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Section 1. Correlating Calcium Score and Atherosclerotic Plaque

Section 2: Correlating Electron Beam CT with Angiographic and Myocardial Perfusion Abnormalities

Section 3: The Prognostic Value of EBCT

Section 4: Using EBCT to Track Progression or Regression of Coronary Atherosclerosis

Section 1. Correlating Calcium Score and Atherosclerotic Plaque

These two articles demonstrate the intimate relationship between the amount of calcium in the coronaries as measured with EBCT and the amount of atherosclerotic plaque as measured by traditional pathologic staining methods. In effect, the calcium score measures the total plaque burden in the artery walls, which is the best predictor of future risk for coronary events.

1. Coronary Artery Calcium Area by Electron Beam Computed Tomography and Coronary Atherosclerotic Plaque Area- A Histopathologic Correlative Study

Methods and Results: 38 coronary arteries from 13 autopsy hearts were dissected, straightened, and scanned with EBCT in 3-mm contiguous increments. Coronary calcium area was defined as one or more pixels with a density >130 Hounsfield units. Each artery was divided into corresponding 3-mm segments, representative histological sections were stained, and Atherosclerotic plaque area per segment (mm2) was quantified. Coronary artery calcium and coronary artery plaque areas were correlated for the hearts as a whole, for individual coronary arteries, and for individual coronary artery segments. The sums of histological plaque areas versus the sums of calcium areas were highly correlated for each heart and for each coronary artery. However, coronary plaque area was on the order of 5 times greater than calcium area. Furthermore, minimal diffuse segmental coronary plaque could be present despite absence of coronary calcium detectable by EBCT.

Conclusions: This histopathologic study confirms an intimate relation between whole heart, coronary artery, and segmental coronary atherosclerotic plaque area and EBCT coronary calcium area but suggests there is a threshold value for plaque area below which coronary calcium is either absent or not detectable by this methodology.
Rumberger, et al. Circulation 1995; 92: 2157-2162

2. Arterial Calcification and Not Lumen Stenosis Is Highly Correlated With Atherosclerotic Plaque Burden in Humans: A Histologic Study of 723 Coronary Artery Segments Using Nondecalcifying Methodology

Objectives: This study was designed to evaluate whether calcium deposition in the coronary arteries is related to atherosclerotic plaque burden and narrowing of the arterial lumen.

Methods: A total of 37 nondecalcified coronary arteries were processed, sectioned at 3-mm intervals and evaluated by computer planimetry and densitometry.

Results: A significant relation between calcium area and plaque area was found on a per-heart basis (n=13, r=0.87, p<0.0001), per artery basis (left anterior descending: n=13, r=0.89, p <0.0001; left circumflex artery: n=11, r=0.7, p<0.001; right coronary artery: n=13, r=0.89, p<0.0001) and per segment basis (n=723, r=0.52, p<0.0001)….

Conclusions: Coronary calcium quantification is an excellent method for assessing atherosclerotic plaque presence at individual artery sites. Moreover, the amount of calcium correlates with the overall magnitude of atherosclerotic plaque burden.
Sangiorgi, G, et al. J Am Coll Cardiol 1998; 31:126-33

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Section 2: Correlating Electron Beam CT with Angiographic and Myocardial Perfusion Abnormalities

These three articles show how EBCT compares with other modalities used in the diagnosis of coronary heart disease (CHD). The first article demonstrates that a simple equation using the calcium scores in the left anterior descending and the circumflex arteries plus two other risk factors can very accurately predict the presence or absence of left main or three vessel disease in patients with symptoms suggestive of CHD.

The second article indicates that EBCT is more powerful than stress thallium testing or risk factors in predicting the presence of angiographically significant CHD. The third article shows that EBCT is a powerful tool for risk-stratifying patients into groups with low, intermediate, or high likelihood of having abnormal myocardial perfusion on radionuclide stress testing. Taken together, these articles provide a useful cross-section of the many articles in the literature that have shown the validity of the coronary calcium score as a predictor of significant CHD. Conversely, low scores are indicative of a low probability for angiographically significant CHD.

1. An Algorithm for Noninvasive Identification of Angiographic Three Vessel and/or Left Main Coronary Artery Disease in Symptomatic Patients on the Basis of Cardiac Risk and Electron Beam Computed Tomographic Calcium Scores

Objectives: We sought an algorithm for noninvasive identification of angiographically obstructive three-vessel disease based on conventional cardiac risk assessment and site and extent of coronary calcium determined by EBCT.

Methods: Examined 291 patients with suspected, but not previously diagnosed, CAD who underwent coronary Angiography for clinical indications. Cardiac risk factors were determined as defined by the National Cholesterol Education Program. An EBCT scan was performed in all patients, and a coronary calcium score (Agatston method) was computed. Total per-patient calcium scores and separate scores for major arteries were generated. These scores were also analyzed for localization of coronary calcium in the more distal versus proximal tomographic sections. These parameters and the risk factors were considered for the model described in the following section.

Results: Sixty-eight patients (23%) had angiographic three-vessel and/or left main CAD. Multiple logistic regression analysis determined male sex, presence of diabetes and left anterior descending (LAD) and circumflex (LCx) coronary calcium scores, independent from more distal calcium localization, as independent predictors for identification of three-vessel and/or left main CAD. Based on this four variable model, a simple noninvasive index (NI) was constructed as the following: loge(LAD score) + loge(LCx score) + 2[if diabetic] + 3[if male]. Receiver operating characteristic analysis for this NI yielded an area under the curve of 0.88 +/-0.03 (p<0.0001) for separating patients with versus without Angiographic three-vessel and/or left main CAD. Various NI cutpoints demonstrated sensitivities from 87-97% and specificities from 46-74%. The NI values >14 increased the probability of Angiographic three-vessel and/or left main CAD from 23% (pre-test) to 65-100% (post-test), and NI values <10 increased the probability of no three-vessel and/or left main CAD from 77% (pre-test) to 95-100% (post-test).

Conclusions: On the basis of a simple algorithm ("noninvasive index"), EBCT calcium scanning in conjunction with risk factor analysis can rule in or rule out angiographically severe disease, i.e., three-vessel and/or left main CAD, in symptomatic patients.
Schmermund, A, et al. J Am Coll Cardiol 1999; 33:444-52

2. Independent and Incremental Value of Coronary Artery Calcium for Predicting the Extent of Angiographic Coronary Artery Disease

Objectives: The study was done to test the ability to predict the extent of angiographically determined coronary artery disease (CAD) by quantification of coronary calcium using electron beam computed tomography (EBCT) and to compare it with more conventional parameters for delineating the angiographic extent of CAD, that is, cardiovascular risk factors and radionuclide single-photon emission computed tomography (SPECT).

Background: The angiographic extent of CAD is a powerful predictor of future events. Use of EBCT may be able to define it by virtue of its ability to determine plaque burden.

Methods: We examined 308 patients presenting with suspected but not previously known CAD who underwent selective coronary Angiography. As measures of the angiographic extent of CAD, coronary artery greater even 20 (CAGE ³ 20) and CAGE ³ 50 scores represented the total number of coronary segments with ³ 20% or ³ 50% stenoses, respectively. The EBCT-derived total calcium scores were obtained in 291 patients, risk factors as defined by the National Cholesterol Education Program in 239 patients, and SPECT scans in 136 patients.

Results: Using multiple linear regression analysis, total calcium scores were better independent predictors of both CAGE ³ 20 and CAGE ³ 50 scores than either a SPECT-derived radionuclide perfusion score or the risk factors age, male gender and ratio of total/high density lipoprotein (HDL) cholesterol. The association between EBCT and angiographic scores remained highly significant after excluding the influence of all interrelated risk factors and SPECT variables (r = 0.65; p < 0.001 for CAGE ³ 20 scores, r = 0.50; p < 0.001 for CAGE ³ 50 scores).

Conclusions: Coronary calcium predicts the angiographic extent of CAD in symptomatic patients and provides independent and incremental information to the more conventional clinical parameters derived from SPECT or risk assessment.
Schermund,A, et al. J Am Coll Cardiol 1999;34:777-86

3. Severity of Coronary Artery Calcification by Electron Beam Computed Tomography Predicts Silent Myocardial Ischemia

Background: Detection of subclinical coronary artery disease (CAD) before the development of life-threatening cardiac complications has great potential clinical relevance. Electron beam computed tomography (EBCT) is currently the only noninvasive test that can detect CAD in all stages of its development and thus has the potential to be an excellent screening technique for identifying asymptomatic subjects with underlying myocardial ischemia.

Methods and Results: Over 2.5 years, we prospectively studied 3,895 generally asymptomatic subjects with EBCT, 411 of whom had stress myocardial perfusion tomography (SPECT) within a close (median, 17 days) time period. SPECT and exercise treadmill results were compared with the coronary artery calcium score (CACS) as assessed by EBCT. The total CACS identified a population at high risk for having myocardial ischemia by SPECT although only a minority of subjects (22%) with an abnormal EBCT had an abnormal SPECT. No subject with CACS < 10 had an abnormal SPECT compared with 2.6% of those with scores from 11-100, 11.3% of those with scores from 101 to 399, and 46% of those with scores ³ 400 (p < 0.0001). CACS predicted an abnormal SPECT regardless of subject age or sex.

Conclusions: CACS identifies a high-risk group of asymptomatic subjects who have clinically important silent myocardial ischemia. Our results support the role of EBCT as the initial screening tool for identifying individuals at various stages of CAD development for whom therapeutic decision making may differ considerably.
Zuo-Xiang,H, et al. Circulation 2000;101:244-251

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Section 3: The Prognostic Value of EBCT

The following two articles demonstrate the power of EBCT to predict future cardiovascular events. The first article shows that a calcium score over 160 confers a 20 to 35-fold increase in risk, while the second paper was able to show that patients in the highest age-sex matched quartile of calcium scores had a 59-fold increase in risk compared with those in the lowest quartile. This suggests that the rate of progression of calcium scores is a more powerful predictor than the absolute scores. Patients with mild to moderate scores, but whose scores are above the 50th percentile for their age and sex, should receive aggressive risk factor modification.

1. Predictive Value of Electron Beam Computed Tomography of the Coronary Arteries

Background: Coronary electron beam computed tomography (EBCT) detects atherosclerotic coronary artery disease by measuring calcium deposition in the walls of coronary arteries. EBCT-derived coronary artery calcium (CAC) scores correlate with the severity of underlying coronary artery disease.

Methods and Results: We followed 1173 asymptomatic patients who underwent EBCT between September 1993 and March 1994. During average follow-up of 19 months, 18 subjects had 26 cardiovascular events: 1 death, 7 myocardial infarctions, 8 coronary artery bypass graft procedures, 9 coronary angioplasties, and 1 nonhemorrhagic stroke. For CAC score thresholds of 100, 160, and 680, EBCT had sensitivities of 89%, 89%, and 50% and specificities of 77%, 82%, and 95%, respectively. Odds ratios ranged from 20.0 to 35.4 (p<0.00001 for all).

Conclusions: Coronary EBCT predicts future atherosclerotic cardiovascular disease events in asymptomatic subjects.
Arad,Y et al. Circulation 1996;93:1951-53

2. Identification of Patients at Increased Risk of First Unheralded Acute Myocardial Infarction by Electron Beam Computed Tomography

Background: There is a clear relationship between absolute calcium scores (CS) and severity of coronary artery disease. However, hard coronary events have been shown to occur across all ranges of CS.

Methods and Results: We conducted 2 analyses: in group A, 172 patients underwent EBCT imaging within 60 days of suffering an unheralded myocardial infarction. In group B, 632 patients screened by EBCT were followed up for a mean of 32 +/- 7 months for the development of acute myocardial infarction or cardiac death. The mean patient age and prevalence of coronary calcification were similar in the 2 groups (53 +/- 8 versus 52 +/- 9 years and 96% each). In group B, the annualized event rate was 0.11% for subjects with CS of 0, 2.1% for CS 1 to 99, 4.1% for CS 100 to 400, and 4.8% for CS>400. However, mild, moderate, and extensive absolute CSs were distributed similarly between patients with events in both groups (34%, 35%, and 27%, respectively, in group A and 44%, 30%, and 22% in group B). In contrast, the majority of events in both groups occurred in patients with CS > 75th percentile (70% in each group).

Conclusions: Coronary calcium is present in most patients who suffer acute coronary events. Although the event rate is greater for patients with high absolute CSs, few patients have this degree of calcification on a screening EBCT. Conversely, the majority of events occur in individuals with high CS percentiles. Hence, CS percentiles constitute a more effective screening method to stratify individuals at risk.
Raggi,P et al. Circulation 2000;101:850-55.

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Section 4: Using EBCT to Track Progression or Regression of Coronary Atherosclerosis

EBCT is the only noninvasive test that can be used to assess response to therapeutic interventions aimed at shrinking coronary plaque. The first article describes a 12-15 month study showing that statin treatment results in stabilization and even shrinkage of plaque burden, while no statin treatment can result in a 50% increase in plaque burden. The second article found that patients whose scores increase over a 12-36 month study period experience a 10-fold increase in risk of coronary events when compared to patients whose scores remain stabilized.

1. Effect of HMG-CoA Reductase Inhibitors on Coronary Artery Disease as Assessed by Electron Beam Computed Tomography

Background: Angiographic studies of the regression of coronary artery disease are invasive and costly, and they permit only limited assessment of changes in the extent of atherosclerotic disease. EBCT is noninvasive and inexpensive. The entire coronary artery tree can be studied during a single imaging session, and the volume of coronary calcification as quantified with this technique correlates closely with the total burden of atherosclerotic plaque.

Methods: We conducted a retrospective study of 149 patients (61% men and 39% women; age range, 32 to 75 years) with no history of coronary artery disease who were referred by their primary care physicians for screening EBCT. All patients underwent baseline scanning and follow-up assessment after a minimum of 12 months (range, 12 to 15), and a volumetric calcium score was calculated as an estimate of the total burden of plaque. Treatment with HMG-CoA inhibitors (statins) was begun at the discretion of the referring physician. Serial measurements of LDL cholesterol were obtained, and the change in the calcium volume score was correlated with average LDL cholesterol levels.

Results: 105 patients (70%) received treatment with statins, and 44 patients (30%) did not. At follow-up, a net reduction in the calcium volume score was observed only in the 65 treated patients whose final LDL cholesterol levels were less than 120 mg/dl (mean change in the score, -7 +/- 23%; p=0.01). Untreated patients had an average LDL cholesterol level of at least 120 and at the time of follow-up had a significant net increase in mean calcium volume score (mean change, +52 +/-36%; p<0.001). The 40 treated patients who had average LDL cholesterol levels of at least 120 had a measurable increase in mean calcium volume score (mean change, +25 +/-22%, p<0.001), although it was smaller than the increase in the untreated patients.

Conclusions: The extent to which the volume of atherosclerotic plaque decreased, stabilized, or increased was directly related to treatment with statins and the resulting serum LDL cholesterol levels. These changes can be determined noninvasively by electron beam CT and quantified with use of a calcium volume score.
Callister,T et al. N Engl J Med 1998;339:1972-78)

2. Cardiac Events in Patients with Progression of Coronary Calcification on Electron Beam Computed tomography

Background: Coronary artery calcification (CAC) is a sensitive marker of coronary artery disease (CAD). We have previously shown that CAC progression can be accurately followed by means of sequential EBCT imaging employing a volumetric calcium score (VCS). In this study we conducted an outcome analysis of patients who underwent 2 sequential EBCT scans at a minimum interval of 12 months, and related the occurrence of cardiac events to the presence of regression/progression of CAC.

Methods: Telephone interviews of 269 asymptomatic individuals (68% men, mean age 54 +/-7) referred by primary care physicians for a screening and follow-up EBCT scan due to the presence or risk factors for CAD. The medical records of patients with self-reported events were reviewed for information accuracy.

Results: The interscan time ranged between 12 and 36 months and 134 (50%) showed progression of CAC (average VCS increase: 24 +/-7%). Events occurred in 22 patients: 7 myocardial infarctions (MI), 2 cardiac deaths, 7 coronary angioplasties (PTCA), and 9 coronary artery bypass surgeries. 20 of 22 events (91%) occurred in patients showing CAC progression with a mean increase in VCS of 41 +/-10% (p<0.05 for comparison with mean progression in the entire cohort). The proportion of patients with VCS progression was larger in the group suffering events than in the cohort at large (91% vs. 50%, p<0.001). 2 events (1 MI and 1 PTCA) occurred in patients with apparent plaque stabilization (VCS change: -0.07% for both cases). The relative risk for a cardiac event in patients with VCS progression was 10 fold greater than that of patients with stabilization of VCS.

Conclusions: EBCT can accurately assess the evolution of CAD as indicated by changes in volumetric calcium scores. This preliminary study shows that progression of CAC detected by this tool may portend a significantly increased risk of cardiac events.
Raggi, P et al. RSNA Annual Meetings, 11/99

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