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Effects of Adenosine and a Selective A_2A Adenosine Receptor Agonist on Hemodynamic and Thallium-201 and Technetium-99m–SestaMIBI Biodistribution and Kinetics

Choukri Mekkaoui, PhD^_*, Farid Jadbabaie, MD^_*, Donald P. Dione, BS^_*, David F. Meoli, MD, PhD^_*, Kailasnath Purushothaman, PhD, Luiz Belardinelli, MD, Albert J. Sinusas, MD^_*,,_*

^_* Division of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut
CV Therapeutics, Inc., Palo Alto, California

	Abstract

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Objectives: The purpose of this study was to compare a selective A_2A adenosine receptor agonist (regadenoson) with adenosine in clinically relevant canine models with regard to effects on hemodynamics and thallium-201 (²⁰¹Tl) and technetium-99m (^99mTc)-sestaMIBI biodistribution and kinetics.

Background: The clinical application of vasodilator stress for perfusion imaging requires consideration of the effects of these vasodilating agents on systemic hemodynamics, coronary flow, and radiotracer uptake and clearance kinetics.

Methods: Sequential imaging and arterial blood sampling was performed on control, anesthetized closed-chest canines (n = 7) to evaluate radiotracer biodistribution and kinetics after either a bolus administration of regadenoson (2.5 µg/kg) or 4.5-min infusion of adenosine (280 µg/kg). The effects of regadenoson on coronary flow and myocardial radiotracer uptake were then evaluated in an open-chest canine model of a critical stenosis (n = 7). Results from ex vivo single-photon emission computed tomography were compared with tissue well-counting.

Results: The use of regadenoson compared favorably with adenosine in regard to the duration and magnitude of the hemodynamic effects and the effect on ²⁰¹Tl and ^99mTc-sestaMIBI biodistribution and kinetics. The arterial blood clearance half-time was significantly faster for ^99mTc-sestaMIBI (regadenoson: 1.4 ± 0.03 min; adenosine: 1.5 ± 0.08 min) than for ²⁰¹Tl (regadenoson: 2.5 ± 0.16 min, p < 0.01; adenosine: 2.7 ± 0.04 min, p < 0.01) for both vasodilator stressors. The relative microsphere flow deficit (0.34 ± 0.02%) during regadenoson stress was significantly greater than the relative perfusion defect with ^99mTc-sestaMIBI (0.69 ± 0.03%, p < 0.001) or ²⁰¹Tl (0.53 ± 0.02%, p < 0.001), although ²⁰¹Tl tracked the flow deficit within the ischemic region better than ^99mTc-sestaMIBI. The perfusion defect score was larger with ²⁰¹Tl (22 ± 2.8% left ventricular) than with ^99mTc-sestaMIBI (17 ± 1.7% left ventricular, p < 0.05) on ex vivo single-photon emission computed tomography images.

Conclusions: The bolus administration of regadenoson produced a hyperemic response comparable to a standard infusion of adenosine. The biodistribution and clearance of both ²⁰¹Tl and ^99mTc-sestaMIBI during regadenoson were similar to adenosine vasodilation. Ex vivo perfusion images under the most ideal conditions permitted detection of a critical stenosis, although ²⁰¹Tl offered significant advantages over ^99mTc-sestaMIBI for perfusion imaging during regadenoson vasodilator stress.

Key Words: regadenoson • myocardial perfusion imaging • adenosine • biodistribution • tracer kinetics

Abbreviations and Acronyms   AoP = aortic pressure   DPI = dynamic planar Imaging   HR = heart rate   IS = ischemic   LAD = left anterior descending artery   LCX = left circumflex artery   LV = left ventricular   MBF = myocardial blood flow   MPI = myocardial perfusion imaging   NI = nonischemic   %ID = percent injected dose   SPECT = single-photon emission computed tomography   99mTc = technetium-99m   201Tl = thallium-201

The accuracy of MPI is dependent on the biodistribution of tracers in organs adjacent to the heart (i.e., lungs, liver) and affects the optimal timing of MPI (3). Patients with a critical coronary stenosis who are unable to exercise are injected during pharmacological vasodilator stress to mimic alterations in coronary flow associated with exercise stress. The level or type of stress can affect the biodistribution (4–8). The biodistribution of ^99mTc-MIBI is altered by exercise or pharmacological stress, suggesting that the kinetics also are influenced (3). The uptake of ^99mTc-MIBI plateaus at high flows during adenosine vasodilator stress, potentially underestimating myocardial perfusion defect size (9).

Adenosine used for stress MPI causes systemic vascular and hemodynamic side effects, possibly altering the biodistribution of radiotracers (9). Most adverse effects can be attributed to A₁, A_2B, and A₃ adenosine receptor stimulation (10). Selective A_2A adenosine receptor agonists may reduce unwanted effects but may alter radiotracer kinetics. Regadenoson (CVT-3146, CV Therapeutics, Inc., a subsidiary of Gilead, Foster City, California), an A_2A agonist, is a potent vasodilator with a short duration of action and minimal hemodynamic effects (10,11). Recent clinical trials (12–16) have established regadenoson as a vasodilator for MPI.

Studies in conscious dogs and humans demonstrated that the dose and rate of regadenoson administration affects hemodynamics (11) and coronary flow (10,17,18). Differential effects of regadenoson on renal and splanchnic flow may affect the biodistribution and clearance of radiotracers, having an impact on the efficacy of the vasodilator MPI.

Regadenoson duration of action and differential effects on flow (coronary and systemic) compared with adenosine may result in favorable tracer kinetics for MPI. To determine whether regadenoson results in favorable conditions for vasodilator MPI, we evaluated the uptake, biodistribution, and clearance of ²⁰¹Tl and ^99mTc-MIBI during vasodilation with regadenoson and adenosine in chronic, closed-chest canine models. To establish the linearity of radiotracer uptake during regadenoson stress, we used acute open-chest canine models with a critical stenosis.

	Methods

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Surgical preparation.   Fasting adult mongrel dogs (23 ± 0.9 kg) were anesthetized with intravenous sodium thiamylal (20 mg/kg). Animals were intubated and ventilated with a mixture of halothane (0.5% to 1.5%), nitrous oxide and oxygen (N₂O:O₂ = 3:1). An electrocardiogram (ECG) lead was used for heart rate (HR) and rhythm monitoring. The protocol was approved by Yale Institutional Animal Care and Use Committee in compliance with guiding principles of the American Physiologic Society on research animal use.

Chronic Model
Venous access was established for administration of radiotracer and regadenoson or adenosine. A femoral artery was cannulated for blood sampling and hemodynamic monitoring. To determine radiotracer kinetics and biodistribution, sequential imaging was performed in closed-chest (n = 7) dogs under light anesthesia and physiological conditions with monitoring.

Acute Model
To determine the effects of regadenoson on coronary flow and myocardial radiotracer uptake, an open-chest canine preparation (n = 7) with a critical stenosis was used. A left lateral thoracotomy was performed and the heart suspended in a pericardial cradle. The proximal left anterior descending (LAD) and circumflex (LCX) arteries were dissected for placement of flow probes (Transonics Systems Inc., Ithaca, New York). A proximal critical LCX stenosis was created by the use of a hydraulic occluder and adjusted to blunt reactive hyperemia to a transient 10-s total coronary occlusion without impairing resting flow. Central temperature, HR, aortic pressure (AoP), and coronary flows were recorded. Radiolabeled microspheres (15-µm diameter; Sc-46, Nb-95, Ru-103, and Sn-113) were injected in the left atrium.

Protocol.   Chronic Studies
Dogs had ²⁰¹Tl and ^99mTc-MIBI vasodilator stress imaging performed on 2 successive weeks; week 1 with regadenoson and week 2 with adenosine. The week between studies is sufficient to ensure noninteraction between sessions. During the first session (Fig. 1A), each dog received an intravenous injection of regadenoson (2.5 µg/kg) over 30 s and then ²⁰¹Tl (55.5 ± 7.4 MBq) 10 s later. Dynamic planar imaging (DPI; 15 min) followed the injection, along with timed arterial blood sampling for determination of radiotracer clearance kinetics by use of a roller-pump (20 samples at 15 s/sample, then 10 samples at 30 s/sample). Blood (0.5 ml) was collected, weighed, and counted in a gamma-well-counter. Two hours later, the same regadenoson vasodilator stress protocol was repeated with injection of ^99mTc-MIBI (843.6 ± 148 MBq).

View larger version (34K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Experimental Protocols and Timelines The protocol for closed-chest regadenoson studies performed on week 1 (A), for closed-chest adenosine studies performed on week 2 (B), and for an acute open-chest study performed on week 3 (C). Hemodynamic acquisitions started 30 s before infusion of vasodilator. 99mTc = technetium-99m; 201Tl = thallium-201.

Acute Studies
On week 3, open-chest studies were performed (Fig. 1C) after creation of a critical LCX stenosis. Regadenoson (2.5 µg/kg) was injected intravenously over 30 s, and ²⁰¹Tl (51.8 ± 3.7 MBq), ^99mTc-MIBI (873.2 ± 166.5 MBq), and radiolabeled microspheres were injected simultaneously 10 s after the regadenoson bolus. To minimize redistribution, dogs were euthanized 15 min after tracer injection. Regional myocardial flow was measured at rest and stress with radiolabeled microspheres by the use of established methods (2). Hearts were excised and cast with dental molding material (Alginate, Type I, fast-set, Quala Dental Products, ADC Milford, Delaware) for ex vivo single-photon emission computed tomography (SPECT) imaging, avoiding most of the confounding effects of attenuation and scatter. Hearts were sliced (5 mm), and each slice was divided into 8 radial pies. Segments underwent gamma-well-counting for the determination of tracer activity and microsphere flow.

Hemodynamics.   Electrocardiogram, AoP, and coronary flows were recorded 30 s before and after infusion of the vasodilator (Sonolab, Sonometrics Inc., Ontario, Canada). R-waves were used to segment the signals into individual cardiac cycles. Heart rate, systolic and diastolic AoP, and peak LAD and LCX flow were determined every 10 s.

Planar imaging.   Five-second images were acquired for the first 30 s followed by 30-s images for the remaining 14.5 min for analyzing changes in myocardial and background activity. Images were acquired with a large field-of-view gamma-camera (Millennium VG, GE Healthcare, Milwaukee, Wisconsin) by the use of a high-resolution, parallel-hole collimator. Images (256 x 256 matrix) were acquired without magnification in an anterior view by the use of appropriate energy windows for ²⁰¹Tl (71 ± 7.5% keV), and ^99mTc-MIBI (140 ± 7.5% keV). Regions-of-interest were drawn over blood pool, myocardium, liver, lung, and kidney. Time-activity curves were generated for each organ, and activity was expressed as percent-injected dose/pixel (%ID/pixel) by the use of an external point source of known activity. The myocardium-to-liver activity and myocardium-to-lung ratios, at 15 min for ²⁰¹Tl and ^99mTc-MIBI, were compared.

Myocardial blood flow.   Myocardial segments were weighed and counted within 24 h for determination of ²⁰¹Tl and ^99mTc activity in a gamma-scintillation-counter (Packard Instruments, Milford, Connecticut) by the use of energy windows for ²⁰¹Tl, ^99mTc, and all microspheres (²⁰¹Tl: 67 to 91 keV, ^99mTc: 130 to 170 keV, ⁵¹Cr: 290 to 360 keV, ¹¹³Sn: 361 to 440 keV, ¹⁰³Ru: 460 to 550 keV, ⁹⁵Nb: 700 to 810 keV, ⁴⁶Sc: 811 to 1,160 keV). Samples were recounted 1 week after radiotracer injection to determine microsphere flow. Myocardial flow was calculated by the use of previously published methods, with correction for radiotracer decay, spill-up, and spill-down (2). Regional flow was expressed in ml/min/g, as well as a percent nonischemic and ischemic.

Ex vivo SPECT imaging.   Ex vivo dual-isotope ²⁰¹Tl and ^99mTc-MIBI SPECT imaging was performed by use of the same dual-head rotational gamma-camera, collimators, and energy windows applied for in vivo SPECT imaging. Images were acquired by the use of a 360° circular-orbit, in a step-and-shoot fashion (64 x 64 matrix; 5-mm slice thickness). No attenuation or scatter correction was required. Images were reconstructed by the use of filtered back-projection with ramp-filters. A 3-dimensional low-pass filter (Butterworth, order-4 and cutoff 0.35) was applied to post-reconstruction transverse SPECT slices, and images were reoriented into cardiac-specific axes.

The Yale-CQ-algorithm was used to quantify the SPECT images (19,20). Circumferential count profiles were generated for a series of left ventricular (LV) short-axis images. Three anatomic slices were divided into 128 radial sectors. Defects were defined as counts <80% of the maximum. ²⁰¹Tl and ^99mTc-MIBI integrated defect scores (%LV) were calculated, providing an index of both the magnitude and extent of the perfusion abnormality.

Statistical analysis.   Ischemic (IS) and nonischemic (NI) segments were defined by a coronary flow reserve <1.5 and >2.5, respectively. On the basis of this myocardial segmentation, IS/NI tracer and flow ratios were calculated and compared. All values are expressed as mean ± SEM. Statistical differences of the physiologic, hemodynamic, and radiolabeled tracer between the regadenoson- and adenosine-treated animals were assessed using a one-way analysis of variance. For conditions that demonstrated a significant main effect, post-hoc analyses were performed with either a t test (comparison between 2 populations) or a z test (comparison with %baseline).

	Results

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Chronic studies.   Hemodynamics
A 30-s bolus of regadenoson and a 4.5-min infusion of adenosine produced similar hemodynamic effects (p = NS) (Table 1). Peak HR significantly increased (p < 0.05), and peak systolic and diastolic AoP significantly decreased (p < 0.05) relative to baseline values. These parameters were significantly (p < 0.05) different than baseline 2 min after injection of the radiotracers. These values tended to return to baseline within 10 min (Fig. 2). The peak effect of regadenoson occurs 30 s after the bolus, whereas the peak effect of adenosine occurs 1.5 to 2 min after beginning the infusion, corresponding to radiotracer injection. The duration of the peak hemodynamic effect was shorter for regadenoson than for adenosine, although sufficient to create differential uptake of ²⁰¹Tl and ^99mTc-MIBI.

View larger version (40K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Hemodynamic Response in the Chronic Studies Heart rate, systolic, and diastolic aortic pressure time-dependent changes (%baseline) after the stressor infusion (shaded box) for each isotope: (A) 201Tl during regadenoson stress; (B) 201Tl during adenosine stress; (C) 99mTc-MIBI during regadenoson stress; and (D) 99mTc-MIBI during adenosine stress. The dashed line indicates the radiotracer injection. The rapid effect of regadenoson is evident compared with the adenosine response. The hemodynamic effect for each stressor did not differ between isotope injections.

View larger version (57K): [in this window] [in a new window] [Download PPT slide]   Figure 3 Clearance Half-Time and Biodistribution The time-arterial blood activity curves for 201Tl and 99mTc-MIBI after the infusion of regadenoson (A) or adenosine (B) are shown. (C) The clearance half-times for 201Tl and 99mTc-MIBI with regadenoson and adenosine are shown. The clearance half-time is significantly shorter for 99mTc-MIBI than for 201Tl with both stressors. (D) An example of a dynamic series of 99mTc-MIBI planar images, following a 30-s regadenoson infusion is shown. The images show where the regions-of-interest were drawn. The time-dependent biodistribution is shown as the logarithm (%ID/pixel) for 201Tl and 99mTc-MIBI with both stressors (E to H). The biodistribution at 15 min after injection was no different between stressors for 201Tl and 99mTc-MIBI (I and J, respectively).

Acute studies.   Hemodynamics
In the acute studies (n = 7), the 30-s bolus of regadenoson caused a nearly significant increase in HR (p < 0.08) and a decrease (p < 0.05) in both systolic and diastolic AoP during the 2-min post-radiotracer injection, similar to the chronic studies. The pressures remained mildly reduced (10 mm Hg; p < 0.05) at 10 min after regadenoson administration. The flow in the stenotic LCX increased on average 6.7% (p < 0.05) over baseline, which is consistent with ablation of reactive hyperemia. In the LAD, however, the flow significantly increased (2.5- to 3-fold baseline; p < 0.001) during the 2 min after radiotracer injection. The LAD flow returned to baseline values at 10 min after regadenoson infusion (Fig. 4).

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 4 Hemodynamic Response in Acute Studies The hemodynamic response to the 30-s regadenoson bolus (shaded box) for the acute studies: heart rate (A), systolic and diastolic aortic pressure response (B), and LAD and LCX coronary flow (C) responses. All values are %baseline. The dashed line indicates the radiotracer injection. There was a 3-fold increase in nonstenotic LAD flow and no increase in LCX flow. LAD = left anterior descending; LCX = left circumflex artery.

View larger version (19K): [in this window] [in a new window] [Download PPT slide]   Figure 5 Transmural Absolute Myocardial Blood Flow Average microsphere flows for ischemic and nonischemic regions at rest and during vasodilator stress. The blood flows are comparable at rest in both regions. Flows during regadenoson vasodilator stress increased 3-fold in the nonischemic region but remained unchanged in the ischemic region with a critical stenosis.

View larger version (19K): [in this window] [in a new window] [Download PPT slide]   Figure 6 Perfusion Deficit (A) Circumferential profile from a representative left ventricular short-axis slice is shown. There was uniform flow at rest and a significant heterogeneity of flow with regadenoson as measured by microspheres. (B) Tracer activity (%Ischemic) versus flow is shown. Regional myocardial 99mTc-MIBI activity plateaus at greater flows. (C) The ischemic/nonischemic ratio for flow, 201Tl, and 99mTc-MIBI is shown. Both radiotracers significantly underestimate flow heterogeneity. IS = ischemic; NI = nonischemic; other abbreviations as in Figure 1.

View larger version (26K): [in this window] [in a new window] [Download PPT slide]   Figure 7 SPECT Integrated Defect Size (A) Series of 201Tl and 99mTc-MIBI ex vivo short-axis slices from a representative dog are shown. With a critical stenosis, there were no marked perfusion defects; however, the perfusion defects were visually smaller in 99mTc-MIBI images compared with 201Tl images. (B) The integrated defect magnitude calculated using the Yale-CQ-quantitative-program is shown. %LV = percent left ventricular; other abbreviations as in Figure 1.

	Discussion

Top Abstract Methods Results Discussion Conclusions REFERENCES

Although regadenoson and adenosine are known to have differential effects on renal and splanchnic flow (10), both vasodilators caused a similar biodistribution and clearance of ²⁰¹Tl and ^99mTc-MIBI. The use of DPI demonstrated a favorable biodistribution of both radiotracers, which was comparable between the vasodilators. Unexpectedly, we observed a faster blood clearance of ^99mTc-MIBI (1.5 min) compared with ²⁰¹Tl (2.5 min) with both vasodilators. This finding suggests that a longer duration of vasodilator stress, regardless of the specific vasodilator, might be more important after injection of ²⁰¹Tl than after injection of ^99mTc-MIBI. However, ²⁰¹Tl performed better as a perfusion agent for the detection of relative flow heterogeneity using regadenoson as defined by ex vivo SPECT and well-counting techniques.

The injection of ²⁰¹Tl or ^99mTc-MIBI 10 s after the 30-s bolus of regadenoson provided high-quality ex vivo SPECT images, demonstrating significant heterogeneity of relative myocardial perfusion in the presence of a critical stenosis. These ex vivo images were acquired under ideal imaging conditions with minimal attenuation and scatter. On the basis of tissue counting, both ²⁰¹Tl and ^99mTc-MIBI underestimated the true MBF heterogeneity as measured using microspheres. This finding is consistent with previous studies in which the authors evaluated ²⁰¹Tl and ^99mTc-MIBI MPI during adenosine stress (9) and other selective A_2A adenosine agonists (21). We observed the expected plateau of radiotracer uptake at higher flows, which has been attributed to a diffusion limitation of radiotracer uptake. In the case of ²⁰¹Tl, some of the flow underestimation may be attributed to differential washout of ²⁰¹Tl from the normal and ischemic regions, since the radiotracer distribution was evaluated at 15 min after radiotracer injection. Therefore, there may have been a slight component of ²⁰¹Tl redistribution contributing to the observed plateau of ²⁰¹Tl retention. Despite the potential for early ²⁰¹Tl redistribution, the more linear myocardial uptake of ²⁰¹Tl relative to flow during vasodilator stress with regadenoson suggests that ²⁰¹Tl may be better than ^99mTc-MIBI or other similar ^99mTc-labeled perfusion agents for use with vasodilator stress.

Although in this study a matched group of acute studies was not performed with adenosine, Glover et al. (9) previously reported similar results using adenosine in an open-chest canine study. Glover et al. (9) evaluated ²⁰¹Tl and ^99mTc-MIBI uptake relative to microsphere flow in the presence of 2 levels of stenosis. Their creation of a "critical stenosis" was designed to ablate reactive hyperemia, similar to our acute studies. The microsphere flows in both studies demonstrated no increase in flow in the stenotic territory and 3.5-fold flow increase in the remote territory in response to vasodilator stress. Glover et al. (9) used planar imaging of excised LV slices from dogs euthanized 5 min after injection of radiotracers compared with ex vivo SPECT imaging in our study. They demonstrated a similar underestimation of the true flow deficit (0.17 ± 0.03) with both ²⁰¹Tl (0.37 ± 0.05) and ^99mTc-MIBI (0.53 ± 0.06) and that ²⁰¹Tl provided a better estimation of the flow deficit (9), similar to our observation using regadenoson.

The recent ADVANCE (ADenoscan Versus regAdenosoN Comparative Evaluation for Myocardial Perfusion Imaging) phae 3 multicenter international trial showed no difference between regadenoson and adenosine for determination of reversible perfusion defects with ^99mTc-MIBI or ^99mTc-Tetrofosmin, although the chi-squares for both the adenosine-regadenoson and adenosine-adenosine comparisons were only 0.63 or 0.64, respectively, suggesting only a fair concordance (14). On the basis of our experimental findings, ²⁰¹Tl may offer a clinical advantage over the ^99mTc-labeled perfusion agents and improve test reproducibility for determination of the extent of ischemia. Importantly, the current finding regarding the biodistribution and ex vivo SPECT imaging would predict that there should be no significant clinical difference between regadenoson and adenosine for MPI.

Although this pre-clinical study provides important insight regarding regadenoson and adenosine stress MPI, these studies were performed during anesthesia, which could produce confounding effects on systemic hemodynamics. In clinical studies (13,14), the hemodynamic changes associated with regadenoson were less and shorter-lasting than those observed in our study. Our study was specifically performed with the use of the volatile anesthetic halothane. Because Hickey et al. (22) found that there was no significant change in coronary flow reserve between conscious and halothane-anesthetized canines.

In addition, to minimize any potential adverse effect, the chronic studies were performed with the use of a closed-chest preparation that required very light anesthesia with halothane and nitrous oxide. Although halothane is a mild cardiac depressant, the effects are dose dependent (23,24). Therefore, the light plane of anesthesia used should have had little effect on cardiac output and the biodistribution of the radiotracers. Our hemodynamic results on anesthetized dogs closely matched the result from previous studies on conscious dogs (11) and were within physiological ranges throughout the study protocol. Glover et al. (9) used sodium pentobarbital anesthesia in their study and showed very similar hemodynamic responses to adenosine and similar kinetic behavior of ²⁰¹Tl and ^99mTc-MIBI during adenosine stress (9).

Our anesthetized preparation offers advantages over clinical studies or conscious preparations, enabling serial imaging without risk of any subject movement, which is a significant confounder in clinical studies with repeated imaging. The changes in flow that we observed in our experimental model during vasodilator stress are concordant with a clinical study (25) in which the authors used rest and adenosine oxygen-15 water positron emission tomographic imaging in control subjects. Coronary vasodilator reserve (3.16 ± 1.4) in control patients during adenosine stress was nearly identical to the 3.3-fold increase we obtained in the NI territory in response to regadenoson vasodilator stress.

	Conclusions

Top Abstract Methods Results Discussion Conclusions REFERENCES

 
The bolus administration of regadenoson produced a hyperemic response comparable to a standard infusion of adenosine. The biodistribution and clearance kinetics of both ²⁰¹Tl and ^99mTc-MIBI during regadenoson were similar to adenosine vasodilation. Ex vivo perfusion images under the most ideal conditions permitted detection of a critical stenosis, although ²⁰¹Tl offered significant advantages over ^99mTc-MIBI for perfusion imaging during regadenoson vasodilator stress.

	Acknowledgments

 
The authors acknowledge the technical assistance of Xiao-Yu Hu, Brian Bourke, Carol Akirav, Lori Brown, and Stacy Sullivan.

	Footnotes

 
This research was supported in part by a grant-in-aid from the Heritage Affiliate of American Heart Association (to Dr. Purushothaman), Robbinsville, New Jersey, and a grant from CV Therapeutics, Inc. (to Dr. Sinusas).

^_* Reprint requests and correspondence: Dr. Albert J. Sinusas, Yale University School of Medicine, Nuclear Cardiology, 3FMP, P.O. Box 208017, New Haven, Connecticut 06520-8017 (Email: albert.sinusas{at}yale.edu).

Manuscript received September 2, 2008; revised manuscript received June 4, 2009, accepted June 10, 2009.

	REFERENCES

Top Abstract Methods Results Discussion Conclusions REFERENCES

 

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