Patterns of Calcification in Coronary Artery Disease

Selective coronary arteriography has been the “gold standard” for guiding revascularization in coronary artery disease. Despite its widespread acceptance, it has many inherent limitations, including its inability to assess plaque composition with negative contrast imaging. Recently, it has been suggested that coronary arteriography has a limited ability to detect and localize target lesion calcium.¹² Target lesion calcium is both a marker for significant coronary artery disease and the major determinant of the success of various transcatheter therapies.^{2345678910111213}

Intravascular ultrasound (IVUS) provides transmural images of coronary arteries in vivo. The normal coronary arterial wall, the major components of the atherosclerotic plaque, and the changes that occur during the atherosclerotic disease process, after transcatheter therapy, and during restenosis can be studied in humans in a manner previously not possible. The purpose of this study is (1) to use IVUS to evaluate the patterns (eg, magnitude, location, and distribution) of coronary artery calcium in a large number of patients undergoing transcatheter therapy for coronary artery disease and (2) to compare IVUS and coronary angiography in the evaluation of coronary artery calcification.

Methods

Patient Population

From July 1, 1991, to March 1, 1994, 1155 target lesions in 1117 patients were studied by IVUS and coronary angiography. These lesions met the following criteria: (1) native vessel location (thereby excluding vein graft and internal mammary lesions) and (2) ability to assess target lesion morphology by both IVUS and coronary angiography (therefore excluding lesions with previous stent placement). There were 862 men and 255 women 61±11 years old. Target lesion location was left main in 47, left anterior descending in 487, left circumflex in 180, and right coronary artery in 441; diagonal branches were considered part of the left anterior descending, and marginal branches were considered part of the left circumflex artery. One hundred ninety-six lesions were ostial in location. No catheter-based intervention was performed in 149 lesions (21 of which were treated instead with operative revascularization); balloon angioplasty was performed in 127 lesions, directional coronary atherectomy (Devices for Vascular Intervention) in 400 lesions, rotational atherectomy (Heart Technology) in 299 lesions, extraction atherectomy (InterVentional Technologies) in 5 lesions, stent placement (Palmaz and Palmaz-Schatz tubular slotted stents, Johnson and Johnson Interventional Systems; Gianturco-Roubin Flex-Stent, Cook, Inc; and Wiktor coiled stents, Medtronic, Inc) in 33 lesions, and excimer laser angioplasty (Advanced Interventional Systems) in 142 lesions.

IVUS Analysis

Preintervention IVUS imaging was performed in 872 lesions (75%). IVUS studies used one of three commercially available systems. The first (Cardiovascular Imaging Systems Inc/InterTherapy Inc) incorporated a single-element 25-MHz transducer and an angled mirror mounted on the tip of a flexible shaft that was rotated at 1800 rpm within a 3.9F short monorail polyethylene imaging sheath to form planar cross-sectional images in real time; with this system, the transducer was withdrawn automatically at 0.5 mm/s to perform the imaging sequence. The second (Hewlett Packard and Boston Scientific Corp) incorporated a single-element 30-MHz beveled transducer rotated at 1800 rpm within a 3.5F short monorail imaging catheter; with this system, the catheter was advanced or withdrawn manually with fluoroscopic guidance to perform the imaging sequence. The third (Cardiovascular Imaging Systems Inc) incorporated a single-element 30-MHz beveled transducer within either a 2.9F long monorail imaging catheter having a common distal lumen design (the distal lumen alternatively accommodates the imaging core or the guide wire, but not both) or a 3.2F short monorail imaging catheter; with this system, the transducer was withdrawn automatically at 0.5 mm/s to perform the imaging sequence. IVUS studies were recorded on 1/2-in high-resolution s-VHS taped for off-line analysis.

All patients were studied after having given informed consent. All IVUS imaging protocols have the ongoing approval of the Washington Hospital Center Institutional Review Board.

Quantitative analysis of the ultrasound images was performed by a single individual blinded to the angiographic results. A number of cross-sectional measurements were made, including lesion site external elastic membrane or media/adventitia interface, lumen, and plaque-plus-media cross-sectional areas and maximum and minimum plaque-plus-media thicknesses.^{14151617181920} When the atherosclerotic plaque encompassed the catheter, the lumen was assumed to be the size of the imaging catheter. Because media thickness could not be measured accurately, plaque-plus-media cross-sectional area and thickness were used as measurements of the atherosclerotic plaque.²¹ Plaque-plus-media cross-sectional area was calculated as external elastic membrane minus lumen cross-sectional area. Although acoustic shadowing caused by lesion calcification made identification of the external elastic membrane (and therefore measurement of maximum and minimum plaque-plus-media thicknesses) difficult, two types of extrapolation were useful. Briefly, because the cross-sectional geometry of the coronary artery was more or less circular, extrapolation of the circumference of the external elastic membrane was possible provided that each calcific deposit did not shadow more than 60° of the adventitial circumference. Also, real-time axial movement of the transducer just distal and proximal to a calcific deposit (or to find the smallest circumferential arc of calcium within a large calcific deposit) helped unmask and fill in contiguous parts of the adventitia that were otherwise shadowed by that deposit.²²²³

Plaque composition was assessed visually to identify lesion calcium.^1617181924 Calcium produced bright echoes (brighter than the reference adventitia) with acoustic shadowing of deeper arterial structures. The extent and distribution of target lesion calcification was assessed as follows (Fig 1).¹

1. The largest arc(s) of target lesion calcium and superficial lesion calcification were measured in degrees with a protractor centered on the lumen (Fig 1A and 1B). The intraobserver variability of this arc of calcium measurement is ±5°. Calcification was then classified as none, one-quadrant (≤90°), two-quadrant (91° to 180°), three-quadrant (181° to 270°), or four-quadrant (271° to 360°) calcification. If there was more than one calcific deposit in a given imaging slice, then the arcs of calcium were added.

2. The location of target lesion calcium (Fig 1C and 1D) was defined as superficial (calcium at the intimal-lumen interface or closer to the lumen than to the adventitia), deep (calcium at the media/adventitia border or closer to the adventitia than to the lumen), or both (superficial and deep).

3. The location of a superficial or deep calcific deposit within a plaque was assessed relative to the point of thickest plaque accumulation (maximum plaque-plus-media thickness). Then the orientation of the superficial or deep target calcific deposit relative to the point of thickest plaque accumulation was classified as concordant (center of the arc of calcium within 45° of the thickest plaque accumulation), perpendicular (center of the arc of calcium 45° to 135° relative to the thickest plaque accumulation), or opposite (center of arc of calcium ≥135° away from the thickest plaque accumulation, Fig 1E and 1F).

4. In the 1021 lesions studied with a motorized pullback device, the overall lengths (in millimeters) of contiguous and overlapping target lesion and superficial lesion calcium were measured from the number of seconds of videotape in which calcium was identified (millimeters equal to seconds of videotape ×0.5 mm/s).

Reference segment calcification was assessed over a 10-mm length of artery proximal to the target lesion but distal to a major side branch.²⁵ In circumstances in which a proximal reference segment could not be identified (eg, ostial lesion location), distal reference segment calcification (also over a 10-mm length of artery distal to the target lesion but proximal to a major side branch) was analyzed. The largest arc of calcification, the length of calcium, and calcium location within the 10-mm-long reference segment were then assessed as above.

Last, a total length (in millimeters) of calcium was calculated as length of lesion calcium plus length of reference segment calcium.

Angiographic Analysis

Preprocedural angiograms were reviewed by a core angiographic laboratory that was blinded to the ultrasound results. Standard qualitative morphological criteria were recorded on the basis of their identification in any unforeshortened view.²⁶ Calcification was identified as readily apparent radiopacities within the vascular wall at the site of the stenosis and was classified as none/mild, moderate (radiopacities noted only during the cardiac cycle before contrast injection), and severe (radiopacities noted without cardiac motion before contrast injection generally compromising both sides of the arterial lumen).

Target lesion location was designated as ostial, proximal, mid, and distal. Ostial lesions were those lesions that began within 3 mm of a major coronary ostium.

Quantitative angiographic analysis used a computer-assisted, automated edge-detection algorithm (ImageComm). With the external diameter of the contrast-filled catheters as the calibration standard, the minimal lumen diameter at end diastole before intervention was measured from orthogonal projections, and the results from the “worst” view were recorded.²⁷

Statistics

Statistical analysis was performed with statview 4.01 and bmdp.²⁸ Quantitative data are presented as mean±SD. Qualitative data are presented as frequencies. Categorical variables were assessed by χ² statistics. Continuous variables were compared by unpaired Student’s t tests and ANOVA as appropriate. A discriminant analysis was used to find the combination of variables that best predicted the presence of angiographic calcium (yes/no) and the classification of angiographic calcium (none/moderate/severe). The number of cases correctly classified into each group was then summarized.

Results

IVUS Target Lesion Calcium

By IVUS, 841 of 1155 target lesions (73%) contained calcium. The mean arc of target lesion calcium measured 115±110°, and the mean length of target lesion calcium measured 3.5±3.7 mm. The frequency distribution of the arcs and lengths of target lesion calcium is shown in Fig 2.

When present, target lesion calcium was only superficial in 48%, only deep in 28%, and both superficial and deep in 24% (Fig 3). The mean arc of superficial calcium measured 85±108°, and the mean length of superficial calcium measured 2.4±3.4 mm. The frequency distribution of the arcs and lengths of superficial calcium is shown in Fig 4. When present, superficial calcium was concordant to the maximum plaque-plus-media thickness in 71%, perpendicular in 23%, and opposite in 6% (Fig 5A). When present, deep calcium was concordant to the maximum plaque-plus-media thickness in 71%, perpendicular in 24%, and opposite in 5% (Fig 5B).

By IVUS, 373 of 1155 reference segments (32%) contained calcium (P<.0001 compared with target lesion calcium). The frequency distribution of the arcs and lengths of reference segment calcium is shown in Fig 6. When present, reference segment calcium was only superficial in 78%, only deep in 13%, and both superficial and deep in 9%. The mean arc of reference segment calcium measured 42±80°, and the mean length of reference segment calcium measured 1.7±3.6 mm (both P<.0001 compared with target lesion calcium). Only 44 vessels (4%) had reference segment calcium in the absence of target lesion calcium.

The total (lesion-plus-reference segment) mean length of calcium was 5.2±5.7 mm.

Angiographic Results

The mean reference segment diameter measured 3.09±0.60 mm, the mean preintervention minimum lumen diameter measured 1.14±0.67 mm, and the mean percent diameter stenosis measured 63.3±20.0%.

Coronary angiography detected target lesion calcium in 440 of 1155 lesions (38%, P<.0001 compared with IVUS); 306 lesions (26%) had moderate calcium, and 134 lesions (12%) had severe calcium. The presence and classification of angiographic calcium correlated with an increasing arc and length of IVUS target lesion calcium, IVUS superficial calcium, and IVUS reference segment calcium (Figs 2, 4, and 6 and the Table). In addition, coronary angiography detected superficial calcium more often than deep calcium (Fig 3, P<.0001). Furthermore, coronary angiography detected superficial calcium that was concordant to the maximum plaque-plus-media thickness more often than it detected superficial calcium that was opposite the maximum plaque-plus-media thickness (P=.0011, Fig 5A). No similar relation was noted with deep target lesion calcium (Fig 5B).

The overall sensitivity of angiography in detecting the presence of target lesion calcium was 48%; it was lowest in those lesions with one-quadrant calcium and highest (85%) in lesions with four-quadrant calcium. The overall specificity of the angiographic detection of target lesion calcium was 89%, and it was 98% for the angiographic classification of “severe” lesion calcium (Table; Fig 2). Coronary angiography had a false-positive rate of 11% in indicating the presence of target lesion calcium, a rate that was not explained by the presence of isolated reference segment calcification.

IVUS Determinants of Angiographic Calcification

By univariate analysis, the angiographic detection and classification of target lesion calcium depended on the arcs, lengths, location, and distribution of target and reference segment calcium (Table; Figs 2 through 6). By discriminant analysis (variables are listed in the Table), a predictive model of angiographic calcium classification (none/moderate/severe) was constructed; this model included the arc of target lesion calcium, the arc of superficial calcium, the length of reference segment calcium, and the location of calcium within the lesion. It correctly predicted the angiographic classification in 62.8% of lesions. A second predictive model of calcium detection (yes/no) was then constructed; this model included the arc of target lesion calcium, the arc of superficial calcium, and the length of reference segment calcium and correctly predicted the angiographic detection of calcium in 74.4% of lesions.

Discussion

Pathological studies have shown that lesion-associated coronary artery calcium increases with the extent and severity of atherosclerosis, increasing patient age, and the presence of primary or secondary chronic hypercalcemia, hyperlipidemia, or chronic renal insufficiency.^{345293031323334} The highest pathological incidence reported is 79%.⁵ Because coronary artery calcium is a marker for significant coronary atherosclerosis, procedures are being developed to detect coronary artery calcium noninvasively as a screening test for significant coronary artery disease.^{69353637383940}

Importance of IVUS Target Lesion Calcium

The IVUS identification of tissue calcium has been validated in vitro.^1617181924 Calcium has a characteristic acoustic signature: brighter than the reference adventitia, with shadowing of deeper arterial structures. By this definition, IVUS detected target lesion calcium in 73% of the 1155 lesions studied. This approaches the highest pathological incidence reported.

IVUS can assess the arc, length, and distribution patterns of coronary artery calcification (eg, superficial versus deep, lesion-associated versus reference segment, concordant versus opposite maximum plaque thickness).¹ The mean arc of target lesion calcium was 115°; 26% of the lesions had >180° of lesion calcium. Target lesion calcium was most often superficial in location; in an eccentric lesion, calcium was most often concordant to the maximum plaque-plus-media thickness.

Besides being a marker for significant coronary artery disease, target lesion calcification is the major determinant of the acute procedural success of many transcatheter therapies. The final lumen dimensions, the amount of residual plaque, and the weight of tissue retrieved after directional coronary atherectomy are related to the arc and location of IVUS target lesion calcium.¹²⁴¹⁴² Conversely, rotational atherectomy preferentially ablates calcium.²²²³ For a given burr size, rotational atherectomy achieves a larger lumen in the presence of significant calcium than in the absence of calcium.⁴³ Although excimer laser angioplasty appears to ablate calcium in vitro,⁴⁴⁴⁵ this has not been confirmed by IVUS in vivo; instead, excimer laser angioplasty causes shattering of lesion-associated calcific deposits.⁴⁶

Target lesion calcium has been implicated in some procedural complications and as a risk factor for restenosis.⁴⁷ For example, calcification (even focal calcium) is the major reason for dissection after balloon angioplasty, and it may influence the length and severity of balloon angioplasty–induced dissections.¹¹

The relation of the calcific deposit to the maximum plaque thickness may also be important. Thus, a relatively small arc of superficial calcium “protecting” the leading edge of an eccentric lesion may have a greater impact than a larger, deeper arc. This type of lesion appears to occur frequently and may be better treated with rotational atherectomy. Balloon angioplasty may just stretch the thinner wall opposite the calcific plaque; similarly, the calcific plaque may lead a directional atherectomy device to cut into the thinnest part of the plaque. Conversely, although uncommon, an arc of calcium superficial to the minimum plaque thickness may be equally important. If such a lesion is treated with rotational atherectomy, preferential calcium ablation could result in erosion of the burr through the thinnest part of the plaque. Even though calcified, this type of lesion may be better approached with other transcatheter techniques.

There are limitations to the ultrasound assessment of target lesion calcium. IVUS can identify only the leading edge of a calcific deposit, not its thickness. Similarly, IVUS cannot detect a deep calcific deposit behind a superficial calcific deposit. As transducer frequencies are increased to improve resolution and tissue characterization, the ability of ultrasound to see through significant amounts of noncalcified plaque may be tested. Thus, deep calcium may be hidden until the bulky superficial plaque is removed; and densely fibrotic noncalcified plaque may not be penetrated and cause shadowing to be confused with calcium. On IVUS imaging, all calcium appears the same; however, there is evidence that not all calcium has the same physical properties.⁴⁸

Determinants of Angiographic Calcification

The overall diagnostic accuracy of coronary angiography was 59%. Although angiography may be highly specific (89%) for the presence of lesion calcium, it was fairly insensitive in the presence of one or two quadrants or short lengths of calcium. These results are similar to other reports in which IVUS detected target lesion calcium far more often than angiography.²

By discriminant analysis, the IVUS variables predictive of angiographic calcification were (1) the arc of target lesion calcium, (2) the arc of superficial calcium, (3) the length of reference segment calcium, and (4) the location (superficial versus deep) of lesion calcium. In fact, however, calcium thickness may be as important a determinant of the angiographic detection of lesion-associated calcium. Coronary angiography not only detected superficial calcium more often than deep calcium but also detected superficial calcium that was concordant to the maximum plaque-plus-media thickness more often than superficial calcium that was opposite the maximum plaque-plus-media thickness. Because ultrasound cannot measure calcium thickness, superficial calcium (especially superficial calcium that is concordant to the maximum plaque thickness) may represent a thicker (and therefore more radiopaque) calcific deposit compared with deeper lesion calcium.

The fact that the reference segment length of calcium was an independent predictor of angiographic calcification emphasizes the limitations of angiography in localizing calcium. Reference segment calcium may be partially responsible for the false-positive rate of coronary angiography in predicting IVUS target lesion calcium. In this study, however, isolated reference segment calcium (reference segment calcium in the absence of lesion calcium) was distinctly unusual. The presence of periadventitial calcification (beyond the penetration depth of IVUS and, therefore, not included in this analysis) could be an alternative explanation.

Last, this study validated the morphological classification of angiographic calcium (none versus moderate versus severe). Severe angiographic calcification (radiopacities noted without cardiac motion before contrast injection generally compromising both sides of the arterial lumen) was associated with quantitatively more ultrasound calcium (and qualitatively more superficial calcium) compared with moderate angiographic calcium (radiopacities noted only during the cardiac cycle before contrast injection).

Limitations

This was neither an acute nor chronic outcome study. Therefore, the primary limitation of this study is the lack of outcome data relative to the patterns of ultrasound calcification described. However, on one hand, focal calcification has been shown to be important in the genesis of dissections after percutaneous transluminal coronary angioplasty,¹¹ while on the other hand, the overall arc of target lesion calcium has been shown to be important in determining the acute results after directional coronary atherectomy.⁴² Additional study with a larger number of lesions in each subset will be necessary to relate each pattern of calcification to specific (eg, device-related) outcomes. Similarly, additional study will be necessary to determine the discriminating threshold that precludes specific device use.

Conclusions

IVUS analysis shows that target lesion calcification is ubiquitous in coronary artery disease; the prevalence of target lesion calcification exceeds 70%, and the mean arc of calcification is 115°. IVUS can assess the arc, length, and distribution patterns of coronary artery calcification (eg, superficial versus deep, lesion-associated versus reference segment, relation to maximum plaque thickness). The sensitivity of angiography approaches 50%, with a specificity of almost 90%. By discriminant function analysis, angiographic calcium detection and classification were dependent on the IVUS arc of target lesion calcium, arc of superficial calcium, length of reference segment calcium, and location of calcium within the lesion.

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Footnotes