Despite recent advances in therapeutic and diagnostic approaches, coronary artery disease (CAD) and its related cardiac disorders represent the most common cause of death in the United States. Nuclear myocardial perfusion imaging (MPI) technologies play a pivotal role in the diagnosis and treatment design for CAD. Recently, in order to develop improved MPI agents for diagnosis of CAD, 99mTc-[bis(dimethoxypropylphosphinoethyl)-ethoxyethyl-amine(PNP5)]-[bis(N-ethoxyethyl)dithiocarbamato(DBODC)]nitride(N-DBODC5)(99mTc-N-DBODC5) with a faster liver clearance than conventional single-photon emission computed tomography (SPECT) imaging agents (technetium 99m sestamibi (99mTc-MIBI) or technetium 99m tetrofosmin) has been introduced. In preclinical and phase I studies, 99mTc-N-DBODC5 has shown characteristics of an essentially ideal MPI tracer. Importantly, however, there is no data to support the use of 99mTc-N-DBODC5 to evaluate myocardial ischemia in patients with suspected CAD. The present study was designed to assess the clinical value of this agent; the findings of stress and rest MPI after the administration of this agent were compared to those of stress and rest 99mTc-MIBI, as well as those of coronary angiography, with respect to the detection of CAD. Our findings indicated the usefulness of 99mTc-N-DBODC5 as a promising MPI agent.
Coronary artery disease (CAD) remains the single greatest cause of death in men and women in the USA, despite a declining total death rate. Using 2005 data, over 445,000 (or 1 in every 5) deaths in the USA were due to CAD, and it ranked highest among all disease categories in hospital discharges [
Nuclear cardiology, cardiovascular magnetic resonance, cardiac computed tomography, position emission computed tomography, and coronary angiography (CA) are imaging modalities that have been used to measure myocardial perfusion, left ventricular function, and coronary anatomy for clinical management and research [
The most commonly used imaging modality for this purpose is single-photon emission computed tomography (SPECT) [
Thallium-201 (201Tl), technetium 99m sestamibi (99mTc-MIBI), and technetium 99m tetrofosmin (99mTc-tetrofosmin) are three traditional, routinely used, MPI tracers and are clinical-validated tracers for evaluation of SPECT MPI [
Recently, 99mTc-N-DBODC5 with a faster liver clearance than conventional SPECT imaging agents has been introduced. It is a new lipophilic, monocationic 99mTc-labeled compound that is currently under clinical investigation as a MPI agent [
In order to evaluate the clinical value of this agent, the findings of stress and rest MPI after the administration of this agent were compared to those of stress and rest 99mTc-MIBI MPI, as well as those of CA, with respect to the detection of CAD.
Of 120 patients admitted to the hospital because of chest pain from March 2010 to December 2011, 46 (31 males; mean age,
Study group.
Parameter | Value |
---|---|
|
46 |
M/F | 31/15 |
Age (yr) | 60.08 |
Hypertension | 31 |
Hyperlipidemia | 19 |
Diabetes mellitus | 14 |
Smoking | 26 |
Trigger of chest pain | |
Effort | 22 |
Rest | 13 |
Not specific | 11 |
ECG abnormality | 11 |
ST-T elevation | 3 |
ST-T depression | 8 |
≥50% of luminal narrowing | 29 |
One-vessel disease | 14 |
Two-vessel disease | 11 |
Three-vessel disease | 4 |
Data are presented as mean
99mTc-N-DBODC5 was prepared using a lyophilized kit formulation purchased from Beijing Shihong Pharmaceutical Center. The saline solution of sodium pertechnetate (1.0 mL, 1110 MBq) was added to an SDH vial (Vail A: 5.0 mg of succinate dehydrogenase, 5.0 mg of 1,2-diaminopropane-N,N,N′,N′-tetraacetic acid, and 0.05 mg of SnCl2·2H2O). Then, the solution was kept at room temperature for 15 min to form a [99mTcN]2+ intermediate. The other two lyophilized vials (Vail B: 2.0 mg of PNP5, Vail C: 2.0 mg of DBODC) were dissolved with 1.0 mL of saline solution, respectively. And then the saline solutions of Vails B and C were added to the vial of [99mTcN]2+ intermediate (Vail A). The resulting solution was heated at 100°C for 15 min. Before injection, the solution was filtrated through a 0.22-
Radiochemical purity (RCP) was determined by thin-layer chromatography (TLC). TLC was conducted on polyamide film as the station phase and saline/acetone (v / v = 6 : 1) as the mobile phase. Retention factor (Rf) for 99mTc-N-DBODC5 is 0.3–0.6. The RCP was more than 95% in each experimental study, and the purity was still greater than 95% at least 6 h.
Figure
99mTc-N-DBODC5 and 99mTc-MIBI imaging protocols: two-day exercise stress/rest.
Each patient underwent an exercise 99mTc-MIBI study within 7 days of the 99mTc-N-DBODC5 study. For the 99mTc-MIBI (
Patients were imaged in the supine position with their arms raised. SPECT images were acquired with a fixed 90° two-headed gamma camera (Infinia VC Hawkeye, General Electric, USA), using a low-energy, high-resolution, parallel-hole collimator, from the 45° right anterior oblique to the 45° left posterior position. Acquisition parameters were as follows: detectors at 90°, 180° rotation at 3° steps with automatic body contouring, 35 s acquisition per step,
99mTc-N-DBODC5 and 99mTc-MIBI heart-to-organ count ratios were calculated from the anterior projection of each tomographic acquisition. Regions of interests (ROIs) were drawn around the entire left ventricular myocardium, over the hepatic margin adjacent to the inferoapical wall of the left ventricle, excluding the biliary tree, and over the inferior left ventricular wall adjacent large intestine activity. The mean counts per pixel in the three ROIs were normalized to the injected tracer activity after decay correction and to a standard acquisition time of 1 min. Heart-to-liver and heart-to-intestine ratios were then computed [
For MPI analyses, at first, two experienced observers judged which image sets from 99mTc-MIBI and 99mTc-N-DBODC5 were superior in image quality on the basis of patient motion, statistical noise, tracer activity below the diaphragm, heart-to-organ count ratio, and sharpness, without knowledge of the radiopharmaceutical or patient identity [
Both overall qualitative diagnosis and semiquantitative 17 segment with 5-point [
All coronary angiograms were interpreted with quantitative CA in a coronary angiography core laboratory blinded to the clinical or imaging results. A coronary stenosis was considered present when there was a stenosis ≥ 50% in diameter in any epicardial coronary artery. The presence of one or more coronary stenoses defined the presence of significant CAD.
All statistical analyses were performed using the statistical package SPSS 16.0 (Chicago, IL, USA). The results were expressed as the mean value ± SD. The difference in left ventricular function parameters and perfusion scores were compared using a paired Student’s
Of the 46 patients studied, 29 had ≥50% luminal diameter stenosis in at least one major coronary vessel. Fourteen had single-vessel disease, 11 had two-vessel disease, and four had three-vessel disease; 15 patients showed significant stenosis in the RCA, 19 in the LAD, and 14 in the LCX. The remaining 17 patients had normal or nonsignificantly stenosed coronary arteries.
Qualitative analyses of images acquired of 99mTc-N-DBODC5 both at rest and during stress revealed no significant overlap between tracer accumulation in the inferior wall of the ventricle and in the subdiaphragmatic region (Figure
Comparison of liver clearance of the two tracers in anterior tomographic planar images of a patient (as shown in the black arrow; H, heart; Lv, liver). (a) Exercise stress 99mTc-N-DBODC5, (b) Exercise stress 99mTc-MIBI, (c) rest 99mTc-N-DBODC5 and (d) rest 99mTc-MIBI.
Figure
Heart-to-liver ratio and heart-to-intestine ratio measured with an anterior projection images at stress for 30 min and rest for 60 min for 99mTc-N-DBODC5 and 99mTc-MIBI in 46 patients.
In the stress perfusion imaging, 99mTc-N-DBODC5 MPI was superior in quality to 99mTc-MIBI MPI in 37 of the 46 patients studied. In the remaining nine patients, the MPI was judged to be of equal quality. In the resting perfusion imaging, 99mTc-N-DBODC5 images were superior in all the patients studied. In general, the 99mTc-N-DBODC5 MPI had more counts with less statistical noise, less tracer activity below the diaphragm, and desirable heart-to-organ count ratio compared with 99mTc-MIBI MPI.
Table
The comparison of myocardial perfusion in a total of 782 segments with 99mTc-N-DBODC5 and 99mTc-MIBI SPECT exercise imaging.
99mTc-N-DBODC5 | 99mTc-MIBI | Total | ||
---|---|---|---|---|
Normal | Reversible defect | Nonreversible defect* | ||
Normal | 302 (39%) | 17 (2%) | 71 (9%) | 390 |
Reversible defect* | 16 (2%) | 119 (15%) | 105 (13%) | 240 |
Nonreversible defect | 12 (2%) | 4 (1%) | 136 (17%) | 152 |
| ||||
Total | 330 | 140 | 312 | 782 |
Data are presented as number; *
Table
MPI findings of two tracers on left ventricular function parameters and ischemia scores in 46 patients.
Parameter | 99mTc-MIBI | 99mTc-N-DBODC5 |
---|---|---|
LVEF (%) | ||
Exercise | 54.2 |
56.7 |
Rest | 63.1 |
64.8 |
EDV (mL) | ||
Exercise | 81.5 |
83.2 ± 16.3 |
Rest | 97.3 |
99.1 |
ESV (mL) | ||
Exercise | 43.2 |
41.4 |
Rest | 59.4 |
60.2 |
SSS | 12.1 |
9.6 |
SRS | 7.2 |
7.9 |
SDS | 4.2 |
3.6 |
TID | 0.96 |
0.94 |
Data are presented as mean
Table
Sensitivity, specificity, and diagnostic accuracy of scintigraphic perfusion studies and agreement with coronary angiography.
Overall | LAD | LCX | RCA | |||||
---|---|---|---|---|---|---|---|---|
MIBI | DBODC | MIBI | DBODC | MIBI | DBODC | MIBI | DBODC | |
No. of disease | 25 | 25 | 10 | 12 | 9 | 8 | 13 | 13 |
Sensitivity (%) | 86 | 86 | 53 | 63 | 64 | 57 | 87 | 87 |
Specificity (%) | 65 | 88 | 96 | 96 | 94 | 94 | 68 | 87 |
Accuracy (%) | 78 | 87 | 78 | 83 | 85 | 83 | 74 | 87 |
▲Kappa ( |
0.53 | 0.73 | 0.52 | 0.63 | 0.62 | 0.55 | 0.48 | 0.71 |
Data are presented as number (%); MIBI = 99mTc-MIBI, DBODC = 99mTc-N-DBODC5; LAD: left anterior descending coronary artery; LCX: left circumflex coronary artery; RCA: right coronary artery. ▲CA was used as the “gold standard” for the calculation of the
Abnormal MPI in the vertical long-axis slices of a representative patient. Both 99mTc-N-DBODC5 (a) and 99mTc-MIBI (b) images demonstrate an inferoposterior defect (white arrows). The defect is well visualized on two tracer images corresponding to the CA result. This coronary angiography (c) detected a stenosis of 90% in the RCA. The concordance for diagnosis of myocardial ischemia was seen on 99mTc-N-DBODC5 and 99mTc-MIBI studies.
Table
On the other hand, sensitivity and specificity for RCA stenosis vessel lesion detection using 99mTc-MIBI MPI were 87% and 68% compared to 87% and 87% for 99mTc-N-DBODC5 MPI, LAD stenosis (53% sensitivity and 96% specificity for 99mTc-MIBI, 63% sensitivity and 96% specificity for 99mTc-N-DBODC5, resp.), and left circumflex (LCX) (64% sensitivity and 94% specificity for 99mTc-MIBI, 57% sensitivity and 94% specificity for 99mTc-N-DBODC5, resp.). Angiography agreement was very good for 99mTc-N-DBODC5 (
These preliminary results demonstrate that stress-rest myocardial perfusion SPECT with 99mTc-N-DBODC5 is a sensitive method for detecting CAD and identifying stenosed coronary arteries. For the detection of CAD, more importantly, 99mTc-N-DBODC5 MPI reached good agreement compared with CA (
99mTc-N-DBODC5 is a new lipophilic, monocationic, and nitride 99mTc-labeled tracer that is rapidly cleared from the liver after intravenous injection. It possesses good stability under physiological conditions. Importantly, 99mTc-N-DBODC5 exhibits more rapid liver washout than either 99mTc-MIBI or 99mTc-tetrofosmin. For example, at 60 min after injection in rats, the heart/liver ratio of 99mTc-N-DBODC5 is approximately ten times higher than that of 99mTc-MIBI or 99mTc-tetrofosmin. Preclinical studies have shown that 99mTc-N-DBODC5 SPECT can identify previous ischemia as areas of reduced tracer uptake [
In the present study, the heart-to-organ count ratio of 99mTc-N-DBODC5 MPI was superior to that of 99mTc-MIBI in 46 patients. Compared with 99mTc-MIBI MPI, 99mTc-N-DBODC5 MPI had better image quality in most patients. Furthermore, in this study, exercise stress myocardial images were performed 30 min after 99mTc-N-DBODC5 injection, and excellent MPI with high contrast was possible.
This clinical trial assesses the diagnostic value of this agent to detect CAD comparing it with stress 99mTc-MIBI MPI and CA.
In this study, compared with 99mTc-MIBI MPI, 99mTc-N-DBODC5 MPI indicates the same sensitivity and better specificity and accuracy to detect coronary disease in patients, although none of the differences were significant. On the other hand, more importantly, angiography agreement was very good for 99mTc-N-DBODC5 (
Unsurprisingly, Braat et al. [
For the detection of coronary disease in patients, 99mTc-MIBI produced abnormal results for MPI in four patients who had no angiographically detected stenosis. Some of these false-positive results may be due, in part, to the liver-to-heart artifacts. In this study, we could classify fixed perfusion defects as soft-tissue attenuation artifacts or infarcts by using gated SPECT. Because an artifactual defect would show normal contraction (wall motion or thickening) on a gated image, artifacts can be differentiated from a true infarct [
For the detection of individual vessel stenosis, on the other hand, angiography agreement was very good for 99mTc-N-DBODC5 (
Serial short-axis and vertical long-axis slices of stress-rest 99mTc-N-DBODC5 images (b) and stress-rest 99mTc-MIBI images (c) of a representative patient with normal CA (a). Because of intense uptake of technetium 99mTc-MIBI in the liver, high liver background activity can be observed. Furthermore, a false-positive myocardial perfusion defect was also seen in the inferoposterior wall segments supplied by the RCA territory (white arrows). Importantly, however, at stress and rest, the inferoposterior wall segments of 99mTc-N-DBODC5 images are clearly separated from the subdiaphragmatic activity.
On a segment-to-segment basis, complete agreement between the two imaging agents occurred in 71% of segments. However, more myocardial segments were nonreversible on 99mTc-MIBI images than on 99mTc-N-DBODC5 images. On the contrary, 99mTc-N-DBODC5 MPI had a higher reversible defect than that of 99mTc-MIBI. A possible reason for this difference may be due, in part, to the “liver-heart artifact.” The presence of high liver activity adjacent to the inferior wall results from oversubtraction of activity from the inferior wall. Therefore, the more “liver-heart artifact” in the inferoposterior wall on myocardial images, the more false nonreversible defects in the inferoposterior wall on myocardial perfusion segmental analysis. In other words, the less reversible defects in the inferoposterior wall were deduced on 99mTc-MIBI MPI segmental analysis.
More importantly, however, the main advantage and clinical value of 99mTc-N-DBODC5 can improve diagnostic specificity and reduce the false-positive diagnosis of patients and associated treatment fees.
In this study, we did not attempt to assess the absolute diagnostic accuracy of 99mTc-N-DBODC5, because definitive conclusions in this regard can only be drawn by studying larger patient cohort. In addition, although 99mTc-N-DBODC5 did not track flow as well as 201Tl, the magnitudes of the pharmacologic stress-induced perfusion defects were comparable to those previously reported for 99mTc-tetrofosmin. Thus, direct comparison between 99mTc-N-DBODC5 and 99mTc-tetrofosmin should be further proved in the same patient population. Overall, 99mTc-N-DBODC5 MPI will become an important diagnostic tool in the evaluation of myocardial perfusion.
This preliminary clinical study showed that 99mTc-N-DBODC5 and 99mTc-MIBI MPI provide comparable diagnostic information for patients undergoing exercise rest for detection of CAD. In addition, 99mTc-N-DBODC5 does not exhibit the disadvantages of 99mTc-MIBI in this study. By contrast, because of its high heart-organ count ratio in comparison to 99mTc-MIBI, it improves high degree of diagnostic concordance in defining or excluding perfusion abnormalities in patients with CAD. Therefore, it can become the agent of choice for the evaluation of myocardial perfusion and ventricular function in patients with CAD.
Coronary artery disease
Myocardial perfusion imaging
Coronary angiography
Single-photon emission computed tomography
Positron emission computed tomography
Technetium 99m sestamibi
Thallium-201
Technetium-99m-tetrofosmin
Regions of interest
Left anterior descending artery
Left circumflex artery
Right coronary artery
Summed stress score
Summed rest score
Summed difference score
End-diastolic volume
End-systolic volume
Left ventricular ejection fraction.
This study was conducted in accordance with the Helsinki Declaration. All subjects provided written informed consent before MPI, acknowledging that they understood their rights and obligations. This study was approved by the Research Ethics Committee of Shanxi Medical University.
The authors declare that they have no conflict of interest.
This research is partly supported by Grants from the Youth Science and Technology Research Foundation of Shanxi Province (no. 2009021043-3). The authors acknowledge the members of the participating staff for their contribution to this clinical study.