Conditions: Coronary Artery Disease
Keywords: coronary artery disease exercise regadenoson positron emission tomography
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 43
Healthy volunteers: yes

Brief summary:
This is a single-center study of subjects undergoing clinically indicated heart scans for evaluation of known or suspected heart disease. We will also include 10 healthy subjects without known heart disease. We would like to study stress testing of the heart using exercise and a medication called regadenoson. Imaging of the heart will be performed.

Detailed description:
Regadenoson is stress agent approved by the FDA for use with myocardial perfusion imaging with technetium-99m single photon emission computed tomography (SPECT) in patients that are unable to exercise adequately. We would like to study Regadenoson in conjunction with Exercise Rubidium-82 positron emission tomography myocardial perfusion imaging (PET MPI). Regadenoson is not approved by FDA for use with Rubidium-82 PET MPI. Also, we would like to study a novel stress protocol of Regadenoson combined with symptom limited exercise stress (not FDA approved).

The objectives of this study are to assess the tolerability and safety of combined symptom limited exercise stress test with Lexiscan (Lexercise PET) compared to Lexiscan alone (Lexiscan PET), to assess image quality of Lexercise compared to Lexiscan PET and to compare relative and absolute myocardial perfusion imaging with Lexercise compared to Lexiscan PET to identify CAD.

Arms:
arm 1: Regadenoson Rubidium-82 Positron Emission Tomography arm 2: Exercise plus Regadenoson (Lexercise) Rubidium-82 Positron Emission Tomography

Interventions: intervention 1: Exercise plus Regadenoson (Lexercise) intervention 2: Regadenoson (Lexiscan)
Intervention descriptions: intervention 1: Standard Bruce exercise stress test with regadenoson injection at maximal stress with Rubidium-82 Positron Emission Tomography intervention 2: Regadenoson Rubidium-82 Positron Emission Tomography

Protocol document:
Prot_SAP_000.pdf: 
1 
COVER PAGE 
 
 
 
 
NCT #: 01109992 
 
 
VERSION DATE OF THE DOCUMENT: September 12, 2016 
 
 


2 
 
INTEGRATED DUAL EXERCISE AND LEXISCAN PET: IDEAL PET 
 
 
 
Version Date: September 12, 2016 
 
Study Type: Single Center Study 
 
Sponsor: Investigator initiated study, PI, Sharmila Dorbala 
 
Study Enrollment Period: June 2010 to June 2017    
 
Principal Investigator: Sharmila Dorbala, MD 
 
 
 


3 
TABLE OF CONTENTS 
 
Topic 
Page Number 
I. 
ABBREVIATIONS 
 
3 
II. 
SYNOPSIS 
 
4-7 
III. 
BACKGROUND  
 
8-9 
IV. 
SPECIFIC AIMS 
 
10 
V. 
SIGNIFICANCE 
 
10-11 
VI. 
PRIOR STUDIES 
11-14 
 
VII. 
SUBJECT METHODS AND SELECTION 
 
15-16 
VIII. 
SUBJECT ENROLLMENT 
 
17 
IX. 
STUDY PROCEDURES 
 
18-21 
X. 
BIOSTATISTICAL ANALYSIS 
 
22-23 
XI. 
RISKS AND DISCOMFORT 
 
23-24 
XII. 
POTENTIAL BENEFITS 
 
25 
XIII. 
MONITORING AND QUALITY ASSURANCE 
 
25-26 
XIV. 
REREFENCES 
 
27 


4 
ABBREVIATIONS USED: 
 
Myocardial Blood Flow: MBF 
Positron Emission Tomography: PET 
Computed Tomography: CT 
Myocardial perfusion imaging: MPI 
Coronary Flow reserve: CFR 
Coronary artery disease: CAD 
Lexiscan + Exercise: Lexercise 
 
 
 


5 
SYNOPSIS 
 
Title of Study: Integrated Dual Exercise And Lexiscan PET: IDEAL PET 
 
Planned Study Period:  From 4Q2010 - 2Q2017  
 
Study Objective(s)  
 
Aim 1: To assess the tolerability and safety of combined symptom limited exercise stress test with 
Lexiscan (Lexercise PET) compared to Lexiscan alone (Lexiscan PET). 
 
Aim 2: To assess the image quality of Lexercise compared to Lexiscan PET. 
 
Aim 3: To compare relative and absolute myocardial perfusion imaging with Lexercise compared to 
Lexiscan PET to identify CAD. 
 
Planned Total Number of Study Centers and Location  
Single study center, Brigham and Women’s Hospital, Boston, MA, United States  
 
Design and Methodology  
This is a single-center, prospective cohort study of subjects undergoing clinically indicated PET/CT MPI, 
with documented coronary artery disease or an intermediate to high pretest likelihood of coronary artery 
disease. Following the clinical study, the research study is explained to the subjects. Consenting subjects 
will return on another day (next calendar day or later) for a repeat stress study with Lexercise or a repeat 
Lexiscan stress PET. Approximately 50 subjects (not more than 16 patients with normal Rubidium-82 or 
N-13 ammonia PETMPI, 10 healthy volunteers and 24 patients with reversible perfusion defects) will be 
enrolled in this study. After successful screening and enrollment, 13 random subjects (8 normal and 5 
ischemic) will return for repeat Lexiscan PET, and 37 subjects will return for a Lexercise PET/CT MPI. 
Lexiscan PET will be performed per standard protocol. For Lexercise, a symptom limited exercise 
treadmill study with Lexiscan injection at peak exercise is performed. Rubidium-82 or N-13 ammonia 
will be injected and PET/CT images will be obtained in a list mode acquisition. Images will then be 
unlisted and myocardial blood flow computed.  
 
 
 
Number of Subjects Planned  


6 
Approximately 50 subjects will be enrolled into the study.  
 
Main Selection Criteria 
Subjects will be eligible if they meet all of the following inclusion criteria and none of the exclusion 
criteria:  
Inclusion criteria: 
• 
Age > 18 years 
• 
Clinically indicated Rubidium-82 or N-13 ammonia PET study 
• 
Ten healthy volunteers recruited using web based advertisements. 
• 
Known coronary artery disease (prior percutaneous coronary intervention, prior coronary 
artery bypass surgery or Q wave MI on ECG) or intermediate to high pretest likelihood of 
CAD  
• 
Able to exercise on a treadmill 
• 
Able and willing to provide informed consent to participate in the study  
 
Exclusion criteria: 
• 
Contraindications to exercise stress testing such as 
o unstable angina 
o known severe left main coronary artery stenosis 
o severe  or uncontrolled heart failure 
o uncontrolled atrial or ventricular arrhythmias 
o symptomatic hypotension or severe hypertension (systolic blood pressure < 90 or > 
200 mmHg, respectively) 
o > 1st degree atrioventricular block in the absence of a functioning pacemaker. 
• 
Contraindications to Lexiscan use such  
• 
Allergy or intolerance to aminophylline or regadenoson 
• 
Known severe or oxygen dependent bronchoconstrictive or bronchospastic lung disease 
[e.g., asthma, wheezing, chronic obstructive pulmonary disease (COPD), etc.]. 
• 
Sick sinus syndrome 
• 
History of heart transplantation. 
• 
Dialysis 
• 
Subject requires emergent cardiac medical intervention or catheterization after the 
clinical study. 
• 
Documented myocardial infarction (MI) ≤ 30 days prior to enrollment. 
• 
History of percutaneous coronary intervention (PCI) ≤ 4weeks prior to enrollment. 


7 
• 
History of coronary artery bypass graft (CABG) ≤ 8 weeks prior to enrollment. 
• 
Severe LV dysfunction, with ejection fraction of < 30% 
• 
Serious non-cardiac medical illness (e.g., disseminated malignancy, severe neurological 
dysfunction at time of baseline PET study) or a social situation which will preclude research 
study participation 
• 
History of seizure disorder 
 
 
Discontinuation criteria: 
Subjects should be discontinued for the following discontinuation criteria  
• 
Subject does not fulfill inclusion or exclusion criteria  
• 
Subject experiences a serious or intolerable adverse event  
• 
In the Investigator’s opinion, the subject is non-compliant with the protocol requirements 
(protocol violation) 
• 
Subject’s health would be jeopardized by continued participation  
• 
Subject wishes to withdraw consent  
 
Lexiscan will not be administered to patients with clinical or EKG evidence on ischemia during exercise 
treadmill testing. Clinical or EKG abnormalities during treadmill testing that would preclude 
administration of Lexiscan are listed below: 
 
a) Clinical 
a. Severe chest pain 
b. Severe lightheadedness or dizziness,  
c. Severe shortness of breath 
d. Exercise induced hypotension (> 10mm Hg decrease in systolic blood pressure) 
e. Exercise induced hypertension (systolic blood pressure >210 mm Hg)  
b) ECG changes 
a. Significant ST segment depression (≥2 mm) 
b. Significant ST segment elevation (≥1 mm) 
c. Sustained ventricular or atrial tachycardia,  
d. Exercise induced heart block 
 
 
Statistical Plan:  


8 
The overall aim of this pilot study of 50 patients is to assess the tolerability, safety, diagnostic 
accuracy and image quality between Lexiscan with symptom limited exercise compared to 
Lexiscan alone. 
  
Aim 1. For this aim, we will compare the reported side effect profile for Lexercise to Lexiscan 
PET, using a Pearson Chi square test. A P-value of<0.05 will be considered significant. 
 
Aim 2: For this aim, we will compare objective measures of image quality including signal to 
noise ratio using dynamic Rubidium-82 or N-13 ammonia  images, the frequency of 
misregistration between PET and CT, the frequency of presumed motion artifact and bowel 
radiotracer activity. These measures will be compared using a student’s t-test or a Pearson Chi 
square test, as appropriate. A P-value of<0.05 will be considered significant. 
 
Aim 3: For this aim, we seek to compare measures of semi quantitative relative perfusion, 
absolute perfusion and LVEF using the Lexiscan alone compared to Lexercise PET. Firstly, we 
will compare semi-quantitative defect size, severity and reversibility between the Lexercise and 
Lexiscan PET studies. Based on the results of one prior study using N-13 ammonia and 
comparing dipyridamole versus treadmill exercise2, a sample size of 24 subjects with reversible 
defects should be adequate to identify if significant differences exist between Lexercise and 
Lexiscan PET protocols. Next, we will compare the differences in regional rest and peak stress 
myocardial blood flow and coronary flow reserve in the defect territory compared to normal 
territory between the Lexercise and Lexiscan protocols. Finally, we will study the changes in 
LVEF from rest to peak stress in Lexercise versus Lexiscan PET studies in the normal and 
ischemic subjects.  
 
 
 
 
 
 
 
I. BACKGROUND: 
Myocardial perfusion imaging (MPI) with positron emission tomography (PET) is more accurate 
than single photon emission computed tomography (SPECT)3, enables non-invasive quantitation of 
absolute myocardial blood flow (MBF), and is particularly helpful in the obese individuals and those that 
are unable to exercise.3 Presently PETMPI is indicated only for subjects that are unable to exercise4, 


9 
primarily because exercise stress is not easy with PET. However, due to superior image characteristics, 
faster pace, and radiation dosimetry (compared to Thallium-201), exercise PET with Rubidium-82 is 
being viewed as an excellent alternative to exercise SPECT.  This has become more important lately with 
the recent shortage of Technetium labeled radiotracers. Although exercise PET is feasible with Rubidium-
82,2 the workflow is challenging due to its short-half-life (75 seconds). Exercise PET with N-13 ammonia 
has been studied, but this is only possible in sites with an onsite cyclotron and the production and delivery 
of N-13 ammonia have to be coordinated with the PET scanner due to its 10 minute half-life.2 Finally, in 
high volume nuclear cardiology laboratories, routine clinical use of exercise PET poses the concern of 
high radiation exposure to staff. 5 This is primarily related to the fact that, after the PET radiotracer is 
injected on the treadmill, the staff is directly and closely exposed to the radioactive patient (while walking 
and positioning the subject to the scanner immediately after radiotracer injection).  
 
Effects of exercise and vasodilator stress on myocardial blood flow: 
 
Exercise is the most important physiological stimulus that increases myocardial oxygen demand. 
Exercise results in vasodilation of the normal epicardial coronary arteries (Figure, Top panel).6 The 
resultant increase in coronary blood flow and shear stress lead to endothelial release of nitric oxide and 
several other vasoactive mediators that cause further 
vasodilation of the downstream microvasculature and 
increased MBF. In contrast, diseased epicardial 
coronary arteries vasoconstrict in response to exercise 
resulting (Figure, bottom panel) in an increased flow 
gradient with reduced blood flow to the downstream 
microvasculature during exercise as compared to 
normal territories.  
 
Vasodilator stress agents do not typically result in vasoconstriction of diseased coronary arteries. They 
produce differential vasodilation of both normal and diseased coronary arteries by predominantly by an 
endothelium independent mechanism resulting in estimation of primarily endothelium independent 
changes in MBF, and to a lesser extent endothelium independent changes in MBF.7 
 
Combined standard symptom limited exercise stress testing with injection of Lexiscan at peak exercise 
(Lexercise PET) may be a novel protocol to optimally image maximal endothelium dependent (exercise) 
and endothelium independent (Lexiscan) alterations in MBF, using relative and absolute myocardial 
perfusion PET. Symptom limited exercise produces endothelial activation and vasodilation of normal and 
vasoconstriction of diseased coronary arteries. Addition of vasodilator stress at maximal exercise results 
in further (maximal) vasodilation of the normal coronary arteries; but minimal or no additional 
Wilson R. N Engl J Med 1996;334:1735-1737 


10 
vasodilation of the vasoconstricted diseased coronary arteries. This may result in improved defect contrast 
compared to the normal coronary arteries and better detection of CAD. Indeed a prior study demonstrated 
that defect size is larger with treadmill exercise stress compared to vasodilator stress with dipyridamole.8 
Also, the precise reasons for larger perfusion defects with exercise compared to dipyridamole PET were 
not studied; although, true ischemia from exercise was proposed as a possible mechanistic link for larger 
perfusion defects with exercise.  If endothelial dysfunction and true vasoconstriction are imaged with 
exercise PET, then, we can expect to metabolic abnormalities (switch from fatty acid to glucose 
metabolism) in the corresponding myocardial segments that may be imaged using tracers of fatty acid 
metabolism such as β Methyl-p-[123I]-iodophenyl-pentadecanoic acid (BMIPP) or C-11 Palmitate. 
Lastly, quantitative MBF is estimated predominantly with vasodilator stress and occasionally with bicycle 
exercise stress.9 Quantitative PET with Lexercise PET may be a novel method to image combined 
alterations in MBF related to both endothelium dependent and independent mechanisms of MBF.  
 
 
 
 
 
 
 
 
 
 
 
 
II. SPECIFIC AIMS: 
The overall purpose of the proposed research study is to examine in detail, using relative and quantitative 
Rubidium-82 or N-13 ammonia PET, the feasibility, safety, utility and the mechanistic basis of combined 
symptom limited exercise treadmill test with vasodilator stress compared to vasodilator stress alone in the 
evaluation of known or suspected coronary artery disease. The following specific aims are proposed: 
 
Aim 1: To assess the tolerability and safety of the combined symptom limited exercise and Lexiscan 
protocol (Lexercise PET) compared to Lexiscan alone (Lexiscan PET). 
Hypothesis 1: Lexiscan will cause further/maximal vasodilation in a subject that is already vasodilated 
from exercise; therefore, the safety of this protocol needs to be ascertained. Lexiscan is expected to be 
well tolerated when injected during maximal exercise stress without any increase in major adverse events.  
 


11 
Aim 2: To assess the image quality of Lexercise PET compared to Lexiscan. 
Hypothesis 2: Image quality as assessed by myocardial count density and heart to liver ratio will be 
superior with Lexercise compared to Lexiscan. However, misregistration artifacts from upward 
diaphragmatic creep will be higher with Lexercise compared to Lexiscan. 
 
Aim 3: To compare relative and absolute PET with Lexercise compared to Lexiscan PET in identifying 
CAD. 
Hypothesis 3: Lexercise PET offers the advantage of imaging reduced myocardial blood flow from 
vasoconstriction in diseased territories and maximal vasodilation in normal territories. Therefore, in 
patients with ischemic scans, the defect contrast on relative will be better with Lexercise compared to 
Lexiscan PET. We hypothesize that the differences in regional CFR between normal and abnormal 
territories will be greater with Lexercise compared to Lexiscan. 
 
Significance of the mechanistic questions of this proposal: 
The overall goal of this proposal is to evaluate the feasibility, utility and mechanistic 
underpinnings of a novel protocol incorporating combined maximal symptom limited exercise treadmill 
test with Lexiscan compared to Lexiscan alone. The combined standard symptom limited exercise stress 
testing with Lexiscan has several novel clinical and research applications: 
 
1. This protocol provides exercise data (hemodynamic, electrocardiographic and clinical data) 
combined with high quality PET imaging that is important in patient management. 
2. A PET MPI study can be performed with physiological exercise stress using any of the 
available flow tracers (Rubidium-82, N-13 ammonia, or the new compound BMS747158, an 
F-18 labeled agent) with minimal radiation exposure to the staff. 
3. This protocol makes it feasible to assess both endothelium dependent (exercise) and 
endothelium independent (Lexiscan) mechanisms affecting MBF. 
4. This combined assessment may prove to have a superior diagnostic accuracy compared to 
Lexiscan alone in diagnosing milder degrees of stenoses and balanced ischemia due to ECG 
changes, symptoms, hemodynamic changes, and improved defect contrast on relative and 
absolute PET.8 
5. Also, using Rubidium-82 or N-13 ammonia and exercise PET, peak stress left ventricular 
ejection fraction can be computed. 
6. Finally, the results of this study could be extrapolated to stress imaging with cardiac magnetic 
resonance imaging, making exercise CMR feasible. 
 
b)  Previous studies leading up to or supporting the proposed research 


12 
A major strength of this project is that it represents an outgrowth of techniques pioneered at 
BWH. Within our existing Division of Nuclear Medicine/PET and Cardiovascular Imaging, this project is 
a natural extension of our work to date. We have extensive clinical and research experience with 
Rubidium-82 and N-13 ammonia PET, and have performed over 6000 clinical studies since the initiation 
of our PET program in the fall of 2003.  We have been using Lexiscan with Rubidium-82 PET since 
January 2009 and with N-13 ammonia PET since July 2011. Also, quantitative myocardial blood flow 
estimates have been routinely performed using a home grown software program (soon to be commercially 
available).  
 
Rationale for specific aim 1:  
Study of both endothelium dependent and independent mechanisms of myocardial blood flow is clinically 
relevant and important.9 10 Sub maximal / low-level exercise with vasodilator stress has been studied and 
used clinically to improve image quality and patient tolerance of side effects.11 The combined protocol of 
Lexercise proposes to use a maximal symptom limited exercise stress combined with maximal coronary 
vasodilation with Lexiscan. The safety of this “dual full stress” protocol needs to be established before 
widespread clinical application. At the BWH, we have been using combined symptom limited exercise 
with Lexiscan and SPECT imaging since January 2009 in approximately 5 cases per week. The results 
have not been formally analyzed yet, but, in general the protocol is well tolerated without any major side-
effects. There has been one instance of a side-effect in a subject who exercised ~9 minutes and had sub-
maximal heart rate response, received Lexiscan and vomited during recovery. This was associated with 
high grade heart block that resolved spontaneously. But, this combined symptom limited exercise and 
Lexiscan protocol has not been used in conjunction with PET imaging. 
 
Rationale for specific aim 2: 
Due to increased blood flow to the 
extremities and reduced splanchnic 
flow during maximal exercise 
treadmill testing, the quality of 
myocardial perfusion images as 
assessed by a heart to liver ratio, and 
bowel uptake will be  
superior with Lexercise compared to 
Lexiscan PET. However, with PET MPI, imaging is started soon after stress while the subject is still 
breathing heavy and hence the effects on image quality, both relative PET and dynamic PET images need 
to be determined. A prior study2 from the Ottawa heart institute, evaluated treadmill exercise PET with 
Rubidium-82. Myocardial uptake of Rubidium-82 was significantly greater with exercise compared with 


13 
dipyridamole stress (See Table reproduced from reference 2). Higher ratios of myocardial uptake to gut, 
blood pool, and higher stress myocardial uptake were observed with exercise stress compared with 
dipyridamole stress.  No significant differences in inferior wall defects due to misregistration were noted 
between exercise and dipyridamole stress studies using a dedicated PET scanner. 
 
Rationale for specific aim 3: 
A prior study,2 from the Ottawa heart institute, evaluated treadmill exercise PET with Rubidium-82. This 
study included 50 patients (74% with known CAD and 26% with intermediate to high pretest likelihood 
of CAD) that underwent both exercise and dipyridamole Rubidium-82 PET within a median of 6 days of 
each other. More patients preferred exercise stress over dipyridamole. The summed stress (A), rest (B) 
and difference scores (C) were highly correlated (Figure below reproduced from reference2). Bland-
Altman analysis revealed no significant differences in defect size between the treadmill and dipyridamole 
studies.  Also, the agreement between treadmill and dipyridamole studies was similar to the agreement 
between repeat dipyridamole studies. The authors concluded that treadmill exercise 82Rb PET is feasible 
and provides imaging results of similar diagnostic content and better quality compared with dipyridamole 
stress. 
 
  
 
 
 
In a separate study from the same group, treadmill exercise PET with N-13 ammonia was compared to 
dipyridamole PET.8 This study included 26 patients (41% with prior MI, 35% with prior PCI and 15% 
with prior CABG) that underwent both exercise and dipyridamole N-13 ammonia PET within a median of 
6 days of each other. The summed stress, rest and difference scores were well correlated between the 
treadmill and dipyridamole studies.  The defect size and severity was larger with treadmill exercise 
compared to dipyridamole PET (See Table below reproduced from reference8).  
 


14 
 
 
Myocardial count density of N-13 ammonia was significantly greater with dipyridamole compared to 
exercise stress. Successful performance of exercise ammonia required coordination between the cyclotron 
team and the imaging team. The authors concluded that treadmill exercise produces larger and more 
severe perfusion defects than dipyridamole and may reflect true ischemia.  
 
III. STUDY METHODS 
 
This is a single-center, prospective cohort study of subjects undergoing clinically indicated PET/CT MPI, 
with documented coronary artery disease or an intermediate to high pretest likelihood of coronary artery 
disease based on age gender and symptoms as described in the ACC/AHA/ASNC appropriate use criteria 
for cardiac radionuclide imaging. 12 Following completion of the clinical study, the research study is 
explained to the subjects. Consenting subjects will return on another day for a repeat stress study with 
Lexercise or a repeat Lexiscan stress PET. Approximately 50 subjects (not more than 16 patients with 
normal Rubidium-82 PETMPI and 34 with reversible perfusion defects) will be enrolled in this study. 
After successful screening and enrollment, 13 random subjects (8 normal and 5 ischemic) will return for 
repeat Lexiscan PET, and 34 subjects will return for a Lexercise PET/CT MPI, on the next calendar day 
or within 2 weeks of the clinical Rubidium-82 or N-13 ammonia PET study.  
 
SUBJECT SELECTION 
 
Main Selection Criteria 
Subjects will be eligible if they meet all of the following inclusion criteria and none of the exclusion 
criteria:  
Inclusion criteria: 
• 
Age > 18 years 
• 
Clinically indicated Rubidium-82 or N-13 ammonia PET study 
• 
Ten healthy volunteers recruited using web based advertisements. 


15 
• 
Known coronary artery disease (prior percutaneous coronary intervention, prior coronary 
artery bypass surgery or Q wave MI on ECG) or intermediate to high pretest likelihood of 
CAD  
• 
Able to exercise on a treadmill 
• 
Able and willing to provide informed consent to participate in the study  
 
Exclusion criteria: 
• 
Contraindications to exercise stress testing such as 
o  unstable angina 
o known severe left main coronary artery stenosis 
o severe  or uncontrolled heart failure 
o uncontrolled atrial or ventricular arrhythmias 
o symptomatic hypotension or severe hypertension (systolic blood pressure < 90 or > 
200 mmHg, respectively) 
o > 1st degree atrioventricular block in the absence of a functioning pacemaker. 
• 
Contraindications to Lexiscan use such  
• 
Allergy or intolerance to aminophylline or regadenoson 
• 
Known severe or oxygen dependent bronchoconstrictive or bronchospastic lung disease 
[e.g., asthma, wheezing, chronic obstructive pulmonary disease (COPD), etc.]. 
• 
Sick sinus syndrome 
• 
History of heart transplantation. 
• 
Dialysis 
• 
Subject requires emergent cardiac medical intervention or catheterization after the clinical 
study. 
• 
Documented myocardial infarction (MI) ≤ 30 days prior to enrollment. 
• 
History of percutaneous coronary intervention (PCI) ≤ 4weeks prior to enrollment. 
• 
History of coronary artery bypass graft (CABG) ≤ 8 weeks prior to enrollment. 
• 
Severe LV dysfunction, with ejection fraction of < 30% 
• 
Serious non-cardiac medical illness (e.g., disseminated malignancy, severe neurological 
dysfunction at time of baseline PET study) or a social situation which will preclude research 
study participation 
• 
History of seizure disorder 
 
Discontinuation criteria: 
Subjects should be discontinued for the following discontinuation criteria  
• 
Subject does not fulfill inclusion or exclusion criteria  


16 
• 
Subject experiences a serious or intolerable adverse event  
• 
In the Investigator’s opinion, the subject is non-compliant with the protocol requirements 
(protocol violation) 
• 
Subject’s health would be jeopardized by continued participation  
• 
Subject wishes to withdraw consent  
 
Lexiscan will not be administered to patients with clinical or EKG evidence on ischemia during exercise 
treadmill testing. Clinical or EKG abnormalities during treadmill testing that would preclude 
administration of Lexiscan are listed below: 
 
c) Clinical 
a. Severe chest pain 
b. severe lightheadedness or dizziness,  
c. severe shortness of breath 
d. exercise induced hypotension (> 10mm Hg decrease in systolic blood pressure) 
e. exercise induced hypertension (systolic blood pressure >210 mm Hg)  
d) ECG changes 
a. Significant ST segment depression (≥2 mm) 
b. Significant ST segment elevation (≥1 mm) 
c. Sustained ventricular or atrial tachycardia,  
d. Exercise induced heart block 
a) Source of subjects and recruitment methods 
Patients will be recruited from the nuclear cardiology laboratory at the Brigham and Women’s 
Hospital. Among them, stable and eligible patients meeting all inclusion and exclusion criteria will be 
invited to participate in this study and those who provide informed consent will be enrolled. Referring 
physicians will be informed about the study and asked to discuss the study with their patients being 
referred for PET myocardial perfusion imaging. Ten healthy volunteers will be recruited for this study 
using web based advertisements. 
 
IV. SUBJECT ENROLLMENT 
 
a) Methods of enrollment including procedures for patient registration and or randomization 
The following recruitment methods will be used: 
• 
This is a pilot study of subjects referred for a clinically indicated myocardial perfusion PET 
study. Majority of the subjects will be recruited from the clinical practices of the Brigham and 


17 
Women’s hospital. The patients’ referring physician will introduce the study to the subjects prior 
to the clinical PET study and those subjects that are willing to consider the study will be given the 
written informed consent for the study for review. Subjects’ questions will be answered by Dr. 
Sharmila Dorbala. There will be no time restriction to sign the consent form or participate in this 
study. Subjects that express an interest will be evaluated and provided they meet all the inclusion 
and exclusion criteria, they will be considered for this study. 
• 
On occasion, we may identify subjects with reversible perfusion defects from our clinical 
Rubidium-82 or N-13 ammonia PET studies. In those instances, physicians requesting myocardial 
perfusion imaging studies (primary or specialist health care provider) will be contacted personally 
explaining the purpose of the study. The physicians of those subjects will be asked if they felt 
comfortable introducing the study to their subjects either verbally during the office visit or 
through a recruitment letter. If the physician introduces the study verbally, the subject will be 
asked if they would like to speak with a study physicians after their appointment. If they would 
like to speak with someone, Dr. Dorbala will be notified and she will explain the study to the 
subject and go over the inclusion and exclusion criteria for the study. If they are interested in 
participating in the study an appointment will be made for their first visit.  
• 
Hospital in-patients with request for pharmacologic stress: Attending physicians will be asked if 
they felt comfortable introducing the study to their subjects that they schedule for in-patient 
pharmacologic stress myocardial perfusion study verbally during their visit. If the physician 
introduces the study verbally, the subject will be asked if they would like to speak with a 
coordinator after the visit. If they would like to speak with someone, the coordinator will be 
notified and they will explain the study to the subject and go over the inclusion and exclusion 
criteria for the study. If they are interested in participating in the study an appointment will be 
made for their first visit.  
• 
Special attention will be paid to enroll women and minorities in the study. 
• 
Ten healthy volunteers will be recruited for this study using web based advertisements. They will 
all undergo Lexiscan (regadenoson) followed by Lexercise protocol (exercise + regadenoson) on 
a separate day. 
 
b) Procedures for obtaining informed consent (including timing of the consent process) 
For subjects interested in the speaking to a study staff, Study PI, will go over the inclusion and 
exclusion criteria and will describe the study and procedures to the potential subject over the phone or 
in person.  If the subject qualifies and is interested he/she is encouraged to discuss the study with 
his/her primary care physician or family members. Upon arrival for the study, the subject will be 
given a copy of the consent form to read. After the subject has finished reading the consent form, one 
of the physician investigators will describe the study in detail and answer any questions or concerns 


18 
the subject might have. If the subject agrees to participate in the study they will be asked to provide 
his/her written informed consent. Subjects will be given a copy of the signed consent form for their 
records. The investigator will inform the subject that they have the alternative not to participate in the 
study and can withdraw their consent at any point during the study. 
The subjects will be given as much as 2 weeks to consider participation in the trial. Pregnant women 
and minors are excluded from this trial. Subjects that are determined by the physician to be unable to 
consent due to their physical or mental condition will not be enrolled in this trial.  
 
V. STUDY PROCEDURES  
The patient will have 1-2 study visits and healthy volunteers will have 2-3 study visits. Study visit 1 is the 
same for patients and healthy volunteers. 
 
a. Study visit 1 
a. The subjects that are interested in the study will meet with Dr. Dorbala and go over the consent 
form and details of study participation. 
b. This screening visit will take about 1 hour. The research study team will ask the subject questions 
about medical history, medications, and prior hospitalizations to make sure that the subject 
qualifies for this study. Blood pressure, heart and breathing rates, temperature, and height and 
weight will be measured. Pregnancy is not allowed due to the unknown risks radioactivity may 
have on the mother or the unborn baby from the beginning of the study period through the end of 
the study.  A blood pregnancy test will be performed on the day of the PET scan in women with 
child bearing potential.  
 
Patients: 
a. Study visit 2 
The study visits 1 and 2 can be conducted on the same day. Study visit 2 is for the performance of the 
Lexercise stress Rubidium-82 or N-13 ammonia PET study. This will be scheduled at least the next 
calendar day or within 2 weeks of the clinical Rubidium-82 or N-13 ammonia PET study. While we 
aim to conduct the research scan within 2 weeks of the clinical scan, if there is a scanner malfunction 
or patient schedule conflict, we would like to extend the time frame for enrollment to 4 weeks. 
Approximately 20 cc of blood will be drawn following completion of the Rubidium-82 or N-13 
ammonia imaging study and evaluated for biochemical markers of ischemia.  
 
b. Study Visit 3 


19 
Study visit 3 is for the performance of the Lexercise stress Rubidium-82 or N-13 ammonia PET 
study. This will be scheduled at least the next calendar day or within 2 weeks of the clinical 
Rubidium-82 or N-13 ammonia PET study. Approximately 20 cc of blood will be drawn 
following completion of the Rubidium-82 or N-13 ammonia imaging study and evaluated for 
biochemical markers of ischemia. A part of this blood sample (10 cc) will be sent to the 
laboratory of Dr. XX for the isolation of microRNAs involved in angiogenesis and vascular 
inflammation. This blood sample will be stored for future analysis. 
 
 
Healthy volunteers: 
a. Study visit 2 
The study visits 1 and 2 can be conducted on the same day. Study visit 2 is for the performance of the 
rest and regadenoson stress Rubidium-82 or N-13 ammonia PET study. No blood drawing will be 
performed during this visit.  
 
b. Study visit 3 
Study visit 3 is for the performance of the Lexercise stress Rubidium-82 or N-13 ammonia PET 
study. This will be scheduled at least the next calendar day or within 2 weeks of the Visit 2 rest/stress 
scans. While we aim to conduct the Visit 3 “Lexercise stress” scan within two weeks of the 2 
rest/stress scans, if there is a scanner malfunction or patient schedule conflict, we would like to 
extend the time frame for enrollment to 4 weeks. Approximately 5 cc of blood will be drawn 
following completion of the Rubidium-82 or N-13 ammonia imaging study for troponin levels. Blood 
samples will not be drawn for micro RNA measurements in the healthy volunteer cohort.  
 
 
Detailed Description of PET MPI Methods: The proposed research will utilize the resources of the 
Cardiovascular Imaging center at Brigham and Women’s Hospital, Boston MA. Specifically, PET 
imaging will be performed on a state-of-the-art 64 slice cardiac PET/CT unit.   
 
Before the test: All patients scheduled for a rest- vasodilator stress Rubidium-82 PET or N-13 ammonia 
will receive written instructions to fast overnight, avoid caffeine containing beverages and medications 
for 24 hours prior to the test and bring all their medications (including prescription, over the counter, 
dietary supplements, herbal and vitamins) with them. Upon arrival for the test, all patients are given a 
written questionnaire about allergies and possibility of pregnancy (women of child bearing age will 
undergo a blood pregnancy test prior to the rest Rubidium-82  or N-13 ammonia  PET study), as per 
laboratory protocol. Patients without objection will be detailed about the study and related procedures and 


20 
consenting patients will be recruited into the study. An experienced exercise physiologist/imaging fellow 
obtains a detailed clinical history from each patient and confirms it by a review of electronic medical 
records. Written informed consent for the study is checked and IV line inserted, ECG module connected 
and the patient brought into the PET/CT room for imaging. A detailed datasheet will be used to record 
information on demographics, history on coronary risk factors, reason for the test, nature of symptoms 
(chest pain type, shortness of breath description), resting ECG interpretation (as approved by a 
cardiologist), list of medications, resting and stress hemodynamics, dose of Lexiscan, dose of Rubidium-
82 or N-13 ammonia injected, reason for test termination, symptoms and ECG changes during stress test. 
 
Rubidium-82 or N-13 ammonia PET image acquisition:  
Following skin preparation and ECG lead placement, patient undergoes a symptom limited standard 
Bruce exercise treadmill test. At peak exercise (when patient is unable to exercise for more than 1 
minute), the treadmill is stopped and patient is immediately positioned on the imaging table. Image 
acquisition is started with a CT scout image for positioning the heart (10 mA, AP scout, 9 seconds). Then 
0.4 mg of regadenoson is given by intravenous push over 10 seconds followed by 10 ml of normal saline 
flush. Right after the saline flush, 40-60 mCi of Rubidium-82 or 20 mCi of N-13 ammonia is injected and 
emission imaging started in a list mode fashion started at the time of injection of radiotracer. Following 
completion of the emission imaging, a CT transmission scan (20 mA, 120 KV, non-gated, free tidal 
breathing) is obtained for correction of photon attenuation by soft tissues.  . 
Rest and Lexiscan stress images from the clinical study and the Lexercise stress emission images will be 
unlisted for analysis into a static file, a gated file and dynamic image frames (36 frames of 5 seconds 
each, 8 frames of 15 seconds each, and 6 frames of 30 seconds each for stress and 2 groups for rest of 24 
frames at 5 seconds each and 8 frames at 30 seconds each). In subjects with serious or bothersome 
adverse effects, aminophylline will be administered intravenously (1 mg/kg, to a maximum of 150 mg) to 
alleviate the symptoms.  
 
Myocardial blood flow quantification: 
Myocardial blood flow (in ml/gm/min) at rest and after vasodilator stress will be quantified using a 
software based on GFADS and a 2 compartment model, developed and validated at the Brigham and 
Women’s Hospital.13 Rest and peak stress myocardial blood flow will be computed in ml/gm/min and 
global and regional (vascular territories assigned as described below) coronary flow reserve computed by 
dividing stress myocardial blood flow by rest myocardial blood flow. Coronary vascular resistance at rest 
and stress will be computed by dividing mean aortic pressure [derived as 2 (diastolic blood pressure) + 
systolic blood pressure/3] by myocardial blood flow. In addition to calculating the myocardial blood flow 
for the left ventricle as a whole, myocardial blood flow will be determined for each of three vascular beds 


21 
(left anterior descending [LAD], left circumflex [LCx], and right coronary artery [RCA]). Subendocardial 
and subepicardial myocardial blood flow will be assessed globally. 
 
Interpretation of relative myocardial perfusion images:  
The semi-quantitative clinical interpretation of Rubidium-82 or N-13 ammonia images will be performed 
using a standard 17 segment model and a 0-4 scale (0=normal, 1= mild defect, 2=moderate defect, 
3=severe defect, 4= absent radiotracer uptake). The sum of the scores in the 17 segments at stress and rest 
will be computed as the summed stress score (SSS) and summed rest score (SRS) respectively. The 
summed difference scores (SDS) will be derived as SSS – SRS. The SSS, SRS and SDS will be converted 
into percentages to compute total percent myocardium abnormal, scarred or ischemic determined as 
(100/68)*SSS, (100/68)*SRS or (100/68)*SDS, respectively. Perfusion defects on relative PET will be 
assigned vascular distributions as described previously.14 LV volumes and EF will be estimated using 
FDA approved software (EcTb), with automatic edge detection and manual refinement when needed.  
 
Interpretation of absolute myocardial perfusion images:  
Myocardial blood flow at rest, stress and CFR are calculated for the left ventricle as a whole, as well as 
for each of three vascular beds (left anterior descending [LAD], left circumflex [LCx], and right coronary 
artery [RCA]). Polar plots of CFR will be generated and defect extent and severity computed in relation to 
a quantitative CFR normal limits database (developed at BWH).  
 
Study Endpoints Assessed: 
• 
Diagnostic value:  
o Defect size, severity, extent and contrast with Lexiscan alone compared to exercise 
Lexiscan protocol 
o Left ventricular ejection fraction at rest and immediately post stress will be compared in 
the Lexiscan alone and the exercise Lexiscan protocol. 
o Myocardial blood flow estimates and coronary flow reserve will be compared between 
the Lexiscan alone and Lexercise protocols. 
o Comparison to coronary angiography results when available. 
• 
Safety and tolerability:  
o Side effects, ECG changes, blood pressure changes, will be recorded.  
o Safety blood work will be drawn after the Lexiscan and the Lexercise PET study to 
measure serum troponin T levels.  
o Radiation dose to the staff will be measured using personal dosimeters after the Lexiscan 
as well as the Lexercise PET study. 
• 
Image quality:  


22 
o Motion artifacts 
o Image registration 
o Sub diaphragmatic activity (liver heart ratios)  
o Defect contrast  
o Signal to noise ratio and  
o Dynamic image evaluability will be assessed 
 
VI. BIOSTATISTICAL ANALYSIS 
The overall aim of this pilot study of 50 patients is to assess the tolerability, safety, diagnostic accuracy 
and image quality between Lexiscan with symptom limited exercise compared to Lexiscan alone. 
  
Aim 1. For this aim, we will compare the reported side effect profile for Lexercise to Lexiscan PET, 
using a Pearson Chi square test. A P-value of<0.05 will be considered significant. 
 
Aim 2: For this aim, we will compare objective measures of image quality including signal to noise ratio 
using dynamic Rubidium-82 images or N-13 ammonia, the frequency of misregistration between PET and 
CT, the frequency of presumed motion artifact and bowel radiotracer activity. These measures will be 
compared using a student’s t-test or a Pearson Chi square test, as appropriate. A P-value of<0.05 will be 
considered significant. 
 
Aim 3: For this aim, we seek to compare measures of semi quantitative relative perfusion, absolute 
perfusion and LVEF using the Lexiscan alone compared to Lexercise PET. Firstly, we will compare semi-
quantitative defect size, severity and reversibility between the Lexercise and Lexiscan PET studies. Based 
on the results of one prior study using N-13 ammonia and comparing dipyridamole versus treadmill 
exercise2, a sample size of 35 subjects with reversible defects should be adequate to identify if significant 
differences exist between Lexercise and Lexiscan PET protocols. Next, we will study the changes in LVEF 
from rest to peak stress in Lexercise versus Lexiscan PET studies in the normal and ischemic subjects. 
Finally, we will compare regional rest and peak stress myocardial blood flow and coronary flow reserve 
between Lexercise and Lexiscan PET studies.  
 
 
VII. RISKS AND DISCOMFORT 
 
Time: Participation in this trial entails an exercise vasodilator stress Rubidium-82 PET or N-13 ammonia 
scan. The total time spent for the study procedures is approximately 1 hour.  
 


23 
Intravenous line insertion: Possible side effects intravenous line insertion are pain, bruising, or infection 
where the needle entered the skin.   Some people faint or get dizzy during insertion of the intravenous 
line. 
 
Radioactive imaging agents may have the following side effects: The average dose from the research 
radiation is approximately 2.7 mSv, which is approximately 6% of the amount allowed per year for a 
person who routinely work with radiation sources. For healthy volunteers, the average dose from the 
research radiation is approximately 6.9 mSv, which is approximately 13.8% of the amount allowed per 
year for a person who routinely work with radiation sources. Other side effects include: metallic taste in 
the mouth, burning at the injection site, facial swelling, numbness of the hand and arm, low blood 
pressure, nausea, angina and chest tightness. Radiation exposure associated with both rest and stress 
imaging is well within acceptable safety standards as set forth by the FDA.  Radiation may cause physical 
or genetic damage to a fetus, so subjects that are pregnant or breast feeding will be excluded. A pregnancy 
test will be performed prior to enrolling patients with childbearing potential.  
 
Lexiscan: In previous studies where vasodilator stress agents were given to patients with heart disease at 
the FDA approved doses, they have been reported to be associated with the following side effects 
including dyspnea-shortness of breath (28%), headache (26%), flushing (16%), chest discomfort (13%), 
angina pectoris-chest pain caused by myocardial ischemia (12%), dizziness (8%), chest pain (7%) and 
nausea (6%), flushing, feeling of heat, hypoesthesia (decreased sensitivity), paresthesia (tingling of the 
arms and legs), sensation of heaviness, abdominal pain, palpitations, unpleasant taste in the mouth and 
feeling hot (each 5%).  Increases in heart rate and mild decreases in blood pressure have also been 
associated with administration of vasodilator stress agents.  
In addition to the risks or discomforts listed above, the study drug and procedures may have unknown 
side effects. There is always the possibility that subjects will have a reaction that is currently not known 
or not expected.  All drugs can cause an allergic reaction that, if not treated promptly, could be life-
threatening. Symptoms of such a reaction are: throat tightness, itching, hives ,wheals ,vomiting ,difficulty 
breathing or turning blue. 
 
Risks of withholding medications: Certain medications such as beta-blockers, nitrates, diuretics, calcium 
channel blockers and bronchodilators may have to be held for 12-24 hours prior to the study. Withholding 
these medications may result in chest pain or angina, high or uncontrolled blood pressure, high blood 
glucose, or in very rare instances a heart attack. For these reasons we will only enroll subjects that are 
clinically stable without uncontrolled angina, hypertension or are acutely ill for any reason. The 
medications that will be withheld and the length of the time withheld are shown below. To minimize the 


24 
risk, the prescribing physician will be consulted to give permission for his patient to withhold the 
specified medication for the specified length of time.  
Hold on the morning of the test 
Diabetic agents: Insulin Half of Normal Morning Dose can be taken.  
Hold oral Hypoglycemics till after the test completion: Actos, Amaryl, Avandamet, Avandia, 
Avandaryl, Byetta, Diabeta, Diabinese, Fortamet, Glipizide, Glucophage, Glucovance, Glucotrol, 
Glyburide, Metformin, Micronase, Prandin 
Hold 4-6 hours prior to testing 
Nitroglycerine, Deponit, Nitro-Bid, Nitro-Disc, Nitro-Dur, Nitro-Gard, Nitrol, 
Nitrostat, TransdermNitro, Trasdermal-NTG, Nitro paste 
Hold 12 hours prior to testing 
Nitrates, Isosorbide Dinitrate Isordil, Dilatrate, Sorbitrate, Isosorbide Mononitrate, Imdur, Ismo, 
Monoket 
Hold 24 hours prior to testing 
Bronchodilators Aerolate, Aminophylline, Aquaphyllin, Asmalix, Choledyl, 
Elizophylline Slo-bib, Slo-Phyllin, Thoe-Dur, Theovent 
Calcium Channel Blockers 
Amlodipine Cauduet, Lotrel, Norvasc, Diltiazem Cardizem CD, Cardizem SR,Cartia XT, Dilacor XR, 
Diltia XT, Tiazac, Taztia XT, Felodipine Plendil, Isradipine DynaCirc, Nicardipine, Hydrochloride, 
Cardene, Cardene SR, Nifedipine Adalat, Adalat CC, Procardia, Procardia XL 
Nimodipine Nimotop, Nisoldipine Sular, Verapamil, Hydrochloride, Calan, Calan SR, Covera, 
Isoptin, Isoptin SR, Verelan 
Miscellaneous 
Cafergot, Cialis, Levitra, Ranexa, Ranolazine, Trental, Pletal, Viagra. 
Hold 48 hours prior to testing 
Dipyridamole, Persantine, Aggrenox 
 
Aminophylline: Side effects of aminophylline may include nausea, headache, restlessness, convulsions, 
rapid breathing, a rapid heart rate, and allergic reactions such as rash. 
 
VIII. POTENTIAL BENEFITS 
 
No direct benefit is anticipated to individual subjects.  The results of this study may benefit society 
through evaluation of the diagnostic utility of novel protocol utilizing combined symptom limited 
exercise vasodilator stress test to image endothelium dependent and endothelium independent factors 
affecting myocardial blood flow. 


25 
 
IX. MONITORING AND QUALITY ASSURANCE 
 
Subject safety will be ensured by strict adherence to inclusion and exclusion criteria and close monitoring. 
Subjects that experienced serious adverse events during the study will be removed from the study and 
followed up, but no other study procedures will be performed. We will monitor the subjects closely for 
seizures and ischemic symptoms. History of seizures is an exclusion criteria for the study. Individuals 
who experience seizures for the first time during the initial regadenoson study will be excluded from the 
second regadenoson with exercise study.  Intravenous aminophylline, a competitive agonist, will be 
administered for ischemic symptoms. Subjects with ischemic symptoms will be monitored until complete 
resolution (current clinical practice). As listed in page 22, study endpoints, safety blood work will be 
drawn after the Lexiscan and the Lexercise PET study to measure serum troponin T levels. This study 
does not involve treatment and hence a data safety monitoring board.  
 
This is a pilot clinical study of about 50 subjects. The study PI, Sharmila Dorbala, MBBS, will be 
responsible for monitoring the study procedures after every subject is enrolled, including the accuracy and 
completeness of the case report form entries, source documents and informed consent after every 
enrollment. These documents will be appropriately maintained on submission.  
 
Specification of Source Documents 
The following information will be included in the source medical records: 
• Demographic data (age, sex, and race) 
• Inclusion and exclusion criteria details 
• Participation in study and signed and dated informed consent forms 
• Visit dates 
• Medical history and physical examination details 
• Key efficacy and safety data 
• Adverse events and concomitant medication 
• Results of relevant examinations 
• Laboratory printouts 
• Reason for premature discontinuation 
 
Ethical Conduct of the Study 
The investigator(s) and all parties involved in this study will conduct the study in adherence to GCP, ICH 
Guidelines and the applicable laws and regulations. 
 


26 
Subject Confidentiality 
The principal investigator will be responsible for oversight on maintaining subject confidentiality. All 
study staff are trained in Partners HIPAA procedures as well as in ethical conduct of research. Documents 
relating to the study that contain personal data that may disclose the identity of the subject will remain 
with the investigator and kept confidential in a locked cabinet accessible only to study staff. Subject 
confidentiality will be maintained by utilizing subject identification code numbers to correspond to 
treatment data in the study computer files.  All study center personnel will comply with privacy rules of 
this institution, the ICH guideline for good clinical practice, HIPAA and applicable state law.  Subject 
confidentiality will be maintained by limiting access to data collected to only co-investigators, study staff.  
Data and specimens will not be stored at Partners or non-Partners sites for future uses not described in the 
protocol.  
 


27 
X. REFERENCES:  
 
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iodophenyl-pentadecanoic acid identifies ischemic memory after demand ischemia. Circulation. 
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2. 
Chow BJ, Ananthasubramaniam K, dekemp RA, et al. Comparison of treadmill exercise versus 
dipyridamole stress with myocardial perfusion imaging using rubidium-82 positron emission 
tomography. J Am Coll Cardiol. Apr 19 2005;45(8):1227-1234. 
3. 
Di Carli MF, Hachamovitch R. New technology for noninvasive evaluation of coronary artery 
disease. Circulation. Mar 20 2007;115(11):1464-1480. 
4. 
Klocke FJ, Baird MG, Lorell BH, et al. ACC/AHA/ASNC guidelines for the clinical use of 
cardiac radionuclide imaging--executive summary: a report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC 
Committee to Revise the 1995 Guidelines for the Clinical Use of Cardiac Radionuclide Imaging). 
Circulation. Sep 16 2003;108(11):1404-1418. 
5. 
Schleipman AR, Castronovo FP, Jr., Di Carli MF, et al. Occupational radiation dose associated 
with Rb-82 myocardial perfusion positron emission tomography imaging. J Nucl Cardiol. May-
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6. 
Wilson RF. Assessing the severity of coronary-artery stenoses. N Engl J Med. Jun 27 
1996;334(26):1735-1737. 
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Bache RJ. Vasodilator reserve: a functional assessment of coronary health. Circulation. Sep 29 
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8. 
Chow BJ, Beanlands RS, Lee A, et al. Treadmill exercise produces larger perfusion defects than 
dipyridamole stress N-13 ammonia positron emission tomography. J Am Coll Cardiol. Jan 17 
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9. 
Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med. Feb 22 
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10. 
Camici PG, Rimoldi OE. The clinical value of myocardial blood flow measurement. J Nucl Med. 
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11. 
Holly TA, Satran A, Bromet DS, et al. The impact of adjunctive adenosine infusion during 
exercise myocardial perfusion imaging: Results of the Both Exercise and Adenosine Stress Test 
(BEAST) trial. J Nucl Cardiol. May-Jun 2003;10(3):291-296. 
12. 
Hendel RC, Berman DS, Di Carli MF, et al. ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM 
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of Cardiology Foundation Appropriate Use Criteria Task Force, the American Society of Nuclear 
Cardiology, the American College of Radiology, the American Heart Association, the American 


28 
Society of Echocardiography, the Society of Cardiovascular Computed Tomography, the Society 
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American College of Emergency Physicians. Circulation. Jun 9 2009;119(22):e561-587. 
13. 
El Fakhri G, Sitek A, Guerin B, et al. Quantitative dynamic cardiac 82Rb PET using generalized 
factor and compartment analyses. J Nucl Med. Aug 2005;46(8):1264-1271. 
14. 
Dorbala S, Vangala D, Sampson U, et al. Value of vasodilator left ventricular ejection fraction 
reserve in evaluating the magnitude of myocardium at risk and the extent of angiographic 
coronary artery disease: a 82Rb PET/CT study. J Nucl Med. Mar 2007;48(3):349-358.