Hybrid SPECT/CT Imaging in the Evaluation of Coronary Stenosis: Role in Diabetic Patients

Purpose. Our purpose was to combine the results of the MDCT (multidetector computed tomography) morphological data and the SPECT (single-photon emission computed tomography) data using hybrid imaging to overcome the limits of the MDCT in the evaluation of coronary stenosis in diabetic patients with large amount of calcium in the coronary arteries. Method and Materials. 120 diabetic patients underwent MDCT examination and SPECT examination. We evaluated 324 coronary arteries. After the examinations, we merged CT and SPECT images. Results. CT evaluation: 52 (32.8%) coronaries with stenosis ≥ 50%, 228 (70.4%) with stenosis < 50%, and 44 (13.6%) with a doubtful evaluation. SPECT evaluation: 80 (24.7%) areas with hypoperfusion, 232 (71.6%) with normal perfusion, and 12 (3.7%) with a doubtful evaluation. Of 324 coronary arteries and corresponding areas, the hybrid SPECT/CT evaluation showed 92 (28.4%) areas with hypoperfusion, and 232 (71.6%) with normal perfusion. Conclusion. Hybrid CT/SPECT imaging could be useful in the detection of significant coronary stenosis in patients with large amount of coronary calcifications.


Introduction
Diabetes mellitus type 2 is strictly related to CAD (coronary artery disease); in fact 70-80% of diabetic patients die of cardiovascular complications; moreover, these patients have a risk of myocardial infarction about four times higher than that found in the general population [1][2][3]. erefore, the early detection of CAD in diabetic patients is very important.
Several noninvasive techniques are available for this purpose, including stress ECG and SPECT (single photon emission computed tomography) [4,5] and most recently coronary CT. In fact the latest CT generation with 64 slices has emerged as a truthful alternative to conventional CA (coronary angiography), with excellent diagnostic accuracy allowing us to identify and quantify the degree and extent of coronary artery disease, including the study of wall arteries [6][7][8][9].
Previously published results have proved the high values of sensitivity, speci�city, and negative predictive value (almost 100%) of CT for the assessment of coronary disease, even in patients treated with stent and bypass [10,11]. However, in case of important coronary calci�cations, the CT examination presents several limitations in residual vessel lumen evaluation [12].
Otherwise, MDCT (multidetector computed tomography) sometimes shows some limitations in the grading of coronary stenosis due to motion artefacts or severe vessel calci�cations. It is well known that diabetes causes a large amount of vessel calci�cation, resulting in lower diagnostic accuracy of CT in the detection and evaluation of coronary stenosis in diabetic patients [13]. In this case, it could be useful to work with hybrid imaging, merging the anatomical images of CT to the functional images of SPECT, overcoming the limits of the two techniques.
Our purpose was to combine the results of the MDCT morphological data and the SPECT data using hybrid imaging to overcome the limits of the MDCT in the evaluation of coronary stenosis in diabetic patients with large amount of calcium in the coronary arteries.

Method and Materials
2.1. Population. Between January 2009 and December 2011, we enrolled 120 consecutive diabetic patients (84 males and 36 females), mean age 67 years old (range 50-78), and performed a coronary CT. All the patients had one or more cardiac symptoms such as stable angina, atypical chest pain, and dyspnea.
Twenty patients with a history of known CAD (1 with previous bypass gra surgery, 19 with previous successful angioplasty) were included, while patients with a serious arrhythmia, known allergy to iodinated contrast agents and kidney failure, were excluded. e patients underwent a gated-SPECT examination within 5 days.
Invasive coronary angiography was performed in patients in which the CT examination results were doubtful. Aerwards the imaging fusion results were compared to the coronary angiography evaluation.
All patients, provided informed consent to the examinations and the study was approved by the local ethics committee.

CT Scan.
We used a 64-slice CT scanner (LightSpeed VCT, General Electric Medical Systems, Milwaukee, WI, USA) and a retrospective synchronization technique. Patients with a heart rate higher than 65 bpm were previously (almost 5 days before) treated with oral beta-blocker therapy.
A preliminary unenhanced scan was done to determine the scan extent and to calculate the calcium score (SmartScore protocol). e acquisition stack extended from the ascending aorta superiorly (approximately 1 cm above the tracheal bifurcation) and the heart apex inferiorly (lower portion of the lowest hemidiaphragm), therefore enabling the evaluation of the entire cardiac volume. Scan parameters for the unenhanced baseline scan were beam collimation 8 × 2.5 mm, slice thickness 2.5 mm, table feed 1 cm/4 slices, tube rotation speed 0.35 s, tube voltage 120 kV, intensity 300 mA, FOV 25 cm, craniocaudal scan direction.
A second image stack was then acquired aer intravenous administration of iodinated contrast material using a dualhead automated injector (Stellant, MEDRAD, Pittsburgh, PA, USA). A dose of 80 mL of nonionic iodinated contrast material (Iomeron 400, Bracco, Milan, Italy) was administered through an 18-Gauge needle cannula placed in an antecubital vein, followed by 40 mL of saline solution, both at a rate of 5 mL/s. To synchronize the beginning of the . Image reconstruction was carried out using three temporal windows at 70%, 75%, and 80% of the cardiac cycle, corresponding to the R-R interval or mid to end diastole. In the event of motion artefacts due to sudden changes in heart rate, other reconstruction windows were used (from 40% to 65% of the R-R cycle). e mean radiation exposure dose for patient population was 16.3 mSv.

CT Image
Analysis. e CT datasets were analysed by the agreement of two independent, experienced readers, who used axial source images, multiplanar reformations, volume rendering, and thin-slab maximum-intensity projections on a remote workstation (Advantage Workstation 4.4; GE Healthcare). Each coronary was judged as negative for coronary disease in the presence of one stenosis < 50% and positive in the presence of one stenosis ≥ 50% [14][15][16].

SPECT Scan.
Gated-SPECT was performed on a doubleheaded camera system (SPECT-TC VG Millennium, GE Healthcare, USA). We adopted the single day protocol: stress-rest protocol with 300 MBq 99m Tc-MIBI or tetrofosmin at peak exercise during bicycle ergometry or dipyridamole infusion and 900 MBq at rest ( 203, 77.2%) aer 3 hours. SPECT images were acquired 1 hour aer the radiopharmaceutical injection both for the rest and the stress phases.
irty-two images of 25 sec per frame (matrix 64 × 64, zoom 1.33) were acquired using the "step and shoot" technique (90 g/head). Energy discrimination was provided by a 20% window centred over the 140 KeV photon peak of 99m Tc.

SPECT Image Analysis.
Transverse images were reconstructed by the �ltered back projection method, with a �utterworth �lter (order 10; cuto� 4.0) for processing and a Ramp �lter for back projection using a Xeleris console. Scintigraphic images for stress and rest were evaluated semiquantitatively by an experienced observer. e le ventricular myocardium was divided up into 17 segments; each of the 17 segments was scored according to the guideline for semiquantitative analysis (Semiquantitative Scoring System: the �ve point model: 0 = normal; 1 = mildly reduced-not definitely abnormal; 2 = moderate reduced-de�nitely abnormal; 3 = severe reduced; 4 = absent radiotracer distribution) [17].
2.6. Hybrid SPECT/CT Images. e fusion between stress-SPECT images and CT axial images was done using the Cardiac IQ Fusion protocol on a remote workstation (Advantage Workstation 4.4; GE Healthcare). is soware allows a perfect matching between the images using as reference points the CT myocardium outlines and the SPECT epicardial surface of the le ventricle; furthermore this soware cuts the aorta and the veins. Several 3D protocols permit a better visualization of the coronaries, the wall septum, and the right ventricle. e result of the fusion is an image with a high spatial resolution and a better de�nition of the coronary stenosis.
ese hybrid images have been evaluated separately by a radiologist and a nuclear medicine doctor with eventual agreement.

Conventional Coronary Angiography.
CCA was performed using a Philips �at-panel system with multiple projections (Medical Philips System, e Netherlands). e video clips were analysed by a blind observer using quantitative soware. Stenoses were evaluated as a percentage of the reference diameter determined in two orthogonal projections, taking the mean of the two samples as the �nal value. A value ≥50% was considered a signi�cant stenosis.

Statistical
Analysis. All data were entered into a database for statistical processing. Data were expressed as means plus one standard deviation (SD) or as percentages. Diagnostic accuracy for evaluating signi�cant stenoses was calculated by comparing SPECT/TC with CCA images. e comparison between groups was obtained by analysis of variance or the 2 test, as appropriate. Statistical signi�cance was set at < .

CT Results.
CT study was performed without complications in all patients. Mean heart rate of the patients during the examination was 65 bpm (range 56-77 bpm). Aer the CT scans, 12 (10%) patients were excluded because of motion artefacts due to an increase in heart rate during the acquisition.
Considering the three main coronary branches in the overall count, le anterior descending (LAD) artery, right coronary artery (RCA), and le circum�ex artery (LCX), 324 coronaries were evaluated.

Hybrid SPECT/CT Results and Comparison versus CT.
Of 324 coronary arteries and corresponding areas, the hybrid SPECT/CT evaluation showed 92 (28.4%) of areas with hypoperfusion and 232 (71.6%) with normal perfusion ( Table 2).
In the �rst group of 52 (16%) coronaries with signi�cant stenosis at CT and perfusion defect at SPECT, hybrid images demonstrated a hypoperfusion (Figure 1).
In the second group of 228 (70.4%) with nonsigni�cant stenosis at CT, hybrid images demonstrated a normal perfusion in 212 (65.4%) cases and a low hypoperfusion in 16 (4.9%) cases ( Figure 2); of these 16 cases, 12 (3.7%) cases were described at CT as stenosis of 40-50%, while the other 4 cases were seen at CT as nontransmural myocardial necrosis (with known history of non-ST infarction).
e third group of 44 coronaries was also studied with a conventional CA, con�rming the results of hybrid images (24 signi�cant stenoses and 20 nonsigni�cant stenoses). e patients with 24 signi�cant stenoses also underwent a PTCA (percutaneous transluminal coronary angioplasty) with stenting. erefore the evaluation of hybrid images permitted the identi�cation of all the stenoses and solved the doubts related to the 44 coronaries not well evaluated at CT and SPECT separately, with a diagnostic accuracy of 100% in comparison versus CA (Table 3).

Discussion
A complete evaluation of coronary artery disease requires both functional and anatomical studies. Myocardial perfusion scintigraphy represents the most widely used technique validated in the prognostic strati�cation of diabetic patients with known or suspected ischemic heart disease in order to predict the short and medium terms (generally 1-2 years) for cardiac events such death and myocardial infarction [18,19].
However, the perfusion images obtained with SPECT show a good sensitivity and a low speci�city in the detection of patients with CAD.
e diagnostic accuracy of myocardial scintigraphy is affected by different variables.
is causes the presence of false positives in some areas (false hypoperfusion obtained from attenuation of photons through the tissues of the body), along the passage from the heart to the gamma camera.
Mostly the artefacts are related to the hepatic uptake, due to the interposition of the diaphragm and, in female patients, in the anterior-lateral wall due to the mammary gland; because of this reason, in our study, SPECT was unable to assess the myocardial perfusion in 12 female patients.
Furthermore SPECT reported some false positives when a patient cannot reach 85% of the theoretical maximum heart rate during the exercise testing; this event occurs in obese patients, in older patients, in patients with arterial disease of the lower limbs, and in subjects treated with beta-blockers. In these cases it would be better to use the dipyridamole testing instead of the exercise testing.
Because of these reasons, there is a high variability of values of sensitivity and speci�city reported in previously published meta-analysis [18][19][20][21].
Speci�city and sensitivity have been improved by the introduction of gated technique: especially in women, the number of false positives can be reduced, observing at the same time the perfusion and the functionality of the myocardial region.
However, sometimes the myocardial region that seems to have a normal perfusion aer a stress test could hide a perfusion defect and would not be able to determine a myocardial stunning [21,22].
Coronary CT, when used in selected populations of patients with low-intermediate cardiovascular risk, has been shown to provide essential morphological information about the coronary tree.
e diagnostic accuracy of cardiac CT is widely demonstrated by high values of sensitivity, speci�city, and negative predictive value [23,24]. Actually, the most important limit in the evaluation of the vessel lumen is the presence of large coronary artery calci�cation, causing a blooming type artefact, due to the hardening of the X-ray beam during the passage through the calci�ed plaques [25]. is artefact could cause a signi�cant invalidation of lumen visualization determining false positive in coronary CT and consequently sending a certain number of patients with stenosis < 50% to undergo a CA. In our study the patients, being diabetic, had large cal-ci�cations of the coronary arteries, creating doubts in the interpretation of quantitative coronary stenosis in 44 coronary arteries.
During the postprocessing phase, the use of some convolution �lters (kernel) can decrease the blooming artefact; in particular applying the high-resolution �lters (�one and Detail), the relative density of calcium is reduced, the margins of calci�cation plaque are better delineated, and the width of the vascular lumen increases.
However, in a large number of cases, the quanti�cation of stenosis caused by calci�ed plaque remains still di�cult and it is oen necessary to send the patient to CA examination or a SPECT. Part of medical literature has tried to de�ne the AGATSTON values above which performing CT would be inappropriate. However, although sensitivity and speci�city are reduced, the overall diagnostic accuracy is not reduced and, in our study, it has been implemented with the fusion imaging CT/SPECT [12].
e skillful use of hybrid images, obtained by merging CT and SPECT images, is to have both morphological and functional data with a high spatial resolution, allowing a better strati�cation of diabetic patients, identifying the patient with a signi�cant stenosis and hypoperfusion who needs revascularization and avoiding a CA in patients with unquanti�able calci�cation plaques at CT and SPECT [26,27].
e hybrid images can overcome the limits of coronary CT, permitting the evaluation of large vessel calci�cation, metal stents, and small size vessels.
However, this problem usually does not occur in the evaluation of noncalci�ed native coronary arteries; in fact Ong et al. (2006) demonstrated that in patients with calcium score <142 Agatston score the interpretability of the coronary tree was 93.6% against 86.9% of those patients with values >142 Agatston score [28].
In our experience, hybrid SPECT/CT images provide help in the evaluation and grading of calci�ed stenoses in CT and overcome the problem of the abnormal uptake of the radiopharmaceutical by the breast tissue in SPECT.
In particular in the group of 44 (13.6%) doubtful coronaries at CT, hybrid SPECT/CT images demonstrated 20 (6.2%) normal perfusion areas and 24 (7.4%) hypoperfusion areas (seen at SPECT as 12 perfusion defects and 12 doubtful cases because of breast tissue), described as unquanti�able calci�ed stenosis at CT and �nally evaluated as signi�cant stenosis.
erefore the evaluation of hybrid images permitted the identi�cation of all the stenoses and solved the doubts related to the 44 coronaries not well evaluated at CT and SPECT separately, with a diagnostic accuracy of 100% in comparison to CA. ese results are extremely interesting when applied to a group of patients such as diabetics, in which, until now, the limit of the coronary CT examination in the evaluation of calci�ed coronary was high [24].
On the other hand, the correct identi�cation of an area of myocardial hypoperfusion at SPECT examination is enhanced by the morphological information of the coronary arteries with a signi�cant decrease in the number of false positive and an increase of the prognostic value of scintigraphy.
In fact, SPECT provides a high prognostic accuracy in the prediction of cardiac event (especially in the short-term followup), although it gives only functional information. e perfusion defects can be localized and assigned to a speci�c coronary artery only if the SPECT exam is complemented by a morphological assessment.
According to medical literature, hybrid imaging adds diagnostic clinical value, improving patient risk strati�cation and showing a higher sensitivity and speci�city in the detection of the haemodynamically relevant coronary artery stenoses compared to the side-by-side analysis [29][30][31]. Furthermore the improvement of diagnostic accuracy was obtained with the latest CT scanners, as high-pitch dualsource CT coronary angiography and 320-row cardiac CT, which allow to improve the imaging of coronary plaque and obtain the evaluation of myocardial viability with a high diagnostic accuracy, a reduced radiation exposure and amount of contrast agent, even in patients with heart rates of >80 bpm or atrial �brillation [32][33][34][35].
Our study has the limit of a high exposure of radiation because the patients underwent two different examinations (CT and SPECT) and because we used a retrospective gating during the CT scan; nevertheless, the actual use of the prospective gating and the application of new advanced reconstruction techniques that reduce image noise and improve low contrast detectability and image quality can give higher diagnostic performance of CT scan at very signi�cant lower dose [36,37]. Another limitation of the present study was the only anatomical and not functional evaluation of coronary stenoses. erefore, the usefulness of the fusion between CT and SPECT images is to overcome the limits of CT and the limits of SPECT with a high diagnostic accuracy, especially in patients with high cardiovascular risk and high presence of physical limitations, like the diabetic patients.

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All the authors of the paper gave their contribution to this work and do not have a direct �nancial relation with the commercial identities mentioned in the paper that might lead to a con�ict of interests.