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Invasive Versus Noninvasive Evaluation of Coronary Artery Disease

Joanne D. Schuijf, PhD^_*, Jacob M. van Werkhoven, MSc^_*,, Gabija Pundziute, MD^_*, J. Wouter Jukema, MD, PhD^_*,, Isabel Decramer, MSc^||, Marcel P. Stokkel, PhD, MD, Petra Dibbets-Schneider, MSc, Martin J. Schalij, MD, PhD^_*, Johannes H.C. Reiber, PhD, Ernst E. van der Wall, MD, PhD, William Wijns, MD, PhD^||, Jeroen J. Bax, MD, PhD^_*,_*

^_* Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
The Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands
Department of Nuclear Medicine, Leiden University Medical Center, Leiden, the Netherlands
^|| The Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium.

	Abstract

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Objectives: We sought to compare the diagnostic information obtained from noninvasive characterization of coronary artery disease by using multidetector computed tomography (MDCT) and myocardial perfusion imaging (MPI) and to compare findings with the use of invasive coronary angiography and intravascular ultrasound (IVUS).

Background: Preliminary comparisons have suggested that abnormal myocardial perfusion studies correlate well with significant luminal stenosis on MDCT coronary angiography. However, atherosclerotic coronary lesions may be detectable with the use of MDCT even in the presence of normal myocardial perfusion

Methods: We performed MDCT, MPI, and conventional coronary angiography in 70 patients. In addition, IVUS was performed in 53 patients. Quantitative information was obtained from quantitative coronary angiography (QCA) and IVUS assessment of plaque burden and minimal luminal area.

Results: Of 26 patients with an abnormal MPI study, 23 (88%) showed significant stenosis on MDCT. As compared with QCA, MDCT showed a sensitivity of 96% and specificity of 67% for the detection of stenoses 50% diameter narrowing in these patients. Mean diameter stenosis on QCA was 76% and mean minimal lumen area in IVUS was 3.3 mm². On the other hand, 27 (84%) of 44 patients with normal MPI had evidence of coronary atherosclerosis on MDCT (luminal stenosis 50%: n = 15, luminal stenosis <50%: n = 12, sensitivity of 100% and specificity of 83% as compared with QCA). Using IVUS, we found substantial plaque burden (mean 58.9 ± 18.1% of cross-sectional area), but presence of a stenosis (minimal lumen area <4.0 mm²) in only 14 patients (mean minimal lumen area, 5.8 ± 3.3 mm²). Only 7 patients with normal myocardial perfusion scans demonstrated absence of coronary atherosclerosis by MDCT.

Conclusions: Considerable plaque burden can be observed with MDCT even in the absence of myocardial perfusion abnormalities. This finding does not constitute a false-positive MDCT result, but rather reflects the fact that MDCT can detect atherosclerotic lesions that are not flow-limiting.

Abbreviations and Acronyms   CAD = coronary artery disease   EEM = external elastic membrane   IVUS = intravascular ultrasound   MDCT = multidetector computed tomography   MLA = minimal lumen area   MPI = myocardial perfusion imaging   QCA = quantitative coronary angiography   RI = remodeling index   SPECT = single-photon emission computed tomography

	Methods

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Patients and study protocol.   The study group consisted of symptomatic patients who presented to the outpatient clinic (Leiden, the Netherlands, and Aalst, Belgium) for the evaluation of chest pain. Noninvasive imaging with the use of gated single-photon emission computed tomography (SPECT) and MDCT was performed and, on the basis of clinical presentation and/or imaging results, 70 of these patients were referred for invasive coronary angiography in combination with IVUS and enrolled in the present study. Exclusion criteria were contraindications to MDCT (6) and the presence of unstable angina, heart failure, myocardial infarction, or revascularization between the imaging procedures. Data of 15 patients have been previously reported in a study comparing MDCT and MPI (5). The study protocol was approved by the institutional ethics committee, and informed consent was obtained in all patients.

Clinical characteristics of the study population are presented in Table 1. Of the 70 patients (mean age 62 ± 11 years) included in the study, 46 (66%) were men. Diagnosis of CAD was established in 5 (7%) and suspected in the remaining 65 (93%) patients. Of the patients with known CAD, 4 had previous percutaneous coronary intervention (with stent placement in 2 patients), whereas 1 patient had previous coronary artery bypass grafting. In the latter patients, 2 bypassed (grafted) coronary vascular territories were excluded from analysis. In all patients, MPI, MDCT, and conventional coronary angiography (with quantitative coronary angiography [QCA]) were performed. In 53 patients, additional vascular imaging with IVUS was performed in a total of 109 coronary arteries. In the remaining 17 patients, IVUS imaging was not possible because of the presence of left main stenoses, severe coronary stenosis, or total occlusion (n = 10) and technical problems or time constraints during conventional coronary angiography (n = 7).

The MDCT angiographic examinations were evaluated in consensus by 2 experienced readers, including an interventional cardiologist who was blinded to the SPECT data for the presence of atherosclerosis. Coronary arteries were divided into 17 segments according to the modified American Heart Association classification (7). Each segment was evaluated for the presence of any atherosclerotic plaque with the use of axial images and curved multiplanar reconstructions. Coronary plaques were defined as structures >1 mm² within and/or adjacent to the coronary artery lumen, which could be clearly distinguished from the vessel lumen and the surrounding pericardial tissue, as previously described (8). To describe the degree of stenosis, abnormal segments were further classified as showing: 1) nonobstructive disease (<50% luminal narrowing); 2) borderline stenosis (50% to 70% luminal narrowing); or 3) severe stenosis, showing 70% luminal narrowing. To describe the extent of disease on MDCT, for each patient and vessel, the number of segments showing disease as well as significant (50% luminal narrowing) was determined. Data were recorded on a patient and vessel basis and, in the vessel-based analysis, the left main coronary artery was considered part of the left anterior descending coronary artery.

Myocardial perfusion imaging.   In all patients, stress MPI (with either technetium-99m tetrofosmin or technetium-99m sestamibi) was performed with symptom-limited bicycle exercise or pharmacological (dipyridamole, adenosine, or dobutamine) stress (9). Data were acquired with either a dual-head SPECT camera (Vertex Epic ADAC Pegasus, Philips Medical Systems, Eindhoven, the Netherlands) or a triple-head SPECT camera (GCA 9300/HG, Toshiba Corp., Tokyo, Japan) followed by reconstruction into long- and short-axis projections perpendicular to the heart axis; data were presented in polar map format (normalized to 100%), and a 17-segment model was used in which myocardial segments were allocated to the territories of the different coronary arteries as previously described (10,11). Perfusion defects were identified on the stress images (segmental tracer activity <75% of maximum) and divided into ischemia (reversible defects, with 10% increase in tracer uptake on the resting images) or scar tissue (irreversible defects) (5). Accordingly, examinations were classified as being either normal or abnormal, the latter being further divided in those demonstrating reversible defects and those demonstrating irreversible defects. We used the gated images to assess regional wall motion to improve differentiation between perfusion abnormalities and attenuation artifacts (12). The left ventricular ejection fraction was derived from the gated SPECT data using previously validated and automated software (quantitative gated SPECT [QGS], Cedars-Sinai Medical Center, Los Angeles, California); gating was only performed at rest.

Conventional coronary angiography.   Conventional coronary angiography was performed according to standard clinical protocols. We performed QCA using QCA-CMS 6.0 (Medis, Leiden, the Netherlands). For each coronary artery, the most severe stenosis was identified. The tip of the catheter was used for calibration and, after automated vessel contour detection with manual correction if needed, percentage diameter stenosis was calculated.

IVUS.   We performed IVUS imaging with 2.9-F 20-MHz catheters (Eagle Eye, Volcano, Brussels, Belgium). After intracoronary administration of nitrates, the IVUS catheter was advanced to the distal portion of coronary artery under fluoroscopic guidance. Using automated pullback device, the transducer was withdrawn at a continuous speed of 0.5 mm/s up to the coronary ostium. Cine runs before and during contrast injection were performed to confirm the position of the IVUS transducer before IVUS evaluation was started. All data were stored digitally and were analyzed off-line with the use of QCU-CMS 4.0 (Medis). After motion correction had been applied, coronary arteries were divided into segments according to the modified American Heart Association classification (7) using coronary ostia and side branches as landmarks. In each coronary segment, the frame with the most severe cross-sectional area of narrowing was selected for analysis. In addition, proximal and distal reference sites that had the largest lumen area by IVUS in the proximal and distal portion of the vessel segment in the 10 mm adjacent (but before any side branch) to the lesion site were selected. Subsequently, lumen and external elastic membrane (EEM) contours were manually traced to determine lumen area and EEM area at the lesion site and proximal and distal reference site. EEM area was defined as the area that was circumscribed by the border between the hypoechoic media zone and the surrounding echocardiographically bright adventitia. Plaque plus media area was calculated as the difference between the EEM and the lumen area. Based on these parameters, minimal lumen area (MLA), lesion plaque area, lesion plaque burden, lumen area stenosis, lumen diameter stenosis, and corrected lumen area stenosis were calculated per coronary segment as previously described (1,2). In brief, lesion plaque burden was defined as plaque plus media area divided by the EEM area, resulting in the lesion percentage area stenosis due to plaque. Lumen area stenosis was calculated by subtracting the lumen area at the lesion site from the lumen area at the reference site and subsequently dividing by the lumen area at the reference site.

In addition, vascular remodeling was determined. The number of lesions with positive remodeling was determined by calculating the remodeling index (RI) by dividing the lesion EEM area by the average of the proximal and distal reference EEM area. Subsequently, positive remodeling was defined as a RI 1.0, whereas RI <1.0 was classified as negative remodeling (13).

Statistical analysis.   Data were analyzed on a per-patient and per-vessel basis and, for the corresponding calculations, the coronary artery and coronary segment showing the most severe stenosis on either QCA or IVUS were used, respectively. Continuous variables were described by mean ± SD. Comparisons between patient groups were performed using the independent samples t-test for continuous variables. The chi-square test with Yates’ correction as appropriate or Fisher exact test (2-sided) for sparse data were used for comparison of categorical variables. When not normally distributed (coronary calcium score), continuous variables were compared using the nonparametric 2-tailed Mann-Whitney U test. A p value <0.05 was considered statistically significant. All statistical analyses were performed using SPSS (version 12.0.1., SPSS Inc., Chicago, Illinois).

	Results

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Comparison of MDCT with MPI and invasive angiography.   The results of the analysis on a patient basis (n = 70) are presented in Table 2 and Figure 1. Abnormal perfusion on SPECT was noted in 26 (37%) patients. The abnormal perfusion was associated with an average coronary calcium score of 751 ± 1,143. Calcium scores 400 were observed in 11 (42%) patients. Using MDCT coronary angiography, we found atherosclerosis in all 26 patients; severe stenosis was observed in 14 patients, 9 patients revealed borderline stenosis, and the remaining 3 patients presented with nonobstructive disease. The average number of diseased segments was 6.4 ± 3.1, whereas the average number of significantly stenosed segments was 2.5 ± 2.5 per patient. Considering the most severe stenosis per patient on conventional angiography, QCA showed an average percentage stenosis of 75.9 ± 19.2% with 23 patients showing significant stenosis (50% luminal narrowing). When validating MDCT results against QCA, the sensitivity of MDCT to detect coronary artery stenoses 50% luminal narrowing was 96% (22 of 23) and specificity was 67% (2 of 3).

View larger version (45K): [in this window] [in a new window] [Download PPT slide]   Figure 1 MDCT and QCA Findings in 70 Patients With Abnormal and Normal MPI Results, Respectively Note the discrepancy between the imaging modalities in patients with normal myocardial perfusion imaging (MPI). In most of these patients, multidetector computed tomography (MDCT) was abnormal, with no significant difference in the number of segments with atherosclerosis either (as compared with patients with abnormal perfusion. However, number of significantly stenosed segments was significantly lower in patients with normal MPI, as also reflected by minimal luminal narrowing on quantitative coronary angiography (QCA). *Average in patients with atherosclerosis on MDCT.

Upon analysis by vascular territories instead of patient basis, abnormal myocardial perfusion was noted in 36 (17%) of 208 vascular territories with ischemia in 33 and fixed perfusion defects in 3 vascular territories (Table 3). In the remaining 172 (83%) vascular territories, myocardial perfusion was normal.

Normal perfusion was observed in the remaining 36 (73%) patients. Average coronary calcium score was 247 ± 395 (p = 0.056 as compared with patients with abnormal perfusion). In these patients, calcium scores exceeded 400 in 7 (19%) patients. MDCT revealed atherosclerosis in 32 (89%), of which 18 patients showed nonobstructive disease, 11 patients had borderline stenosis, and 3 patients had severe stenosis. Mean number of diseased segments was similar to that of patients with abnormal perfusion, 5.4 ± 3.1 (p = 0.92) compared with patients with abnormal perfusion, but the mean number of significantly stenosed segments was significantly lower, 0.58 ± 0.91 (p = 0.028). Considering only the most severe percent luminal stenosis per patient, mean luminal narrowing of only 26.2 ± 15.6% was observed on QCA, indicating minimal angiographic stenosis. In line with these observations, preservation of the lumen was confirmed by IVUS with an average MLA of 5.8 ± 3.3 mm², which was significantly greater as compared with patients with abnormal MPI (p < 0.01). Nonetheless, considerable atherosclerosis was identified on IVUS with an average lesion plaque area of 8.7 ± 4.3 mm², which was not significantly different compared with patients with perfusion abnormalities (p = 0.17). Also substantial plaque burden was observed, with an average of 58.9 ± 18.1% (p < 0.01) of the lesion cross-sectional area as compared to abnormal MPI. A positive remodeling was identified in 16 (44%) of patients with normal MPI, as compared with 31% in patients with abnormal MPI (p = 0.20) (Table 4). The results are summarized in Figure 2, whereas in Figure 3, an example of a patient with MDCT- and IVUS-verified significant atherosclerotic burden is presented who had normal myocardial perfusion.

View larger version (50K): [in this window] [in a new window] [Download PPT slide]   Figure 2 MPI, MDCT, and QCA Observations in 49 Patients in Whom Additional IVUS Imaging Was Performed In almost all patients with normal MPI, the presence of atherosclerosis was observed on MDCT with negligible luminal narrowing identified on QCA. Intravascular ultrasound (IVUS) imaging confirmed the presence of substantial atherosclerosis (mean lesion plaque burden 58.9%), yet without luminal compromise (mean minimal lumen area [MLA] 5.8 mm2). Abbreviations as in Figure 1.

View larger version (83K): [in this window] [in a new window] [Download PPT slide]   Figure 3 Coronary Artery Disease by MDCT Coronary Angiography With Normal Myocardial Perfusion A 60-year old male presented to the outpatient clinic with dyspnea and an elevated risk profile for coronary artery disease, including hypertension, hypercholesterolemia, and smoking. Contrast-enhanced multidetector computed tomography (MDCT) coronary angiography revealed considerable atherosclerosis in the left anterior descending coronary artery (A). B and C are cross-sectional images of the areas indicated by the arrows in (A). In contrast, myocardial perfusion imaging (D), which was performed during exercise stress (first and third row) and rest (second and fourth row), showed normal perfusion. On intravascular ultrasound imaging (E and F), considerable plaque burden was demonstrated, yet with preserved coronary lumen.

In the remaining 94 (86%) coronary arteries without perfusion abnormalities, average coronary calcium score was 94 ± 178 (p = 0.04) as compared with coronary arteries with abnormal perfusion. On MDCT, aatherosclerosis was absent in 19 (20%), whereas the average degree of luminal stenosis on QCA was 21.4 ± 13.8%. Further details of the IVUS measurements on a vessel basis are provided in Table 5. Finally, as shown in Figure 4, significant differences in IVUS measurements were observed when comparing patients with and without atherosclerosis on MDCT.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 4 Differences in IVUS Measurements Between Coronary Arteries With CAD and Without CAD as Determined on MDCT (A) MLA (mm2) and corrected lumen area stenosis (%) and (B) plaque area (mm2) and plaque burden (%). All measurements were significantly different between coronary arteries with and without coronary artery disease (CAD) identified on MDCT. Abbreviations as in Figures 1 and 2.

	Discussion

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Hemodynamically relevant stenoses.   The flow-limiting lesions as determined by MPI were also associated with significant focal luminal narrowing on MDCT as well as invasive imaging. In total, 14 patients showed severe stenosis on MDCT, confirmed by a stenosis 70% luminal narrowing on QCA in all patients. In all patients with abnormal MPI, a mean percent diameter stenosis of 75.9 ± 19.2% was observed whereas IVUS showed mean MLA of 3.3 ± 1.3 mm². This observation is in consonance with an earlier report that compared IVUS measurements in 70 coronary lesions to gated SPECT and observed a 3.3-mm² MLA of coronary lesions corresponding to a positive SPECT study (1). Similar findings have been obtained in other studies employing fractional flow reserve (13,14), indicating an agreement among various imaging modalities in the presence of hemodynamically relevant CAD.

Atherosclerosis in the presence of normal perfusion.   In 63% of our patients, a normal MPI study was obtained. In these patients, only mild luminal narrowing (mean diameter stenosis 26.7 ± 17.7%) was observed during conventional invasive coronary angiography; 23% of patients had normal coronary angiograms (QCA <20% luminal narrowing). However, MDCT revealed normal coronary arteries only in 7 (16%) patients. In addition, the extent of disease, as reflected by a mean number of abnormal segments per patient, was not significantly different from patients with abnormal MPI. The presence of extensive atherosclerotic disease in such cases with normal MPI was confirmed by IVUS, which showed considerable plaque burden (average 58.9 ± 18.1 of cross-sectional area). These lesions were positively remodeled and did not inflict significant luminal stenosis (mean MLA of 5.8 ± 3.3 mm²). The presence of extensive atherosclerotic disease in the setting of normal myocardial perfusion has been described previously. In a large cohort of 1,195 patients without historical CAD, extensive atherosclerosis, as reflected by a calcium score >400, was observed in 31% of patients with normal MPI studies (15). The presence of substantial disease has also been previously described in angiographically normal segments; Mintz et al. (16) showed in a large series of consecutive patients that atherosclerosis was commonly present in angiographic reference segments and <7% of segments were classified as entirely normal by IVUS imaging.

Accordingly, various imaging modalities provide distinct morphological and functional information about coronary atherosclerotic disease. Conventional coronary angiography and MPI detect anatomically significant and hemodynamically relevant stenoses, respectively. In contrast, the techniques remain limited in depicting the disease in its earlier stages, or even when the disease is mature but does not compromise luminal integrity because of expansive vascular remodeling.

Clinical implications.   The current study reconfirms the expectation that the patients with perfusion defects on MPI indicating hemodynamically obstructive stenoses and representing advanced CAD, revealed significant stenoses on MDCT as well as on invasive angiography with QCA and IVUS. On the other hand, patients with (preclinical) atherosclerosis may present with normal perfusion on MPI, with (nearly) normal invasive angiography/QCA, but many of these patients may demonstrate extensive atherosclerosis in absence of obstructive stenoses on MDCT, which is verified subsequently by the IVUS observations. Thus, the presence of atherosclerotic plaque in MDCT in the setting of a normal MPI does not constitute a false-positive result. Rather, it reflects the fact that MDCT can detect atherosclerotic lesions that are not flow limiting, as confirmed by the use of IVUS in our study. Clinically, it is important to make a clear distinction between the presence of plaque and the presence of stenosis in MDCT. Since the large, positively remodeled lesions are harbingers of plaque rupture, it remains to be determined whether such advanced characterization of atherosclerotic lesions will result in superior prognostification of patients.

Study limitations.   In the present study, MDCT examinations were visually assessed because no validated quantification algorithms are currently available. Moreover, it is important to realize that interpretation of MDCT results is seriously limited in presence of calcific lesions. Also, IVUS imaging was not performed in all vessels in every patient. Furthermore, the current observations should be confirmed in less selected populations that would decrease the influence of selection bias. Finally, as the patients underwent multiple examinations, the radiation burden in the current study was high. The radiation dose of MDCT in particular is high, although the recent development of dose reduction strategies such as tube modulation or snapshot pulse scanning mode will result in considerably lower radiation exposures.

	Conclusions

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The current findings demonstrate a good agreement between noninvasive imaging techniques (MPI, MDCT) and invasive techniques (angiography, QCA, and IVUS) in patients with flow-limiting CAD. These patients exhibited abnormal perfusion on MPI, predominantly obstructive atherosclerosis on MDCT, and obstructive stenoses on invasive quantitative angiography and IVUS. In another subset of symptomatic patient population with normal myocardial perfusion, the use of MDCT uncovered considerable atherosclerosis in a great number of patients. Although invasive angiography did not confirm severe coronary lesions, the presence of MDCT-based atherosclerosis was validated by the use of IVUS.

Accordingly, considerable plaque burden can be observed on MDCT without inducing perfusion abnormalities on MPI. Rather than MDCT being a false positive result, atherosclerosis without flow-limiting luminal narrowing is detected.

	Footnotes

 
Dr. Pundziute is financially supported by the training fellowship grant of the European Society of Cardiology, Huygens scholarship, and Toshiba Medical Systems Europe; Dr. van Werkhoven is supported by the Netherlands Society of Cardiology; Dr. Jukema is an established investigator of the Netherlands Heart Foundation, grant number 2001T032; and Dr. Bax has research grants from GE Healthcare and BMS Medical Imaging.

^_* Reprint requests and correspondence: Dr. Jeroen J. Bax, Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands. (Email: j.j.bax{at}lumc.nl).

Manuscript received December 3, 2007; accepted December 16, 2007.

	REFERENCES

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This Article Abstract Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Schuijf, J. D. Articles by Bax, J. J. Search for Related Content PubMed Articles by Schuijf, J. D. Articles by Bax, J. J.