John A. Rumberger

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

BACKGROUND Coronary calcium identified by electron-beam computed tomography (EBCT) correlates poorly with luminal atherosclerotic narrowing, but calcium, an intimate part of coronary plaque, may be more directly related to atheromatous plaque area. METHODS AND RESULTS Thirty-eight 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 (0.18 mm2/pixel). 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 five times greater than calcium area. Furthermore, minimal diffuse segmental coronary plaque could be present despite the 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 that there is a threshold value for plaque area below which coronary calcium is either absent or not detectable by this methodology.

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. BACKGROUND Many studies have recently documented the feasibility of electron beam computed tomography to detect and quantify coronary artery calcification in patients. Although these studies suggest a general relation between calcification and severity of coronary artery disease, the value of coronary calcium in defining atherosclerotic plaque and coronary lumen narrowing is unclear. Previous pathologic comparisons have failed to detail such a relation in identical histologic sections. This finding may be due to atherosclerotic remodeling. METHODS A total of 37 nondecalcified coronary arteries were processed, sectioned at 3-mm intervals (723 sections) 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 coronary artery [LAD]: n = 13, r = 0.89, p < 0.0001; left circumflex coronary artery [LCx]: n = 11, r = 0.7, p < 0.001; right coronary artery [RCA]: n = 13, r = 0.89, p < 0.0001) and per-segment basis (n = 723, r = 0.52, p < 0.0001). In contrast, a poor relation existed between residual histologic lumen area and calcium area for individual hearts (r = 0.48, p = NS), individual coronary arteries (LAD: r = 0.59, p = NS; LCx: r = 0.10, p = NS; RCA: r = 0.59, p = NS) and coronary segments (r = 0.07, p = NS). Longitudinal changes in external elastic lamina areas were highly correlated with changes in plaque area values (r = 0.60, p < 0.0001), whereas lumen area did not correlate with plaque size change (r = 0.01, p = NS). CONCLUSIONS Coronary calcium quantification is an excellent method of assessing atherosclerotic plaque presence at individual artery sites. Moreover, the amount of calcium correlates with the overall magnitude of atherosclerotic plaque burden. This study suggests that the remodeling phenomenon is the likely explanation for the lack of a good predictive value between lumen narrowing and quantification of mural calcification.

Long-Term Prognostic Value of Coronary Calcification Detected by Electron-Beam Computed Tomography in Patients Undergoing Coronary Angiography

Background— Electron-beam CT (EBCT) quantification of coronary artery calcification (CAC) allows noninvasive assessment of coronary atherosclerosis. We undertook a follow-up study to determine whether CAC extent, measured at the time of angiography by EBCT, predicted future hard cardiac events, comprising cardiac death and nonfatal myocardial infarction (MI). We also assessed the potential of selected coronary artery disease (CAD) risk factors, prior CAD event history (MI or revascularization), and angiographic findings (number of diseased vessels and overall disease burden) to predict subsequent hard events. Methods and Results— Two hundred eighty-eight patients who underwent contemporaneous coronary angiography and EBCT scanning were contacted after a mean of 6.9 years. Vital status and history of MI during follow-up were determined. Cox proportional hazards models were used to compare the predictive ability of CAC extent with selected CAD risk factors, CAD event history, and angiographic findings. Median CAC score was 160 (range 0 to 7633). The 22 patients who experienced hard events during follow-up were older and had more extensive CAC and angiographic disease (P <0.05). Only 1 of 87 patients with CAC score <20 experienced a subsequent hard event during follow-up. Event-free survival was significantly higher for patients with CAC scores <100 than for those with scores ≥100 (relative risk 3.20; 95% CI 1.17 to 8.71). When a stepwise multivariable model was used, only age and CAC extent predicted hard events (risk ratios 1.72 and 1.88, respectively;P <0.05). Conclusions— In patients undergoing angiography, CAC extent on EBCT is highly predictive of future hard cardiac events and adds valuable prognostic information.

Noninvasive definition of anatomic coronary artery disease by ultrafast computed tomographic scanning: A quantitative pathologic comparison study

OBJECTIVES The aim of this study was to determine the relation between coronary artery calcification detected by ultrafast computed tomographic scanning and histopathologic coronary artery disease. BACKGROUND Recent studies suggest that discrete coronary artery calcification as visualized by ultrafast computed tomographic scanning may facilitate the noninvasive detection or estimation, or both, of the in situ extent of coronary disease. Such quantitative relations have not been established. METHODS Thirteen consecutive perfusion-fixed autopsy hearts (from eight male and five female patients aged 17 to 83 years) were scanned by ultrafast computed tomographic scanning in contiguous 3-mm tomographic sections. The major epicardial arteries were dissected free, positioned longitudinally and scanned again in cross section. Coronary artery calcification in a coronary segment was defined as the presence of one or more voxels with a computed tomographic density > 130 Hounsfield units. Each epicardial artery was sectioned longitudinally, stained and measured with a planimeter for quantification of cross-sectional and atherosclerotic plaque areas at 3-mm intervals, corresponding to the computed tomographic scans. A total of 522 paired coronary computed tomographic and histologic sections were studied. RESULTS Direct relations were found between ultrafast computed tomographic scanning coronary artery calcium burden and atherosclerotic plaque area and percent lumen area stenosis. However, the range for plaque area or percent lumen stenosis, or both, associated with a given calcium burden was broad. Three hundred thirty-one coronary segments showed no calcification by computed tomography. Although atherosclerotic disease was found in several corresponding pathologic specimens, > 97% of these noncalcified segments were associated with nonobstructive disease (< 75% area stenosis); if no calcification was determined in an entire coronary vessel, all corresponding coronary disease was found to be nonobstructive. To determine the relation between arterial calcification and any atheromatous disease, computed tomographic calcium burden for each segment was paired with the histologic absence or presence of disease. Ultrafast computed tomographic scanning had a sensitivity and specificity of 59% and 90% and a negative and positive predictive value of 65% and 87%, respectively. A direct correlation was found (r = 0.99) between total calcium burden calculated from tomographic scans of the heart as a whole and scans of the arteries obtained in cross section. CONCLUSIONS The detection of coronary calcification by ultrafast computed tomographic scanning is highly predictive of the presence of histopathologic coronary disease, but the use of this technique to define the extent of coronary disease may be limited. However, the absence of coronary calcification at any site is highly specific for the absence of obstructive disease.

Aggressive Versus Moderate Lipid-Lowering Therapy in Hypercholesterolemic Postmenopausal Women Beyond Endorsed Lipid Lowering With EBT Scanning (BELLES)

Background—Women have been underrepresented in statin trials, and few data exist on the effectiveness and safety of statins in this gender. We used sequential electron-beam tomography (EBT) scanning to quantify changes in coronary artery calcium (CAC) as a measure of atherosclerosis burden in patients treated with statins. Methods and Results—In a double-blind, multicenter trial, we randomized 615 hyperlipidemic, postmenopausal women to intensive (atorvastatin 80 mg/d) and moderate (pravastatin 40 mg/d) lipid-lowering therapy. Patients also submitted to 2 EBT scans at a 12-month interval (mean interval 344±55 days) to measure percent change in total and single-artery calcium volume score (CVS) from baseline. Of the 615 randomized women, 475 completed the study. Mean±SD percent LDL reductions were 46.6%±19.9% and 24.5%±18.5 in the intensive and moderate treatment arms, respectively (P<0.0001), and National Cholesterol Education Program Adult Treatment Panel III LDL goal was reached in 85.3% and 58.8% of women, respectively (P<0.0001). The total CVS% change was similar in the 2 treatment groups (median 15.1% and 14.3%, respectively; P=NS), and single-artery CVS% changes and absolute changes were also similar (P=NS). In both arms, there was a trend toward a greater CVS progression in patients with prior cardiovascular disease, diabetes mellitus, and hypertension, whereas hormone replacement therapy had no effect on progression. Conclusions—In postmenopausal women, intensive statin therapy for 1 year caused a greater LDL reduction than moderate therapy but did not result in less progression of coronary calcification. The limitations of this study (too short a follow-up period and the absence of a placebo group) precluded determination of whether progression of CVS was slowed in both arms or neither arm compared with the natural history of the disease.

Coronary Calcium, as Determined by Electron Beam Computed Tomography, and Coronary Disease on Arteriogram Effect of Patient’s Sex on Diagnosis

BACKGROUND Coronary artery calcium identified by electron beam computed tomography (EBCT) has potential for noninvasive localization of coronary atherosclerotic disease. However, the effect of a patients sex on its diagnostic capability has not been examined in a clinical population. METHODS AND RESULTS Fifty women and 89 men had EBCT scans done an average of 1 day after coronary arteriography. Maximum arteriographic percent luminal diameter stenosis of any artery was paired with the total EBCT coronary calcium score for each subject. The women (age, 56 +/- 11 years [mean +/- SD]) were older than the men (age, 47 +/- 7 years), but the subjects were matched for indications for arteriography and extent of disease as assessed by arteriography. Sensitivity, specificity, and positive and negative predictive values for coronary calcium were nearly identical for men and women, regardless of the degree of arteriographic disease. EBCT was highly sensitive to the presence of arteriographic disease (range, 94% to 100%), but had only moderate specificity (57% to 66%) for significant disease (> or = 50% stenosis) and low specificity (35% to 38%) for any arteriographic disease (> 0% stenosis). Negative predictive values in men and women ranged from 79% to 91% for any arteriographic disease and from 95% to 100% for significant disease, respectively. Numerical calcium scores were significantly different between subjects with normal arteriograms and those with significant disease; however, calcium score had limited power to separate trivial, moderate, and significant disease. Receiver operating characteristic curve areas, determined as an extension of the analyses of sensitivity and specificity, were high for EBCT-defined calcium scores for both any arteriographic disease and significant arteriographic disease, and were not different between the sexes. CONCLUSIONS In a middle-aged population, noninvasive definition of coronary calcium by EBCT has similar predictive value for arteriographic coronary artery disease in men and women.

Relation of coronary calcium determined by electron beam computed tomography and lumen narrowing determined by autopsy

Coronary calcium determined by electron beam computed tomography (CT) has not been systematically evaluated regarding prediction of histopathologic atherosclerotic disease. Furthermore, gender specificity has not been examined. The 3 major epicardial arteries were dissected from 13 consecutive hearts (5 women and 8 men) after autopsy. Each artery was straightened and scanned using CT in contiguous 3 mm thick cross sections. After imaging, histologic sections were prepared at corresponding intervals and luminal area obstruction determined by planimetry. Electron beam CT scans were analyzed to determine coronary calcium area (i.e., tomographic area with CT density > 130 Hounsfield units). A total of 522 histologic specimens were examined and paired with corresponding CT scans (182 in women, 340 in men). Receiver-operating characteristic (ROC) analysis was used to define site specificity of calcium area for luminal area narrowing by atherosclerosis. ROC curve areas for segmental CT calcium and prediction of atherosclerosis representing mild, moderate, or severe disease were, respectively, 0.712, 0.843, and 0.857 for women and 0.732, 0.793, and 0.841 for men. Curves relating false-positive rate (1-specificity) to predefined degrees of atherosclerotic narrowing versus calcium area were curvilinear. In both women and men, calcium areas on the order of 1 mm2/coronary segment were necessary to predict at least mild atherosclerosis with a false-positive rate of 0% (i.e., 100% specificity), whereas a calcium area > 3 mm2 was necessary to predict the same result for severe disease. In conclusion, coronary artery calcium area as determined by electron beam CT has the potential to predict segmental histopathologic coronary disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary Artery Calcium in Acute Coronary Syndromes A Comparative Study of Electron-Beam Computed Tomography, Coronary Angiography, and Intracoronary Ultrasound in Survivors of Acute Myocardial Infarction and Unstable Angina

BACKGROUND Quantification of coronary artery calcified plaques by electron-beam CT (EBCT) may predict cardiovascular events. However, whereas advanced coronary atherosclerotic plaques can be identified, mildly stenotic lipid-rich (soft) plaques may be difficult to detect. The value of EBCT in a subgroup of patients has therefore been questioned. To investigate this, we evaluated patients with acute coronary syndromes by EBCT and compared the results with coronary angiography and, in patients with an indeterminate angiogram, intracoronary ultrasound (ICUS). METHODS AND RESULTS EBCT was performed in 118 consecutive patients (57+/-11 years of age) with previous myocardial infarction (n=101) or unstable angina (n=17). A standard protocol requiring a CT density >130 Hounsfield units in an area > or =1.03 mm2 was used for the definition of coronary artery calcium. We found that 110 patients had moderate to severe coronary artery disease by coronary angiography, and 8 had either mildly stenotic plaques at a single site (4 patients, confirmed by ICUS) or nonatherosclerotic causes of the unstable coronary syndrome (4 patients). One hundred and five of the 110 patients (96%) with moderate to severe angiographic disease but only 1 of the 8 other patients (13%) had a positive EBCT. Patients with acute coronary syndromes and negative EBCTs were significantly younger than patients with positive EBCTs (46+/-12 versus 58+/-10 years, P<.001), and a higher percentage was actively smoking (100% of the smokers versus 46%, P<.05). CONCLUSIONS The vast majority of patients with acute coronary syndromes and at least moderate angiographic disease have identifiable coronary calcium by EBCT. Those patients with negative EBCTs have minimal or no atherosclerotic plaque formation. They are younger and tend to be active cigarette smokers.

Aprotinin for coronary bypass operations: Efficacy, safety, and influence on early saphenous vein graft patency. A multicenter, randomized, double- blind, placebo-controlled study

The purpose of this study was to evaluate the efficacy and safety of aprotinin in a U.S. population of patients undergoing coronary artery bypass grafting. Early vein graft patency rates were assessed by ultrafast computed tomography. A total of 216 patients at five centers were randomized to receive either high-dose aprotinin or placebo during the operation; 151 patients underwent primary operation, and 65 underwent repeat procedures. Total blood product exposures in the primary group were 2.2 per patient receiving aprotinin as compared with 5.7 per patient receiving placebo (p = 0.010). The repeat group had 0.3 exposures per patient receiving aprotinin as compared with 10.7 per patient receiving placebo (p = < 0.001). Consistent reductions in the percent of patients requiring donor red blood cells and in the number of units of platelets, fresh frozen plasma, and cryoprecipitate required were associated with the use of aprotinin in both primary and repeat groups. Mortality was 5.6% in the aprotinin group and 3.7% in the placebo group (p = 0.517). In the primary group, clinical diagnoses of myocardial infarction were made in 8.9% of patients receiving aprotinin as compared with 5.6% of the patients receiving placebo (p = 0.435). In the repeat group, infarctions occurred in 10.3% of patients receiving aprotinin and 8.3% of patients receiving placebo (p = 1.000). Secondary analysis of electrocardiograms and available enzyme data showed no significant difference in infarction rates between the treatment groups. There was no difference in clinically significant renal dysfunction. The early vein graft patency rates were 92.0% in the aprotinin group and 95.1% in the placebo group (p = 0.248). In this study, aprotinin was effective in reducing bleeding and blood product transfusion rates, and its use was not associated with an increase in complications. An adverse effect on early vein graft patency rates was not demonstrated, but the number of grafts assessed was insufficient for absolute conclusions in this regard.

Intravenous electron-beam computed tomographic coronary angiography for segmental analysis of coronary artery stenoses.

OBJECTIVES We sought to identify and localize significant coronary stenoses on a segmental basis by electron-beam computed tomography (EBCT) and intravenous administration of a contrast agent. BACKGROUND The clinical applicability and limitations of intravenous EBCT coronary angiography have not been defined. METHODS EBCT was performed within 24 h of selective coronary angiography (SCA) in 28 patients (19 men and 9 women, mean [+/-SD] age 60 +/- 10 years). After examination for coronary calcium, EBCT coronary angiography was performed using overlapping slices (in-plane resolution 0.34 to 0.41 mm) with a nominal slice thickness of 1 mm. Based on quantitative analysis of SCA, lumen diameter narrowing > or = 50% (i.e., significant stenoses) was evaluated in 8 (major) or 12 (including side branches) coronary artery segments, using both two-dimensional (tomographic) and three-dimensional (volume) data sets. RESULTS Of the 330 segments assessable by SCA, 237 (72%) were visualized by EBCT. The sensitivity (+/-SE) for detection of significant stenoses was 82 +/- 6%; specificity was 88 +/- 2%; positive and negative predictive values were 57 +/- 7% and 96 +/- 2%, respectively; and overall accuracy was 87 +/- 2%. If only eight (major) coronary artery segments were considered, 194 (88%) of 221 segments were visualized, and the overall accuracy was 90 +/- 2%. Seven (18%) of 38 significantly stenotic segments were classified as having < 50% stenoses by EBCT. Six of these segments (86%), but only 9 (29%) of the 31 correctly classified stenotic segments, were severely calcified (area > 20 mm2, p = 0.02). In 23 (12%) of 199 nonstenotic segments falsely classified as having > or = 50% stenosis by EBCT, the lumen diameter was significantly smaller than that of the segments correctly classified as negative (mean [+/-SD] 1.5 +/- 0.8 vs. 2.9 +/- 1.1 mm, p < 0.001). CONCLUSIONS Intravenous EBCT coronary angiography allows for accurate segmental evaluation of significant disease in the major coronary arteries and may be of value for ruling out significant disease. The main determinant of false negative results is substantial segmental calcification, whereas the main determinant of false positive results is small vessel size.