain, Massachusetts 02130.
Calcification
Calcification in coronary atherosclerosis versus Monckeberg’s medial sclerosis: Postmortem histologic studies of excised coronary arteries have demonstrated that discrete deposits of coronary calcium in adults are almost invariably located in areas of advanced atheroslcerotic disease.*-6T15 In contrast, in other small and medium-sized muscular arteries of the body, such as the iliac and femoral vessels, calcification may develop as a result of Monckeberg’s medial sclerosis. Involvement of the coronary arteries by Monckeberg’s medial sclerosis is exceedingly rare.15
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ET AL.
The distinction between these two causes of vascular calcification is important because calcification in Monckeberg’s medial sclerosis affects the media of the vessel exclusively and never results in luminal narrowing, whereas atherosclerosis involves the intima and often leads to compromise of the lumen.‘” Radiographically, it may be difficult to distinguish between vascular calcification related to Monckeberg’s medial sclerosis and that associated with atherosclerosis, although differentiation can always be made histologically. The original observation that discrete deposits of coronary calcium were uniquely associated with atherosclerosis was made in 1912 by Faber21 and later corroborated by Monckeberg.22 In reviewing coronary arterial calcification in 1961, Blankenhorn15 reported that a search of German and English studies from 1903 to 1958 revealed no definite cases of Monckeberg’s medial sclerosis of the coronary arteries. To confirm the validity of this observation in a contemporary population, Blankenhorn15 studied at autopsy the coronary arteries of 89 hearts of Los Angeles residents. Microscopic examination of 3,500 coronary arterial segments disclosed that all calcific lesions were related to atherosclerosis. This relation was additionally confirmed in 2,567 subsequent autopsy cases.1-6 However, a single ;exception was recently reported by Lachman et a1.,2” who described the necropsy findings in a 41 year old woman with extensive medial sclerosis of Monckeberg; small deposits of calcium in the media of the left anterior descending coronary artery and its diagonal branches were not associated with atherosclerotic lesions in this patient. Calcification of atherosclerotic plaques: Discrete deposits of calcium in the coronary arteries are most often found in “complicated” atherosclerotic plaques where some necrosis and hemorrhage have occurred.15 However, McCarthy and Palmer4 reported that small deposits may occasionally be observed in fibromuscular plaques close to the internal lamina in the absence of necrosis; these were associated with minimal luminal narrowing. Large deposits (greater than 0.5 cm) were accompanied by necrotic atherosclerotic changes and considerable deposition of lipid and cholesterol. Luminal narrowing of 70 percent or more was more frequently found with these lesions. Distribution of coronary calcification: This distribution was similar in all reported autopsy series. The left anterior descending coronary artery was the most frequently and most heavily calcified of the three major coronary vessels.4,g Calcification was most commonly seen in the proximal 4 cm of the coronary arteries.2*4J.g Eggen et al.” noted that the peak density of calcification occurred between 2 and 4 cm from the origin of both the right coronary artery and the left anterior descending coronary artery. However, calcification was distributed in a more uniform manner along the length of the right coronary artery. Coronary calcification and ischemic heart disease: There was agreement among investigators regarding the relation of calcification to ischemic heart disease. The prevalence of coronary calcification was 142
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greater in subjects with evidence of atherosclerotic heart disease at autopsy than among control subjects, but this difference was less pronounced in the elderly. As evidence of ischemic disease, Beadenkopf et al.’ used the presence of myocardial infarction at necropsy, whereas Eggen et a1.5 used the cause of death (atherosclerotic versus accidental). Calcification was so common at autopsy in the older subjects studied by Eggen et al. that it was necessary to quantitate the extent of calcification, in terms of percent vessel surface area calcified, to observe a difference between the accidental and atherosclerotic deaths in the elderly. Calcification, coronary stenosis and myocardial infarction: A direct relation between the extent of coronary calcification (measured as number of vessels calcified’ or percent surface area calcified” or by a scoring system2T3) and the severity of stenotic lesions or frequency of myocardial infarction was consistently observed in these autopsy series. Vessels without calcification at autopsy exhibited fewer &noses than those with calcium.2,4,” Within the group showing calcification, the more extensively the vessels were calcified the more frequent and the more severe the degree of stenosis.2-” These relations were recognized in all age groups and both sexes, but were most marked in the younger patients. Detection of Coronary Calcification in Living Patients Plain chest X-ray film and conventional fluoroscopy: These techniques are insensitive detectors of coronary calcium in the living subject and reveal calcification only when it is exceptionally heavy. Habbe and Wright24 in 1950 identified calcification in only 3 percent of patients with heart disease over age 40 years on routine cardiac fluoroscopy. Image intensifier fluoroscopy resulted in a major improvement in the detection of coronary calcification. With use of this method, coronary calcification was noted in 15 percent of an unselected population8 and in 54 percent of patients with symptoms of ischemic heart disease.” Image intensifier fluoroscopy and cinefluorography: The most accurate method of detecting calcification is optical viewing of the image intensifier tube, followed closely by cinefluorography with high resolution film.” Television relay of the image intensifier tube is an effective but somewhat inferior technique. Tomography is inadequate because of cardiac motion.” Image intensifier fluoroscopic systems currently in use allow detection of calcific deposits of 2 to 3 rnrn.6,7,9,11In the near future, commercially available image intensifiers may be capable of detecting calcium deposits as small as 1 mm in their largest diameter.7 Clinical Studies of Coronary Calcification Relation to severity of ischemic heart disease: Several clinical investigations found that the frequency of symptoms of ischemic heart disease was greater in subjects with coronary calcification than among those free of fluoroscopically detectable calcium.s-10 A direct relation between the number of vessels calcified and the prevalence of clinically evident ischemic heart disease
CORONARY CALCIFICATION-RIFKIN
was documentedlo; moreover, ischemic heart disease was more common among subjects with severe calcification than among those with lesser degrees of calcification.8 These results are consistent with the findings of autopsy studies. Clinical studies were also in accord with autopsy studies relating coronary calcification to age.8-‘l A progressive increase in the prevalence of fluoroscopitally detectable calcification with increasing age has been noted in subjects with and without symptoms and signs of ischemic heart disease. Prognostic significance: One study regarding the prognostic significance of coronary calcification has been reported. Hudson and Walker7 screened 440 consecutive patients referred for upper gastrointestinal tract X ray series with image intensifier fluoroscopy and identified 78 with coronary arterial calcification. The 5 year survival rate did not differ significantly in this group and an age- and sex-matched control group of 75 subjects who were also selected from the 440 screened patients but had no detectable coronary calcification. A serious defect in this study was the advanced age of the subjects. Eighty-five percent of both the calcification and control groups were over age 60 years and 39 percent were over 70 years. Moreover, the mortality rate was 50 percent in both groups over the 5 year follow-up period (13 percent mortality/year). Among the control subjects under age 60 years, 2 of ll(18 percent) died in the 5 year period (3.9 per cent annual mortality rate). These high mortality rates suggest that the study population was not representative of most clinical groups. Because the investigators did not analyze their data according to cause of death it is not known whether the calcification and control group8 differed with respect to mortality related to ischemic heart disease as such. Correlation with stress testing: In a recent study, Kelly et a1.25correlated the results of fluoroscopy and exercise stress testing in 108 asymptomatic men. They found that ischemic electrocardiographic exercise responses were 8.75 times more common in subjects with fluoroscopically detectable coronary calcification than in those free of calcification and, conversely, that calcification was 3.1 times more common in their subjects who exhibited a positive stress test. Coronary Angiographic Studies Calcification at fluoroscopy as a predictor of coronary stenosis: Despite considerable evidence from
clinical and postmortem investigations suggesting the diagnostic value of detecting coronary calcification, only two studies1”J4 have correlated fluoroscopic with coronary arteriographic findings. The characteristics of these study populations are summarized in Table I, and likelihood ratios calculated from the data are shown in Tables II and III.* In their study of 500 patients, Hamby et al. l3 found an overall sensitivity of 76 percent and a specificity of In both studies, fluoroscopy was performed before arteriography. A fluoroscopic finding of calcification was considered a true positive result if the subject had a major stenosis in any vessel. It was not necessary that stenosis be present in the vessel with calcium or that stenosis be located at the site of the calcium deposit. l
ET AL.
TABLE I Summary of Two Studies Comparing Fluoroscopically Detectable Coronary Calcification Wlth Coronary Anaiograohic Findinos
Patients (no.) Selection Angiographic criterion for significant disease Prevalence of disease in study population Exclusions
78 percent
Hamby et al. I3
Bartel et aLT4
500 Consecutive catheterizations At least one stenosis 250 %
360 Consecutive catheterizations At least one stenosis 370 % 0.74
0.50
Aortic valve disease
associated
None stated
with the finding
of calcium,
yielding a likelihood ratio for stenosis of only 3.52. However, likelihood ratios associated with calcification were higher in their younger subjects. In men less than age 50 years, calcification was associated with a likelihood ratio of 6, whereas among women in this age group the likelihood ratios exceeded 20. Figure 1 indicates that calcification in these men under age 50 is a moderate predictor of stenosis and among women under 50 years it is a strong predictor of major narrowing. Identification of coronary calcification in older patients is not as useful as in younger subjects since the likelihood ratios gradually approach 1 as age increases. The likelihood ratios and sensitivity levels in men under age 50 years are comparable with values associated with a “positive” exercise test. lg In such men, fluoroscopic detection of calcium can be as reliable in the diagnosis of coronary stenosis as the finding of a depressed S-T segment response to exercise. In women under age 50, both the likelihood ratio and the sensitivity of calcification exceed the values associated with a positive exercise stress test. However, the number of young women studied was small, and these findings remain to be confirmed. The absence of calcification was not useful in excluding disease in the subjects studied by Hamby et al., except possibly in men over age 50, among whom the likelihood ratio associated with a negative fluoroscopic examination was equal to 0.26 (Table II). There were insufficient data to draw any conclusions regarding the absence of coronary calcification in women. The sensitivity associated with detectable calcification among the 360 patients studied by Bartel et al. l4 was 56 percent whereas specificity was 95 percent, in-
dicating a likelihood ratio of 11.20. The higher likelihood ratio suggests a greater diagnostic reliability associated with the finding of calcification than is indicated by Hamby’s data. Although the results of these two studies appear to be inconsistent, they may merely reflect the tendency for sensitivity and specificity to vary inversely with changes in resolution or observer threshold.26 The overall likelihood ratios might be in closer accord if the resolution of the fluoroscopic systems were identical. Thus a method is needed to document resolving power at the time of each fluoroscopic examination. July 1979
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143
CORONARY CALCIFICATION-RIFKIN
ET AL.
TABLE II Likelihood Ratios for al Least One Stenosis of 50 Percent or More Associated WHA the Presence or Absence of Coronary Calcification (according lo the data of Hamby et al.13)
All subjects Men
Women
All ages 30-39 yr 40-49 yr 50-59 yr yr 60-69 370 yr All ages 30-39 yr 40-49 yr 50-59 yr 60-69 yr 370 yr
Likelihood Ratios Calcium Present Calcium Absent
Sensitivity+
Soecificitvt
2501250 2191105 14116 53130 103132
0.76 0.75 0.36 0.62 0.81
0.76 0.74 0.94 0.90 0.72
3.52 2.66 6.00 6.20 2.90
0.31 0.34 0.68 0.42 0.26
43120 615 311145 2123 4138 14152 9127 215
0.86 1.00 0.84 0.50 1.00 0.79 1.00 0.50
0.55 0.00 0.81 1.00 0.95 0.81 0.59 0.21
1.90 1.oo 4:§2
O.? 0.20 0.50 0.00 0.26 0.00 2.50
20.00 4.16 2.44 0.63
D = number of subjects with major stenosis; 5 = number of subjects without major stenosis. + Sensitivity = fraction of subjects with major stenosis who exhibited coronary calcification = true positive/(true positive + false negative). Specificity = fraction of subjects free of major stenosis who were free of calcification = true negative/(true negative + false positive). + Numerator and denominator of likelihood ratio equal 0. § Denominator of likelihood ratio equals zero. l
Combined fluoroscopy and exercise testing as predictors of stenosis: Pending the results of further arteriographic studies relating stenosis to the severity
TABLE III Likelihood Ratios for al Least One Stenosis > 70% Associated With Fluoroscopically Detectable Coronary Calcification (according lo the data of Bartel et al.‘*) Sensitivity
Specificity’
0.56
0.95
l
All study subjects, any detectable calcification Detectable calcification in: 1 vessel 2 vessels 3 vessels
Likelihood Ratios Calcium Calcium Present Absent 11.20
0.46
0.19 0.20 0.17
and distribution of calcification, fluoroscopy can still be used effectively for diagnosis in middle-aged subjects in spite of only moderate likelihood ratios if it is used in conjunction with exercise stress testing. Fluoroscopy and exercise testing are complementary techniques for evaluating coronary artery disease because the finding of calcification provides anatomic evidence of atherosclerosis whereas exercise-induced S-T depression suggests hemodynamic impairment to flow.
See footnote, Table II. + Denominator of likelihood ratio equals 0. l
Similar considerations may apply to the decrease in the value of the likelihood ratio associated with calcification among older subjects in the study of Hamby et al. (Table II). Their data indicate that the specificity of calcification diminishes with age whereas sensitivity is increased. In these older subjects a more detailed classification of calcification, based on its distribution and density rather than simply on its presence or absence, may reveal subgroups in which specificity is improved and likelihood ratios are increased in exchange for a lower sensitivity level. This possibility is supported by the observations of Bartel et al. (Table III), which show that the likelihood ratio associated with coronary calcification increases with the number of vessels in which deposits can be identified. Autopsy data relating stenosis to degree of calcification provide additional supporting evidence. Thus, the diagnostic value of fluoroscopy in older subjects may not be accurately reflected by the likelihood ratios derived from the data available at this time.
744
July 1979
The American Journal of CARDIOLOGY
Volume 44
PRE-TEST
RISK
FIGURE 1. Family of curves showing the predictive value as a function of the pretest risk of disease or prevalence of disease in the population. Curves have been constructed for various values of the likelihood ratio, L, according to the likelihood ratio form of &ayes’ theorem (see Appendix 1).
CORONARY
CALCIFICATION-RIFKIN
ET AL.
TABLE IV Values of the Likellhood Ratio Associated With Various Classes of the S-T Segment Response to Exercise in Men With Detectable Coronary Calcification S-T Segment Response to Exercise (mm of horizontal or downsloping depression) 2.0-2.49
1.5-1.99
1.0-1.49
31 mm Age (yr)
L+
Senr
L
Sen
L
Sen
L
Sen
30-39 40-49 50-59 60-69
44.5 46.0 21.5 14.1
0.22 0.39 0.50 0.54
14.1 14.6 8.8 4.5
0.06 0.11 0.14 0.15
56.3 58.2 27.2 17.8
0.04 0.07 0.09 0.10
127.8 132.2 61.9 40.5
0.05 0.08 0.10 0.11
Downsloping S-T* L Sen 385.8 398.7 186.5 122.2
0.16 0.28 0.38 0.39
Downsloping S-T segment with 1 mm or more J point depression. + L = likelihood ratio for the presence of at least one stenosis of 50 percent or greater associated with the finding of detectable coronary calcification and the indicated level of S-T depression. * Sen = sensitivity: the fraction of subjects with at least one stenosis of 50 percent or greater who will exhibit both the indicated level of S-T depression and detectable coronary calcification. For two independent tests the sensitivity of a combined result is equal to the product of the individual test sensitivitv levels (Aooendix 2). Thus. coronarv calcification and S-T depression of 1 mm or more in a 30 to 39 year old man has a sensitivity level of aboui0.61 x’O.‘3;s = 0.22. ’ l
Although arteriographic data for combinations of exercise stress testing and fluoroscopy have not been reported, a quantitative estimate of the diagnostic potential of this approach can be made by calculating the likelihood ratios for such combinations as the product of the likelihood ratios associated with the patient’s exercise response and fluoroscopic result. Similarly, the sensitivity or specificity of a joint result is equal to the product of the sensitivity or specificity levels, respectively, of the test results that constitute the combination (Appendix 2). For example, the prevalence of disease in subjects with chest pain atypical of ischemia is between 0.23 and 0.60.27 Ischemic S-T depression of 1.0 to 1.49 mm (likelihood ratio = 2.35)lg would increase risk to only 0.41 to 0.78. However, if fluoroscopy revealed calcification, the probability of disease in a man aged 40 to 49 years with this exercise response would reach 0.81 to 0.95 (combined likelihood ratio of 2.35 X 6 = 14.1). Conversely, if less than 0.5 mm of S-T depression were found and no calcification were present in this same subject, the probability of disease would be reduced to 0.03 to 0.15 (combined likelihood ratio of 0.12). Tables IV and V list the likelihood ratios and sensitivity levels associated with various combinations of S-Tsegment responses and fluoroscopic findings* and
can be used in conjunction with Figure 1 to determine the probability of disease associated with any set of results when the pretest risk is known (Appendix 1). It is evident from these tables that combined use of fluoroscopy and exercise stress testing may substantially enhance diagnostic reliability when test results are concordant (both test results associated with likelihood ratios greater than 1 or both associated with likelihood ratios less than 1). Discordant test results-for example, a positive exercise test and negative fluoroscopic result-will be associated with intermediate values of the likelihood ratio and, with some exceptions, will not be ’ The data of Hamby et aLi were used to calculate these combined likelihood ratios because they take into account age and sex variations, whereas the data of Sartel et al.14 do not. Values of the likelihood ratio for S-T depression were obtained from published data.lg
TABLE V Likelihood Ratios Associated With the Finding of a “Negative” Exercise Test and Absent Coronary Calcification in Men S-T Segment Response to Exercise (mm S-T depression)
