Author + information
- Received December 15, 2005
- Revision received April 18, 2006
- Accepted April 25, 2006
- Published online August 15, 2006.
- Gardar Sigurdsson, MD⁎,
- Patricia Carrascosa, MD†,
- Mohammad H. Yamani, MD⁎,
- Neil L. Greenberg, PhD⁎,
- Sergio Perrone, MD‡,
- Gustavo Lev, MD‡,
- Milind Y. Desai, MD⁎ and
- Mario J. Garcia, MD⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Mario J. Garcia, Cardiovascular Imaging Center, Cleveland Clinic Foundation, Desk F15, 9500 Euclid Avenue, Cleveland, Ohio 44195.
Objectives This study sought to determine whether multidetector computed tomography (MDCT) may be able to detect occlusive coronary disease in transplanted hearts.
Background In heart transplant recipients, asymptomatic coronary disease requiring frequent surveillance commonly develops. Recent advancements in MDCT allow for noninvasive assessment of the coronary vessels.
Methods Electrocardiogram-gated contrast-enhanced MDCT scans (16 × 0.75-mm detectors, 420 ms rotation, 100 ml contrast) with multisegment reconstruction were performed on 54 transplant recipients within 6 ± 11 days of quantitative coronary angiography (QCA). Heart rate at the time of the scan was 90 ± 11 beats/min. Coronary arterial segments >1.5 mm in diameter were analyzed by independent investigators.
Results There was a good correlation between MDCT and QCA percent stenosis (r = 0.75, p < 0.01, SEE = 15%). Of the 791 segments identified by QCA, 754 (95%) were analyzable by MDCT. The sensitivity, specificity, and positive and negative predictive values of MDCT compared with QCA for the detection of segments with significant (>50%) stenosis were 86%, 99%, 81%, and 99%, respectively. The MDCT correctly identified 15 of the 16 (94%) transplant patients classified by QCA as having occlusive coronary artery disease and 29 of the 37 patients without significant stenosis (78%). In 1 patient who received intravenous beta-blockers, transient bradycardia requiring temporary pacing developed, but there were no other complications.
Conclusions Detection of occlusive coronary disease in heart transplant recipients with elevated resting heart rate by MDCT is feasible using multicycle reconstruction. The need for surveillance invasive coronary angiography in transplant recipients might be mitigated by use of MDCT.
Heart transplant therapy has resulted in a significant improvement in the survival of patients with end-stage heart failure. Coronary disease is the leading cause of decreased survival after the first year post-transplantation (1). Clinically, the development of coronary disease can be insidious because of denervation of the heart after transplantation (2). Currently, most institutions perform annual surveillance by conventional coronary angiography (3,4). However, invasive coronary angiography carries risks including stroke, myocardial infarction, and vascular injury (5), and performing multiple procedures on heart transplant recipients is associated with an increased rate of these complications (6).
Recent advancements in multidetector computed tomography (MDCT) with improved gantry speed and submillimeter spatial resolution have made it possible to visualize the coronary arterial tree noninvasively (7,8). Additionally, MDCT angiography is capable of assessing both lumen size and the vessel wall characteristics, detecting both noncalcified and calcified lesions (9,10). Temporal resolution of current MDCT scanners using half-scan reconstruction is typically 188 to 210 ms, thus administration of beta-blockers is often required to reduce heart rate and motion artifacts. Heart transplantation patients often have an elevated heart rate and are relatively insensitive to beta-blockade. Recent data, however, suggest that MDCT temporal resolution may be improved using multisegment reconstruction (11). Accordingly, we conducted the present study to determine the diagnostic accuracy of 16-slice MDCT using multisegment reconstruction for detecting occlusive coronary disease and proliferative vessel wall changes in heart transplant recipients.
Fifty-four consecutive heart transplant recipients (age 54 ± 11 years, 89% male) who were scheduled for surveillance coronary angiography were recruited. Subjects with a history of contrast allergy, diabetes, renal dysfunction (creatinine above 1.5 mg/dl), atrial fibrillation, and pregnancy were excluded. Institutional review committees approved the study, and all patients gave written consent. Blood pressure and heart rate were measured before and after each MDCT study. Serum creatinine was measured immediately before the MDCT and 3 to 7 days after invasive catheterization. Serious adverse events were monitored and defined as allergic reaction to contrast resulting in hospital admission, persistent hypotension, bleeding requiring transfusion, extravasations, and increase in creatinine above 2.0 mg/dl.
Invasive coronary angiography was performed in a standard fashion and was evaluated using quantitative coronary angiography (QCA) by independent investigators blinded to the MDCT results. A commercially available analysis program (Inturis Suite 2.2, Philips Medical Systems, Highland Heights, Ohio) was used. Results from the QCA were used as a gold standard. Only those segments that had a diameter by QCA >1.5 mm at their origin were analyzed. A subset of the study population also underwent intravascular ultrasound (IVUS) examination in the following standard fashion. All patients received aspirin 100 to 325 mg/day and/or clopidogrel for at least 72 h, 70 IU/kg of unfractionated heparin, and 0.2 mg of nitroglycerin intra-arterially immediately before the procedure. The IVUS studies were performed under fluoroscopic guidance with an ultra-cross 3.2-F, 30-MHz coronary imaging catheter, resolution 0.07/0.20 mm (Boston Scientific Corporation, Natick, Massachusetts). The IVUS catheters were advanced over a guidewire for each of the main coronary arteries and branches until a vessel diameter of 2 mm was reached. Continuous images were recorded as the catheter was automatically pulled back (0.5 mm/s) from the distal to the most proximal segments. The equipment gain and gray scale were kept constant to avoid variation. After the IVUS procedure, an additional dose of 0.2 mg nitroglycerin was administered intracoronarily to avoid coronary spasm. The IVUS images were analyzed off line, and cross-sectional images from MDCT and IVUS data sets were matched according to the distance from the coronary ostia to ensure that identical segments and plaques were assessed. Two independent investigators then performed separate analysis of the MDCT (described in later text) and IVUS images. In patients who underwent both IVUS and MDCT examination, we qualitatively recorded the presence or absence of proliferative changes in the coronary arterial wall. We excluded those segments in which QCA showed a stenosis of >50% by QCA.
Spiral electrocardiogram (ECG)-gated contrast-enhanced MDCT coronary angiography was performed with 16-detector MDCT scanners (Mx8000ID, Philips Medical Systems). The MDCT scan parameters included 140 kVp, 400 mAs, 0.75-mm slice thickness, 0.4-mm slice increment, 0.42-s rotation time, 0.2 to 0.3 pitch. After a noncontrast survey scan, a total of 100 ml of nonionic iodinated contrast medium (iopromide, iohexol, or ioversol 350 to 370 mg/dl) was administered intravenously (4 ml/s) in the antecubital vein using a power injector (Stellant, Medrad, Indianola, Pennsylvania). The scan was initiated 4 s after the contrast-enhanced ascending aorta reached a target value of 150 Hounsfield units (HU). The entire heart was imaged within a single breath-hold (20 to 30 s). After the scan, the desired phases (typically between 40% to 50% or 70% to 80%) within the RR interval were reconstructed using the synchronized ECG signal and X-ray projection data. An adaptive multisegment reconstruction algorithm yielded images with temporal resolutions between 53 and 210 ms (12). The reconstructed images were transferred to a workstation for analysis (MxView, Philips Medical Systems). Coronary vessel analysis was done from both volume-rendered and curved multiplanar images by investigators blinded to the invasive angiographic results. Coronary arterial segments of >1.5 mm in diameter by MDCT were analyzed for the presence of stenosis and defined as a percent diameter reduction in comparison with an adjacent segment. The proposed American Heart Association classification was used for vessel segmental analysis (13).
Heart rate during MDCT was recorded, and heart rate variability was defined as the standard deviation of the change in the RR interval during scan time. Heart rate variability in transplant patients was compared with that of patients without a heart transplant who underwent MDCT angiography during same study period.
Quantitative MDCT and QCA measurements of percent stenosis were compared using linear regression analysis and Bland-Altman analysis of agreement (14). Qualitative analysis was performed to assess the accuracy of MDCT for detecting significant stenosis (defined as >50% diameter reduction). Performance characteristics were evaluated using: 1) segments, 2) vessels, and 3) patients as the unit of analysis. For vessel-based analysis, the coronary tree was separated into the left anterior descending, left circumflex artery, and right coronary artery territories. The left main trunk was assigned to both the left anterior descending and the left circumflex territories. Vessels with 1 or more obstructed segments were encoded as stenotic for comparison. In a similar manner, patients with 1 or more obstructed segments were encoded as stenotic for patient-based analysis classification. All vessels and patients were analyzed even if they included segment(s) not visualized by MDCT. Nonvisualized segments were categorized as nonstenotic by MDCT for this purpose. Sensitivity, specificity, and positive and negative predictive values (for QCA vs. MDCT and IVUS vs. MDCT) are presented with their estimated 95% confidence intervals. In 13 patients, interobserver variability of stenosis detection by MDCT was tested by a second observer blinded to the measurements of the first observer. Interobserver variability was calculated as bias (the average difference between the readers) as well as the average absolute difference between the 2 readers. Finally, to evaluate whether overall quality of the computed tomographic angiography (CTA) study affected final results, we performed a multiple logistic regression. As predictor variables we used percent stenosis by CTA and the ratio between the number of visualized segments by CTA divided by the total number of segments present (an indicator of CTA study quality). The dependent variable was the presence or absence of significant (>50%) stenosis on QCA. Statistical analysis was performed using MedCalc version 8.1 (MedCalc Software, Mariakerke, Belgium), HyperStat on-line (Houston, Texas), and Microsoft Excel 2003 analysis tools (Microsoft, Seattle, Washington).
The average patient’s height and weight for the study group were 1.8 ± 0.08 m and 91.8 ± 15 kg. In 1 patient pacemaker-induced tachycardia developed at the time of the MDCT, and the patient was excluded from the study. Three patients received intravenous metoprolol (10 to 20 mg) before the procedure. In 1 patient, transient bradycardia and hypotension requiring temporary pacing developed; the other 2 showed no response. Our negative initial experience deterred us from further use of beta-blockers in this study. No other serious adverse events were related to MDCT. Serum creatinine was 1.2 ± 0.3 mg/dl immediately before MDCT and remained unchanged (1.2 ± 04 mg/dl) 2.8 ± 2.2 days after coronary angiography. In only 2 patients did a transient increase in creatinine above 1.5 mg/dl (highest measured 1.7 mg/dl) develop, subsequently returning to baseline values. The average radiation exposure during the MDCT scan was estimated at 10 ± 2 mSv.
Heart rate was significantly higher in transplant patients (90 ± 11 beats/min) compared with nontransplant controls (66 ± 14 beats/min, p < 0.001). Heart rate variability during scan time measured as the standard deviation of the RR interval was significantly lower in heart transplantation patients compared with controls (32 ± 40 ms vs. 83 ± 70 ms, p < 0.001). The elevated heart rate was not found to significantly affect image interpretability (Fig. 1).In this study, reconstruction of the end-systolic phase was used in 76% of studies and of the mid-diastolic phase in 24%.
There were 791 segments with a diameter ≥1.5 mm as defined by QCA. Of these, 754 were identified by MDCT. Thus, only 37 segments (5%) were excluded for analysis because of poor vessel opacification (n = 14), motion artifacts (n = 22), or beam hardening artifact caused by stent (n = 1). Calcified plaques, when present, were typically discrete and did not interfere with visualization of the lumen by MDCT. There were 51 segments classified as having >50% stenosis by QCA. Of these, only 1 segment was deemed not evaluable by MDCT, and 7 were incorrectly classified as nonstenotic. The MDCT correctly identified 703 of the 713 (99%) segments classified as nonstenotic by QCA. There was a good correlation between MDCT and QCA percent stenosis (r = 0.75, p < 0.01, standard error of estimate = 15%). Bland-Altman analysis suggested that MDCT overestimated stenosis severity by 0.8% (Fig. 2).For assessment of interobserver variability, the average bias between 2 readers was 1.1 ± 16.9% (p = NS when compared with 0), and the average absolute difference was 4.31%. By logistic regression analysis, only percent stenosis by CTA predicted a presence of significant stenosis on QCA (p < 0.001), whereas study quality had no effect (p = 0.79).
Of the 159 vessels available, MDCT correctly identified 29 of the 30 (97%) vessels classified as having occlusive disease by QCA, and 119 of the 129 (92%) nonstenotic vessels (Figs. 3 to 5).⇓⇓⇓The prevalence of occlusive disease was slightly higher in the left anterior descending (n = 14) and left circumflex (n = 11) compared with the right coronary artery (n = 5) distribution. The MDCT correctly identified 15 of the 16 (94%) transplant patients classified by QCA as having occlusive coronary artery disease and 29 of the 37 patients without significant stenosis (78%). Total occlusion was found in 11 vessels or 8 patients. The sensitivity, specificity, positive and negative predictive values for segment, and vessel- and patient-based evaluations are summarized in Table 1.
A subset of patients (13) also underwent IVUS examination along with QCA. In such patients, the accuracy of MDCT at qualitatively identifying the coronary segments with proliferative changes was assessed (excluding the lesions with stenosis >50%). A total of 154 segments (an average of 12 segments per patient) were analyzed. The MDCT correctly identified 49 of the 51 segments with proliferative changes and 90 of the 102 segments without the proliferative changes as identified by IVUS. The sensitivity, specificity, and positive and negative predictive values are as follows: 96% (95% confidence interval [CI] 87% to 99%), 88% (95% CI 80% to 94%), 80% (95% CI 69% to 88%) and 98% (95% CI 92% to 99%), respectively. Diffuse wall thickening was detected in 53 segments (34%) by IVUS and 54 segments (35%) by MDCT. The sensitivity and specificity of MDCT for detecting abnormal wall thickening were 92% (95% CI 82% to 98%) and 95% (95% CI 89% to 98%).
Annual surveillance for coronary disease is of great importance to heart transplant recipients because development of occult coronary disease is a major cause of late mortality (1). Conventional coronary angiography carries high cost and considerable inconvenience to the transplant recipient (6). Although the risk of adverse events is relatively small, serious and potentially life-threatening sequelae may occur, including arrhythmia, stroke, coronary artery dissection, and access site bleeding, for a total complication rate of 1.8% and a mortality rate of 0.1% (15). It would be of great importance to establish a noninvasive test that could reduce the number of invasive procedures that each patient has to undergo. Several noninvasive tests, including exercise electrocardiogram, radionuclide scintigraphy, exercise echocardiography, and dobutamine echocardiography, have proven unsatisfactory as tools for the screening of coronary artery disease when compared with coronary angiography or IVUS (16).
Recent improvements in contrast-enhanced MDCT imaging allow for a noninvasive evaluation of both the lumen size of the coronary artery and the vessel wall characteristics (7–9). Limited experience exists on how contrast-enhanced MDCT can detect coronary artery disease in transplant recipients (17). The MDCT was recently evaluated in a small feasibility study in 8 children after heart transplantation. The MDCT could detect coronary artery disease, but image quality was thought to suffer from motion artifacts related to elevated heart rate (18). In our study, subjects were also found to have an elevated heart rate but without significant compromise to image interpretability. Image quality of MDCT is limited with increasing heart rate because of the limited temporal resolution imposed by the gantry rotational speed. Traditionally beta-blockers are used to improve image quality. Only 2 patients received beta-blockers in this study and showed no immediate response, but 1 had delayed symptomatic bradycardia. Although it was unclear whether the use of metoprolol was related to bradycardia in this case, we elected to discontinue its use in the remaining study subjects. Safety concerns have been raised regarding the use of beta-blockers in some patients after cardiac transplantation because the denervated hearts may be largely dependent on circulating catecholamines to increase cardiac output. Beta-blocker use has been incriminated as one of the contributing risk factors for the hypotension, acidosis, and vasodilatation syndrome reported after transplantation (19). An alternative therapy for heart rate reduction might be nondihydropyridine calcium channel antagonists, such as verapamil (20), but this was not used in the current study. Despite the elevated heart rate during image acquisition, only 5% of segments >1.5 mm were deemed not evaluable. This might be explained by several factors, including decreased heart rate variability, use of end-systolic phase for reconstruction, and a specific gating algorithm that smoothes heart rate change (21). An elevated heart rate facilitates multisegment reconstruction algorithms that can provide temporal resolution of 53 to 105 ms (12).
In our study design we restricted the analysis to segments >1.5 mm in diameter. This gives MDCT a value in detecting the lesions that are of the greatest clinical significance. Smaller vessels are not as well visualized, but as this technique evolves and spatial resolution improves, the accuracy of detecting stenosis in smaller vessels will likely improve.
In our study population, densely calcified plaques were uncommon. This finding may be unique to transplant vasculopathy and may explain why the number of segments that needed to be excluded for analysis in our study was significantly lower than previously reported in nontransplantation patients. One of the potential advantages of MDCT over invasive coronary angiography is its ability to define vessel wall characteristics (Figs. 3 to 5). Recent studies suggest that MDCT can establish and quantify with reasonable accuracy the presence of calcified as well as noncalcified plaques. Intravascular ultrasound studies have shown abnormal thickening of the vessel wall in transplant vasculopathy, even in the absence of angiographic abnormalities. Whether MDCT might replace IVUS in transplantation patients remains to be determined.
This study was limited to subjects with normal renal function because study patients also were scheduled to undergo invasive coronary angiography. Renal insufficiency is common in heart transplantation patients. Multidetector computed tomography may still be feasible in patients with mild renal insufficiency because image quality has been obtained with a lower contrast dose (9).
Radiation with MDCT in our study is somewhat higher than would be expected with conventional coronary angiography. Prospective electrocardiographically guided X-ray dose modulation could reduce significantly the total radiation dose toward an equivalent dose used during invasive coronary angiography (22).
A direct and comprehensive comparison with IVUS was not available in all patients because that was not the original goal of the study. However, a subgroup analysis showed that MDCT has a high degree of accuracy in detecting proliferative wall changes compared with IVUS. Although IVUS has greater spatial and temporal resolution than MDCT, it its very costly and invasive, and its use is limited only proximal segments. Studies with IVUS indicate that vasculopathy with wall thickening >0.5 mm could carry prognostic significance (23,24). The slice thickness of 16-slice MDCT is 0.75 mm, limiting the detection of mild vasculopathy but not of moderate or severe vasculopathy. Spatial resolution can be as low as 0.4 mm with the newer 64-slice scanners and will likely improve in the future.
In general, elevated heart rates would be considered a limitation to MDCT imaging, but in this patient population it seemed to facilitate multisegment imaging with improved temporal resolution. The expected motion artifacts accompanied by an elevated heart rate were also circumvented by use of an end-systolic phase rather than a mid-diastolic phase during reconstruction, as previously described (25,26).
Imaging of the coronary vessels in heart transplantation patients with 16-slice MDCT with adaptative multisegment reconstruction, seems to be both feasible and safe, and should not be limited to patients with a low heart rate. Our results indicate that MDCT detects significant coronary stenoses with excellent diagnostic accuracy. In particular, the high negative predictive value makes MDCT ideal for screening. If vessel wall analysis with newer-generation MDCT proves to be clinically valuable, MDCT could also represent an alternative to IVUS in patients with suspected transplant vasculopathy.
The authors thank Zoran Popovic, MD, for his assistance with statistical analyses.
Drs. Carrascosa and Garcia receive research grant support from Philips Medical Systems. This study was funded in part by a Cleveland Clinic RPC grant and by Philips Medical Systems.
- Abbreviations and Acronyms
- confidence interval
- computed tomographic angiography
- intravascular ultrasound
- multidetector computed tomography
- quantitative coronary angiography
- Received December 15, 2005.
- Revision received April 18, 2006.
- Accepted April 25, 2006.
- American College of Cardiology Foundation
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