Primer on Cardiac Imaging

THE UNIVERSITY OF NEW MEXICO HEALTH SCIENCES CENTER COLLEGE OF PHARMACY ALBUQUERQUE, NEW MEXICO

Correspondence Continuing Education Courses for Nuclear Pharmacists and Nuclear Medicine Professionals

VOLUME 11, LESSONS 2 AND 3 Primer on Cardiac Imaging

Richard J. Kowalsky, Pharm D, BCNP, FAPhA University of North Carolina

The University of New Mexico Health Sciences Center College of Pharmacy is accredited by the Accredication Council for Pharmacy Education as a provider of continuing pharmaceutical education. Program No. 039-000- 04-003-H04. 5.0 Contact Hours or .50 CEUs. Expires 05/25/2007.

Primer on Cardiac Imaging

By:

Richard J. Kowalsky, Pharm D, BCNP, FAPhA

Coordinating Editor and Director of Pharmacy Continuing Education William B. Hladik III, MS, RPh College of Pharmacy University of New Mexico Health Sciences Center

Managing Editor Julliana Newman, ELS Wellman Publishing, Inc. Albuquerque, New Mexico

Editorial Board George H. Hinkle, MS, RPh, BCNP, FASHP, FAPhA David Lawrence Laven, NPh, CRPh, FASHP, FAPhA Jeffrey P. Norenberg, MS, PharmD, BCNP, FASHP Neil A. Petry, MS, RPh, BCNP, FAPhA Timothy M. Quinton, PharmD, MS, RPh, BCNP, FAPhA

Guest Reviewer Nicki L. Hilliard, PharmD, MHSA, BCNP, FAPhA Associate Professor of Nuclear Pharmacy University of Arkansas College of Pharmacy 4301 W. Markham, Slot 522 Little Rock, AR 72205

While the advice and information in this publication are believed to be true and accurate at press time, the author(s), editors, or the publisher cannot accept any legal responsibility for any errors or omissions that may be made. The publisher makes no war- ranty, expressed or implied, with respect to the material contained herein.

3 PRIMER ON CARDIAC IMAGING

STATEMENT OF OBJECTIVES

Upon completion of this lesson, the reader should be able to:

1. Explain the physiologic basis of myocardial perfusion imaging.

2. Compare and contrast the radiopharmaceuticals used in myocardial perfusion imaging.

3. Compare and contrast the methods used to induce cardiac stress in myocardial perfusion imaging.

4. Describe the methods used to perform myocardial perfusion imaging.

5. List the agents used to induce pharmacologic stress and discuss their side effects, precautions, and limitations of use.

6. Describe the radiopharmaceuticals and methods used in myocardial ventriculography studies.

7. Describe the biochemical mechanisms involved with radiopharmaceuticals used in myocardial viability and metabolism studies.

8. Describe the mechanisms of localization of radiopharmaceuticals used in myocardial perfusion imaging and infarct-avid imaging.

9. Describe the strengths and limitations of SPECT and PET myocardial imaging agents for the diagnosis of heart disease.

4 COURSE OUTLINE

INTRODUCTION

MYOCARDIAL IMAGING

MYOCARDIAL BLOOD FLOW

VIABILITY

CARDIAC STRESS METHODOLOGY

Exercise Stress

Pharmacologic Stress

Adenosine

Dipyridamole

Dobutamine

Precautions, Side Effects, and Contraindications

MYOCARDIAL EXTRACTION

SPECT RADIOPHARMACEUTICALS

Thallous Chloride Tl 201 Injection

Technetium Tc 99m Sestamibi Injection

Technetium Tc 99m Tetrofosmin Injection

Technetium Tc 99m Teboroxime Injection

Technetium Tc 99m NOEt

PET RADIOPHARMACEUTICALS

PET Perfusion Agents

Ammonia N 13 Injection

Rubidium Chloride Rb 82 Injection

Water O 15 Injection

PET METABOLISM AGENTS 5 Fludeoxyglucose F 18 Injection

Carbon C 11 Palmitate

Sodium Acetate C 11 Injection

VIABILITY ASSESSMENT

BLOOD POOL IMAGING AGENTS

Technetium Tc 99m Red Blood Cells

In Vitro Method

In Vivo Method

Modified In Vivo Method

Labeling Mechanism of Tc Red Blood Cells

GATED EQUILIBRIUM RADIONUCLIDE VENTRICULOGRAPHY

INFARCT-AVID IMAGING AGENTS

Technetium Tc 99m Pyrophosphate

Indium In 111 Imciromab Pentetate

Technetium Tc 99m Glucaric Acid

Technetium Tc 99m Annexin V

REFERENCES

QUESTIONS

6 PRIMER ON CARDIAC IMAGING

By Richard J. Kowalsky, Pharm D, BCNP, FAPhA University of North Carolina

In more recent years positron emission INTRODUCTION tomography (PET) imaging has commanded Cardiac imaging has played a key role in a greater role in cardiac imaging due to the the diagnostic workup of patients with heart establishment of cyclotrons in regional nu- disease. The use of radiotracers in nuclear clear pharmacies and PET cameras in nu- medicine for the diagnosis of heart disease clear medicine facilities. Fluorodeoxyglu- began its major development in the 1970’s. cose labeled with fluorine-18 (18F-FDG) is a During this time agents were introduced for glucose metabolism agent which is princi- infarct-avid imaging and myocardial perfu- pally used for assessing myocardial viabil- sion imaging. Initially, infarct-avid imaging ity, while 13N-ammonia and 82Rb-rubidium 99m with Tc-pyrophosphate, was widely used. chloride are used for measuring myocardial It provided an important contribution to the perfusion. Other PET agents, such as 11C- workup of patients who sustained an acute acetate and 11C-palmitate, are used in the cardiac event because at the time there was a assessment of myocardial metabolism. lack of sensitive diagnostic tests for identify- The radiopharmaceuticals for heart im- ing MI. Today, serum enzyme assays, such aging fall into four main groups (1) blood as CK-MB, myoglobin, and troponin, can flow agents to evaluate coronary artery provide the necessary information soon after blood flow and ischemia, (2) blood pool the MI event. While infarct-avid imaging in agents to evaluate heart function, (3) infarct- nuclear medicine has declined over the avid agents for myocardial infarction, and years, perfusion imaging has expanded. (4) metabolism agents to assess myocardial 201 Thallous chloride Tl was introduced for viability and metabolic processes (Table 1). myocardial perfusion imaging in 1975 and has remained an important radiopharmaceu- MYOCARDIAL IMAGING tical for this application despite the later in- The goals of cardiac imaging in nuclear troduction of 99mTc-labeled complexes. medicine are broad, encompassing the as- 99mTc-sestamibi and 99mTc-tetrofosmin are sessment of the cardiac chambers, myocar- currently the major myocardial perfusion dial perfusion, metabolism, and infarction, agents used in single-photon emission com- with the major focus in current practice on puted tomography (SPECT) imaging. While the assessment of myocardial perfusion and these agents have significant imaging advan- ventricular function. Measurement of re- tages over thallium, such as improved image gional myocardial perfusion in humans has resolution and the ability to assess ventricu- clinical applicability for identifying ische- lar function, thallium is still used for myo- mia, defining the extent and severity of dis- cardial perfusion imaging and has an impor- ease, assessing myocardial viability, estab- tant role in the assessment of myocardial lishing the need for medical and surgical viability with SPECT. intervention (revascularization), and moni- toring the effects of treatment.

7 Table 1. Myocardial Imaging Agents SPECT Agents Application 99mTc-Red Blood Cells Blood Pool Markers 99mTc-Pyrophosphate Infarct Avid Agents 111In-Imciromab Pentetate* 99mTc-Glucaric Acid 99mTc-Annexin V 201Tl-Thallous Chloride Perfusion Agents 99mTc-Sestamibi 99mTc-Tetrofosmin 99mTc-Teboroxime* 99m Tc-Nitrido dithiocarbamate [Tc-N-(NOEt)2] PET Agents Application 82Rb-Rubidium Chloride Perfusion Agents 15O-Water 13N-Ammonia 11C-Acetate Metabolism Agents 11C-Palmitate 18F-Fludeoxyglucose (FDG) * No longer marketed in the U.S. (Reprinted by permission from Radiopharmaceuticals in Nuclear Pharmacy and Nu- clear Medicine. © 2004 by the American Pharmacists Association).

The majority of clinical nuclear medi- lumen diameter eventually predisposes one cine studies today use SPECT methods for to myocardial ischemia, a condition where data acquisition; however, PET is increasing coronary blood flow decreases to a level be- as centers with these capabilities become low that needed to meet oxygen demand. In established. Approximately 30 to 60% of all advanced ischemic CAD, where blood flow nuclear medicine procedures involve cardiac and tissue oxygenation is so low that it can- studies. The majority (~84%) of these studies not sustain cardiac function at rest, myocar- involve myocardial perfusion imaging, 15% dial infarction results and the affected tissue are for radionuclide ventriculography, and the dies. Clinically, it is important to distinguish remainder are for miscellaneous studies, e.g., between ischemic and infarcted myocardium infarct imaging and metabolism studies.1 because ischemic, and therefore, viable Myocardial perfusion imaging provides in- myocardium can be restored to health by formation regarding coronary artery blood medical and surgical intervention. flow, an indirect measure of oxygenation and Resting myocardial blood flow to most metabolism in the myocardium, while ven- regions of the left ventrical ranges from 0.6 triculography studies provide information to 0.8 mL/min/g.3 At rest, the oxygen extrac- about cardiac function. tion efficiency of the heart is about 70%, compared with 20% for skeletal muscle.4 MYOCARDIAL BLOOD FLOW Consequently, an increased myocardial oxy- Coronary artery disease (CAD) arises gen demand necessitates increased coronary principally from a gradual narrowing of blood flow. Coronary blood flow can in- coronary arterial lumen due to atheroscle- crease in almost direct proportion to the rotic deposits. The progressive narrowing of metabolic consumption of oxygen by the 8 heart. Under normal conditions and follow- amounts going to those regions of the myo- ing appropriate stimuli, such as exercise or cardium supplied by stenosed coronary ves- the administration of specific pharmacologic sels due to their limited vasodilatory reserve agents, blood flow can increase 5 to 6 fold, (Figure 1).8 The basis for detecting CAD or up to 3 to 4 mL/min/g3. However, in the with cardiac stress imaging is founded on clinical setting with healthy volunteers and the ability to detect the difference in blood patients, maximal induced flows are typi- flow between well-perfused and poorly-per- cally in the range of 2 to 4 times baseline.5-7 fused myocardium. Early on it was shown The difference between baseline flow and with 201Tl-thallous chloride that imaging de- maximal flow is known as coronary flow fects are detectable during induced hypere- reserve. This reserve is progressively lost as mia when flow into normal coronary vessels vessels become stenosed and hardened by exceeds that into stenotic vessels by a ratio atherosclerosis. of 2.4 or greater.9 The methods for inducing Studies in dogs have shown that resting cardiac stress used in nuclear medicine im- coronary blood flow does not change until aging procedures are capable of achieving coronary arterial stenosis exceeds 85%, this blood flow differential. whereas maximal coronary blood flow begins to decrease when stenosis exceeds VIABILITY 45%.8 Thus, only the most severe coronary Myocardial cells are considered to be obstruction will likely be detected by perfu- nonviable when some basic aspect of cell 8 sion imaging under resting conditions. It fol- behavior no longer functions. The uncor- lows then that assessment of regional myo- rected progression of atherosclerosis and cardial perfusion under conditions of cardiac myocardial ischemia can result in electrical stress would substantially increase the sen- conduction abnormalities with loss of con- sitivity for detecting obstructive CAD. In- tractile function in the affected tissue. How- deed, perfusion abnormalities can be de- ever, the loss of functional integrity can be tected in patients whose coronary arterial reversed if blood flow is restored to the lumen diameter is reduced by 50%, but pa- ischemic regions of viable myocardium. tients are usually asymptomatic.1 When lu- Two primary cellular functions can be used men diameter is reduced by 70%, however, to measure viability: membrane ion trans- 8 clinical symptoms of chest pain (angina) be- port and intermediary metabolism. Under come evident during myocardial stress be- normal circumstances the Na-K-ATPase cause tissue oxygenation is temporarily be- membrane pump maintains cell function and low that required for myocardial function. volume by maintaining high extracellular + + Therefore, nuclear medicine procedures are Na and high intracellular K concentrations 9 typically conducted in conjunction with car- (Figure 2). During ischemia it is believed diac stress, induced either by exercise or that the energy available for the pump is de- + - through the use of pharmacologic agents, to creased so that Na , along with Cl and wa- + identify regions of subcritical coronary arte- ter, accumulate within the cell, while K rial stenoses that may be candidates for leaks out into the extracellular space. This reperfusion. process decreases the intracellular-extracel- + During maximal coronary artery dilata- lular K concentration differential and pro- tion following exercise or pharmacologic duces a marked effect on membrane polarity stress, a greater portion of the increased and cardiac muscle function. This disparity blood flow to the heart goes to normally per- in ion shift forms the basis for using potas- 201 + 82 + fused myocardial regions, with lesser sium analogs such as Tl and Rb for imaging. These agents participate in the ion 9 Figure 1. Schematic representation of the Figure 2. Diagrammatic representation of principle of rest/stress myocardial perfu- sodium, potassium, and calcium ion trans- sion imaging. (Top) Two branches of a coro- port between myocyte cytoplasm and inter- nary artery are shown; one is normal (left) and stitial fluid demonstrating alterations in ion one has a significant stenosis (right). (Middle) concentration in normal and necrotic cells. Myocardial perfusion images of the territories (Reprinted by permission, from Radiopharma- supplied by the two branches. (Bottom) Sche- ceuticals in Nuclear Pharmacy and Nuclear matic representation of coronary blood flow in Medicine. © 2004 by the American Pharma- the branches at rest and during stress. At rest, cists Association). myocardial blood flow is equal in both coro- Normal Heart Cell Diseased Heart Cell nary artery branches. When a myocardial radiotracer is injected at rest, uptake is homo- + Na + Na-K ATPase K H2 O + geneous (normal image). During stress, coro- + K Na Pump Cl- nary blood flow increases 2.0 to 2.5 times in + K + the normal branch, but not to the same extent Na + Na + in the stenosed branch, resulting in heteroge- K neous distribution of blood flow. This hetero- ++ -7 ++ geneity of blood flow can be visualized with Ca 10 M Ca 201Tl, 99mTc-sestamibi or 99mTc-tetrofosmin as HA Crystals an area with relatively decreased uptake (ab- -3 ++ 10 M normal image with a myocardial perfusion Ca Ca++ defect). (Modified from original and reprinted by permission of the Society of Nuclear Medi- transport process similar to potassium and cine from: Wackers FJTh. Exercise myocar- are able to assess membrane integrity and dial perfusion imaging. J Nucl Med 1994;35: cellular viability.8 726-29.) Under resting conditions the myocardium derives the majority of its energy by the aerobic metabolism of fatty acids.9 More than 95 percent of the energy liberated during metabolism is in the form of ATP. How- ever, during hypoxia or ischemia, glucose becomes an important source of energy. There are several functions involved in intermediary metabolism that can be exploited for assessing myocardial viability. They include glucose utilization measured by FDG uptake, fatty acid metabolism measured by 11C-palmitate uptake, and oxygen consumption measured by 11C-acetate uptake.10 Each of these agents has been used with PET, but the most useful of them is FDG. Thallium, as a membrane viability agent has been compared with FDG as a metabolism marker and these agents were shown to be equivalent for assessing myocardial viability under the proper conditions.11

10 CARDIAC STRESS METHODOLOGY the patient’s age in years) and a double- Two conditions are required for valid product (heart rate x systolic BP) of ≥ measurement of coronary blood flow deficit: 25,000. Heart rate13 and double-product14 (1) maximum coronary blood flow and, (2) have been shown to increase linearly with use of a radiotracer whose myocardial ex- workload, and coronary blood flow is traction is proportional to coronary artery closely related to the double-product.15 In blood flow. The key aspect of perfusion im- general, exercise stress under this protocol aging is the induction of a disparity of flow increases blood flow to about 2 times the between well perfused and poorly perfused resting flow which is adequate for diagnostic myocardium. Under these circumstances, evaluation. Exercise stress provides impor- radiotracer uptake will be increased in nor- tant prognostic information. Experience has mally perfused regions of the heart whereas shown that patients with CAD have a better regions supplied by stenosed arteries will survival rate if they can exercise longer than demonstrate a decreased uptake of radio- Stage IV of the Bruce protocol, achieve a tracer (Figure 1). The current methods em- heart rate >160 bpm at peak exercise, and ployed to achieve maximal coronary dilata- show no ST-segment depression on an exer- tion are intense exercise or administration of cise ECG.16 pharmacologic agents that increase blood A maximal increase in coronary blood flow either through coronary vasodilatation flow following exercise may be difficult to or increased cardiac output. achieve clinically because patients suspected of having heart disease often cannot achieve Exercise Stress the intense level required to produce maxi- Exercise is a natural method of stress mal coronary dilatation. Additionally, exer- that increases cardiac work and metabolic cise cannot be used in some patients for rea- demand on the heart. When challenged by sons such as claudication, cerebrovascular an increased physical workload, segments of accidents, arthritis, amputation, severe anxi- the myocardium perfused by stenotic arter- ety, or current use of beta-blocking medica- ies are likely to become ischemic because of tions. inadequate blood flow to meet oxygen demand. Ischemic cells lose their ability to re- Pharmacologic Stress tain ion-transport radiotracers (e.g., 201Tl+) An alternative to exercise stress is phar- because of altered membrane integrity. macologic stress with agents such as Therefore, ischemia is readily detected fol- dipyridamole, adenosine, or dobutamine lowing exercise because less tracer is local- (Figure 3).17-22 Dipyridamole and adenosine ized in these regions due to reduced tracer are coronary vasodilators. Following ad- delivery (low blood flow) and reduced tracer ministration of either of these agents, normal extraction (leaky cells). vessels dilate maximally while stenosed, In general, treadmill exercise is used ac- non-compliant vessels fail to dilate suffi- cording to the modified Bruce protocol.12 ciently, creating a pefusion deficit. Hence, a The method increases the speed and grade of heterogeneity of blood flow to the heart is the exercise in a stepwise manner to achieve created relative to the severity of CAD. the required workload on the heart. The de- Maximal coronary dilatation is more consis- sired endpoints are an age-related heart rate tently achieved with these agents than with ≥ 85% of maximal predicted rate (220 minus exercise.

11 Figure 3. Chemical structures of caffeine short, reported to be between 4 and 10 sec- 24,25 and the pharmacologic interventional agents onds. adenosine, dipyridamole, and dobutamine. Adenosine’s stimulatory effect is (Reprinted by permission, from Radiophar- blocked by methylxanthine compounds such maceuticals in Nuclear Pharmacy and Nu- as caffeine, theophylline, and aminophyl- 26 clear Medicine. © 2004 by the American line. Food or beverages containing caffeine Pharmacists Association). or methylxanthine medications must be dis- continued for at least 12 hr prior to adeno- CH3 HO O N N sine administration. Patients taking oral HO CH2-CH2-NH-CH-CH2-CH2 OH N N CH H C 3 dipyridamole should discontinue this medi- 3 CH O 3 Dobutamine cation for 12 hours before adenosine stress Caffeine testing because of potentiation.18 NH 2 Adenosine also causes a slowing of elec- N N N N CH2-CH2-OH trical conduction through the atrioventricular N HO-CH -CH N N N 2 2 CH -CH -OH N N 2 2 node, potentially causing mild to severe O HO-CH -CH N HOCH 2 2 N 2 heart block. Thus, the use of adenosine (and HO OH dipyridamole) in patients with these condi- Adenosine Dipyridamole tions should be approached with caution or may be contraindicated.27 Adenosine has Dobutamine is a predominant beta-1 been shown to cause bronchospasm in asth- agonist, increasing heart rate and myocardial 22 matic patients. Both dipyridamole and contractility and systolic blood pressure. adenosine are contraindicated in these pa- Consequently, dobutamine increases myo- tients.28,29 cardial oxygen demand, being more akin to For cardiac imaging, adenosine is exercise. Normal coronary arteries dilate to administered at a standard dosage of 0.14 increase perfusion in order to meet the de- mg/kg/min for a total of 6 minutes (Figure mand while stenotic arteries may not be able 4). The radiotracer is injected 3 minutes into to increase flow to the same degree as nor- the infusion when maximum vasodilation is mal vessels, creating a perfusion deficit predicted. Adenosine infusion is continued similar to exercise stress. for 3 additional minutes to facilitate tracer uptake and localization in the myocardium Adenosine under the stress condition. Following cessa- Adenosine is an endogenous nucleoside tion of the adenosine infusion, imaging can present in all cells of the body including the begin within a few minutes with 201Tl, or at myocardium. In the heart it is involved with later times (30 to 60 minutes) with 99mTc- the autoregulation of coronary artery blood sestamibi or 99mTc-tetrofosmin, to allow for flow. It is produced by enzymatic dephos- hepatobiliary clearance of these agents.30 phorylation of ATP by 5′ nucleotidase. It Thallium imaging must commence and be has been shown that interstitial concentra- completed before significant redistribution tions of adenosine rise in response to in- occurs, whereas the 99mTc agents are more creased metabolic oxygen requirements or firmly fixed in the heart and imaging can ischemia in the heart.23 Adenosine readily begin once background activity clears. With diffuses into the interstitial space where it the standard dosage of adenosine, it is re- causes vasodilation by activating receptors ported that 84% of normal patients achieve on coronary endothelial cells and by increas- an average coronary vasodilation equal to ing intracellular cAMP. Its half-life is very 4.4 times the resting coronary blood flow. 23

12 Figure 4. Adenosine dosing, radiotracer Figure 5. Dipyridamole dosing, radiotracer injection, and imaging protocol during injection, and imaging protocol during pharmacologic stress imaging. (Reprinted by pharmacologic stress imaging. (Reprinted by permission, from Radiopharmaceuticals in permission, from Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine. © Nuclear Pharmacy and Nuclear Medicine. © 2004 by the American Pharmacists Associa- 2004 by the American Pharmacists Associa- tion). tion).

Adenosine Start Imaging Dipyridamole Start Imaging 140 ug/kg/min 201Tl 99mTc-MIBI 140 ug/kg/min Wait 201Tl 99mTc-MIBI

/ / / / (min) 0 3 6 9 60 (min) 0 4 7 9 12 60

Inject Tracer Inject Tracer Dipyridamole Technetium-99m agents have more uptake in the splanchnic bed than 201Tl.17 An Dipyridamole increases plasma adeno- intervention to reduce this uptake is mild sine levels indirectly by inhibiting adeno- hand-grip exercise or walking, which stimu- sine’s metabolism. The standard dosage of lates the release of catecholamines that will dipyridamole is 0.56 mg/kg administered reduce sphanchnic blood flow and activity over 4 minutes. Because its action is indi- accumulation in this area when dypyrida- rect, dipyridamole is predicted to achieve its 17 mole is used. maximum dilator effect 6 to 8 minutes after the start of infusion. This dilator effect is Dobutamine sometimes indicated by a drop in blood pressure and a rise in heart rate.31 It in- Being principally a beta-1 agonist, dobu- creases coronary blood flow about 4 times tamine causes a combined positive iono- baseline, similar to adenosine. The radio- tropic and chronotropic effect on the myo- tracer should be injected when maximal ef- cardium, increasing contractility and oxygen fect is anticipated, about 7 minutes after the demand and causing coronary vasodilation. start of infusion (Figure 5). Imaging with A general imaging protocol is to administer 201Tl is begun at about 12 to 15 minutes the dosage slowly, ramping up in 10 from the start of infusion and at later times µg/kg/min steps every 3 minutes for 12 min- (approximately 60 minutes) with 99mTc- utes to a maximal dose of 40 µg/kg/min sestamibi or 99mTc-tetrofosmin. The plasma (Figure 6).22 The radiotracer is injected 1 half-life of dipyridamole is about 30 min- minute after the highest dose is begun (~ 10 utes.28 Therefore patients must be monitored minutes from start of infusion) and the following administration of dipyridamole for dobutamine infusion is continued for 2 min- about 20 minutes because ischemia may be utes while tracer is localizing in the myocar- induced.17 Some institutions routinely ad- dium. If heart rate is less than 85% of the minister 50 to 100 mg of aminophylline in- predicted rate after the maximal dose of travenously 5 minutes after tracer injection dobutamine, atropine 0.2 to 1 mg IV may be to reduce the incidence of dipyridamole- administered.32 32 Imaging with 201Tl is be- induced ischemia. If a patient complains of gun at about 3 minutes following cessation shortness of breath or wheezes, dipyridamole of infusion while imaging with 99mTc agents administration should be halted and amino- is begun in 60 minutes. The plasma half-life phylline administered immediately.17 of dobutamine is 2 minutes. 13 Figure 6. Dobutamine dosing, radiotracer and both agents are contraindicated in asthma injection, and imaging protocol during and COPD. pharmacologic stress imaging. (Reprinted by permission, from Radiopharmaceuticals in Table 2. Percent of Reported Side Effects Nuclear Pharmacy and Nuclear Medicine. © of Pharmacologic Agents 2004 by the American Pharmacists Associa- Dipyrida Dobuta- Effect Adenosinea tion). moleb minec

Inject Start Imaging Flushing 36.5 3.4 14 Tracer 201Tl 99mTc-MIBI Dyspnea 35.2 2.6 14 Dobutamine Chest Pain 34.6 19.7 31 µg/kg/min 10 20 30 40 0 / / Gastroin- 14.6 5.6 - (min) 0 3 6 9 12 15 60 testinal Headache 14.2 12.2 14 Precautions, Side Effects, and Contraindica- Dizziness 8.5 11.8 4 tions Palpitation - - 29 Adenosine, dipyridamole, and dobuta- Data from; a. Ref 34; b. Ref 32; c. Ref 35 (Reprinted by mine are potent pharmacologic agents that permission from Radiopharmaceuticals in Nuclear Phar- should be administered with caution and full macy and Nuclear Medicine. © 2004 by the American Pharmacists Association). awareness of their side effects and potential toxicities. Blood pressure, heart rate, and a 12-lead ECG should be monitored continu- The distribution of cardiac output to various organs is different with adenosine ously. An electronic infusion pump should 2 be used to administer these agents to provide and dipyridamole than with exercise stress. precise control.33 The relative blood flow to abdominal viscera The relative merits of adenosine and increases with these agents, whereas with 34 exercise it decreases. Thus, perfusion imag- dipyridamole have been compared and their 99m 35-37 ing agents, particularly Tc-sestamibi and adverse effects have been reported. The 99m most common side effects of dipyridamole Tc-tetrofosmin, will tend to accumulate and adenosine are chest pain, headache, diz- in the liver and spleen areas to a greater ex- ziness, flushing, dyspnea, ST-T changes on tent with adenosine and dipyridamole than ECG, and ventricular extrasystoles. Other with exercise. This visceral activity may interfere with assessing perfusion of the infe- effects occurring with less incidence include 2 nausea, hypotension, and tachycardia (Table rior wall of the left ventricle. Additionally, 2). These effects are related to the plasma adenosine and dipyridamole will not work level of vasodilator and may be readily re- effectively if patients have taken caffeine or versed, in the case dipyridamole by giving other methylxanthine substances as noted intravenous aminophylline (50 to 100 mg above and these substances are contraindi- IV), or for adenosine by simply stopping the cated for vasodilator studies. infusion because of its short plasma half-life. Dobutamine is not affected by caffeine Because of dipyridamole’s long half-life pa- or methylxanthine drugs and is an alterna- tients who receive it should be monitored for tive if adenosine or dipyridamole are contra- potential drug-induced ischemia before being indicated. The principal side effects of dobutamine are chest pain, palpitation, headache, released from the nuclear medicine depart- 38 ment. Adenosine and dipyridamole should be flushing, and dyspnea (Table 2). These ef- used with caution in patients with heart block fects should readily abate with cessation of the infusion. However, the beta-1 blocking 14 agent esmolol should be available if prob- Retention of activity is a function of tracer lems arise. Its recommended loading dose is back-diffusion and binding to myocytes. 0.5 mg/kg/min for 1 minute followed by Each of these processes can be affected by 0.05 mg/kg/min for 4 minutes as a mainte- disease. The mechanism of localization of nance dose. Dobutamine is contraindicated perfusion imaging agents is different and for the same conditions that apply to exer- will be discussed later in the text. While cise stress. thallium is taken up by active transport via the Na-K-ATPase membrane pump, it is re- MYOCARDIAL EXTRACTION tained longer than potassium. Thallium is not The principal uptake mechanisms of bound to myocytes and eventually diffuses perfusion tracers are active transport, via the back out of these cells proportional to blood Na-K ATPase pump by monovalent cations, flow.44 Technetium-99m-labeled sestamibi, as and passive diffusion of lipophilic com- a lipophilic mono-valent cation, is taken up pounds. A primary requirement for a useful into myocytes by passive diffusion associated myocardial perfusion tracer is high extrac- with negative plasma and mitochondrial tion efficiency proportional to blood flow membrane potentials. Sestamibi retention is over the range of flows seen clinically and dependent on maintenance of these mem- heart retention long enough to conduct im- brane potentials.45 Technetium-99m tetro- aging studies. Myocardial extraction versus fosmin uptake is also associated with mem- flow has been measured for several perfu- brane potential-driven transport mechanisms 39-41 sion tracers. Most diffusible tracers used and its retention is long. clinically have extraction fractions that decline as blood flow increases because the SPECT RADIOPHARMACEUTICALS time available for tracer exchange at the Myocardial perfusion imaging agents, or capillary surface is shortened. Thus, tracer “cold spot” markers, demonstrate decreased uptake becomes diffusion-limited at higher accumulation of activity in poorly perfused flows.40-43 This diffusion limitation, how- regions of myocardium. Early on, several ever, does not present a problem with the radioisotopes of potassium and its monova- clinical use of flow markers in nuclear medi- lent cation analogs were investigated for cine procedures. myocardial perfusion studies.46 Potassium- Once a radiotracer is localized it must 43 had the disadvantages of beta particle remain fixed for the period of time required decay and high photon energy (619 keV) for imaging, otherwise a correction must be that degraded image resolution. Of the po- made for back-diffusion of tracer. For ex- tassium analogs, 201Tl gained clinical accep- ample, imaging with 201Tl must be com- tance because it has rapid blood clearance, pleted within about 45 minutes following high myocardial extraction, and a reasonable injection because of its redistribution over shelf-life. However, its low-energy photons time. 99mTc-teboroxime requires completion produce poor quality images compared to of imaging within 10 to15 minutes of injec- 99mTc agents, and its long retention time in tion due to rapid back-diffusion. However, the body limits the amount of activity that this agent is no longer marketed. Techne- can be administered safely. tium-99m-labeled sestamibi and tetrofosmin The limitations of thallium led to the de- have relatively long myocardial retention, velopment of 99mTc-labeled complexes that which is an advantage if repeat imaging is would allow administration of larger required. amounts of activity with improved image Uptake of activity by the myocardium is quality and lower radiation dose. Early stud- a function of tracer delivery and extraction. ies with 99mTc-DMPE, a phosphine com- 15 pound, demonstrated that this complex could minutes in the resting state and by 5 minutes image the human myocardium but intense during exercise stress. In humans about 4% liver uptake obscured the cardiac apex. of the injected dose (ID) is localized in the Heart-to-liver ratios in man were much less heart. The heart activity is sustained long than in the dog, creating inferior images to enough after exercise stress so that imaging those obtained with thallium. In 1982 Jones can be performed, but by 30 minutes after prepared 99mTc-sestamibi.47 This stable Tc(I) injection thallium’s rate of release from the complex was easy to prepare, and achieved heart parallels the loss of activity from the myocardial uptake proportional to blood blood pool. Consequently, redistribution of flow when compared to 201Tl.48 Techne- thallium activity from the heart requires that tium-99m-teboroxime was developed in imaging be completed within this time frame 1989.49 It is a complex of Tc(III) known as a following radiotracer injection.The half-life boronic acid adduct of technetium dioxime from the heart following intravenous injec- (BATO). The complex is neutral and lipo- tion in clinical studies is 4.5 to 8 hours.44 philic with very high extraction by the myo- Under normal coronary blood flow thal- cardium proportional to blood flow. How- lium’s extraction fraction is about 85%. ever, its rapid washout presented logistical However, its extraction is not proportional problems for imaging. 99mTc-sestamibi and to blood flow, being only 60% higher when 99mTc-teboroxime were approved for routine blood flow is increased 3 to 4 times normal use by the Food and Drug Administration following dipyridamole53 or adenosine54 (FDA) in December 1990. Subsequently, administration. Nonlinear extraction begins 99mTc-tetrofosmin was developed and ap- to occur when blood flow is increased 2 to proved for use by the FDA in 1996. It is a 2.5 times normal, which is about the level phosphine complex of Tc(V), that exhibits that flow increases with exercise stress dur- similar biological properties to 99mTc- ing thallium imaging.53 sestamibi.50,51 The sestamibi and tetrofosmin Total body elimination of thallium is agents were shown to be comparable to slow, with a biologic half-time of 10 days.52 201Tl-thallous chloride in myocardial perfu- Only about 5% is excreted in the urine by 24 sion imaging but their heart activity was hours accompanied by insignificant fecal fixed and did not show redistribution as did excretion. These factors plus the long physi- thallium. Thus, while a thallium stress-rest cal half-life (73 hours) are undesirable prop- imaging protocol can be accomplished with erties of 201Tl and contribute to its high ra- one dose of thallium because of its redistri- diation absorbed dose. The critical organs bution in the myocardium, two separate are the thyroid (2.3 rad(cGy)/mCi) and the doses of the technetium agents must be ad- testes (3 rad(cGy)/mCi). The effective dose ministered, one at stress and one at rest. is 1.3 rad(cGy)/mCi injected. Following transcapillary diffusion from Thallous Chloride Tl 201 Injection blood into the interstitial space, thallium is Thallium is a potassium analog localiz- taken up into myocytes by the membrane- ing in the heart in proportion to myocardial bound sodium/potassium ATPase pump due blood flow. Following intravenous admini- to a monovalent cationic charge and hy- 201 stration Tl disappears rapidly from the drated ionic radius similar to K+.54 While blood. In the resting state, 90 percent of the there is a close relationship between thal- plasma activity disappears by 20 minutes, lium uptake and blood flow, adequate tissue but under stress the same percentage of ac- oxygenation to support cellular metabolism 52 tivity disappears by 1.5 minutes. Maxi- is also required for uptake.55 A significant mum myocardial uptake occurs in 10 to 30 16 reduction in blood flow and an oxygen defi- apparent irreversible defects were able to cit leading to necrosis will impair this cellu- achieve restored perfusion following myo- lar uptake function. Since thallium uptake is cardial revascularization procedures. Thus, dependent on adequate blood flow for its although late imaging improved diagnosis, it delivery to the myocardium and active still overestimated the frequency and sever- transport across an intact sarcolemma, it is ity of myocardial fibrosis.61 well suited as a marker of myocyte viability. To improve specificity, a thallium rein- Thallium has been used as a marker of jection technique was introduced to increase myocardial perfusion and viability for many plasma levels of thallium during the redistri- years beginning in the mid 1970s.56 The first bution phase of the study. Reinjection of 1 thallium procedures were conducted with mCi (37MBq) of 201Tl, either after the stan- two separate injections; one injection for the dard 3- to 4-hour redistribution study or af- exercise stress study and one injection for ter a late 24-hour redistribution study, facili- the rest study. The rest study was conducted tates uptake of thallium into many viable 1 to 2 weeks after the stress study because of regions of myocardium with apparently irre- thallium’s long effective half-life in the versible defects. With this technique, up to body. The thallium procedure changed to a 49% of apparent irreversible defects on the 1-day protocol when it was observed that 4-hour redistribution study 62 and 39% of thallium redistributed in the heart over time. such defects on the 24-hour redistribution By 3 to 4 hours following an exercise study study 63 improved or showed normal uptake it was observed that normal myocardial re- after thallium reinjection. A number of stud- gions demonstrated a decrease in thallium ies have also shown the ability of thallium activity while ischemic regions increased in reinjection to predict improved ventricular activity.57 Subsequently, the standard proce- function following revascularization.62,64-66 dure became a one-day thallium protocol Thus, the thallium stress-redistribution-rein- (exercise study followed by a 3 to 4 hour jection protocol has become a standard pro- redistribution study) to differentiate ische- cedure for evaluating myocardial perfusion mia from infarction. This procedure was and viability. shown to provide an accurate assessment of A routine perfusion study with thallium myocardial viability when perfusion defects is conducted in two parts. One of two proto- on the exercise study showed redistribution cols is typically used, depending on the in- on delayed imaging. While this procedure formation required (Figure 7). If only viabil- had high sensitivity for predicting viability ity information is sought in a patient with of reversible defects, its specificity for pre- known CAD and left ventricular dysfunc- dicting non-viability of irreversible defects tion, a rest/redistribution protocol is pre- was found to be low.58,59 Incomplete redis- ferred with a quantitative method of reversi- tribution of thallium was believed to have bility assessment. If viability is questionable occurred on the initial redistribution image, on the 4 hour redistribution image, a repeat causing an overestimation of infarct size. image at 24 hours is often done. If inducible Henceforth, late (8 to 24 hour) redistribution ischemia and viability is the goal a stress- imaging was instituted to allow more time redistribution-reinjection protocol is pre- for thallium to redistribute.60 Kiat demon- ferred for assessment of the extent and se- strated that 61% of irreversible thallium de- verity of myocardial ischemia. Some institu- fects on 3- to 4-hour images reversed on late tions perform only a stress-reinjection pro- redistribution at 18 to 72 hours.61 However, tocol electing to skip the 4 hour redistribu- a high percentage of patients (37%) with tion image.

17 Figure 7. Thallium rest/redistribution imaging protocol and stress/redistribution/ reinjection imaging protocol. (Reprinted by permission, from Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine. © 2004 by the American Pharmacists Association). 201Thallium Rest / Redistribution Protocol

Rest Injection 2 to 4 mCi

REST REDISTRIBUTION SPECT SPECT // 0 15 min 35 min 240 min 260 min

201Thallium Stress / Redistribution / Reinjection Protocol

Stress Injection Rest Reinjection 2 to 4 mCi 1 mCi TM STRESS REDISTRIBUTION REST SPECT SPECT SPECT 0 // 10-15 min 180-240 min 15 min

In the rest-redistribution protocol the cise or by administration of a pharmacologic thallium dose is injected into a patient who agent (dipyridamole, adenosine, or dobuta- has fasted for at least 4 hours. Imaging is mine). Exercise stress should continue for begun 15 to 20 minutes post injection and 30 to 60 seconds following tracer injection proceeds for about 20 minutes. Perfusion to ensure heart uptake. Imaging should deficits seen on the resting study that reverse commence as soon as possible following on the 4-hour redistribution study may result tracer injection and by no later than 15 min- from clearance of 201Tl from normal regions utes. With pharmacologic stress, tracer in- and accumulation of 201Tl in the defect re- jection and the start of imaging should fol- gion during the redistribution phase. Re- low the protocols given in Figures 4, 5, and versiblity of perfusion deficits indicates vi- 6. Under these conditions, thallium ion will able myocardium. be extracted by the myocardium in propor- The first part of the stress-redistribution- tion to regional blood flow. Normally per- reinjection protocol is designed to produce fused myocardium will take up the radio- near maximal dilatation of the coronary ves- tracer well, whereas poorly perfused sels just prior to administration of the thal- (ischemic) or non-perfused (infarcted) myo- lium dose (2 to 4 mCi [74 to 148 MBq]). cardium will show decreased or absent Dilatation is achieved either through exer- radiotracer uptake, appearing as a perfusion

18 defect (Figure 8). After a 3- to 4-hour period verse, thallium reinjection is done to im- of rest the redistribution study is performed. prove specificity of the study (Figure 11). At this time the patient is re-imaged to as- The patient is reimaged 15 minutes follow- sess myocardial redistribution of the 201Tl ing the reinjection. The reinjection study can activity administered during the stress study. also be done the next day. A lack of reversi- Images of the heart are usually displayed in bility on the reinjection image would indi- three planes as short axis, vertical long axis, cate myocardial infarction (scar). and horizontal long axis views (Figure 9), with the stress images on top and the corre- Technetium Tc 99m Sestamibi Injection sponding rest images underneath. During the Technetium Tc-99m sestamibi (Cardio- rest phase, 201Tl ion redistributes in the lite™, Dupont) is a monovalent cationic myocardium, washing out of normally per- lipophilic complex comprised of a Tc(I) core fused myocardium well, but less well from coordinated by six monodentate, 2-methoxy- areas of compromised flow during the stress. isobutylisonitrile (MIBI) ligands (Figure Thus, the redistribution image of the heart 12). Since the MIBI ligands are neutral, the 99m will demonstrate “filling-in” of activity (re- Tc-sestamibi complex retains the single + versibility) in ischemic areas (Figure 10). positive charge of the Tc core. When a stress perfusion defect does not re-

Figure 8. Model of the left ventricle (short axis view) at stress and at rest following a 4-hour redistribution of thallium 201Tl in the normal heart, in heart with a region of significant stenosis, and in heart with a region of infarction. At stress, heart activity is at high count density in normal well perfused myocardium, at less density in stenotic regions that are poorly perfused, and absent in infarcted regions that are scarred. At rest (redistribution), normal myocardium washes out thallium more quickly than stenotic regions, appearing as a “filling in” of the stress defect in stenotic areas. A persistent defect remains in areas of infarct. (Reprinted by permission, from Radiopharma- ceuticals in Nuclear Pharmacy and Nuclear Medicine. © 2004 by the American Pharmacists Asso- ciation).

19 Figure 9. Cardiac tomography. Pictorial illustration of short-axis, vertical long-axis, and horizontal long-axis views of myocardial walls on SPECT imaging. (Reprinted by permission of Bristol-Meyers Squibb Medical Imaging).

Short Axis

Vertical Long Axis

Horizontal Long Axis

20 Figure 10. Adenosine stress and rest redistribution study following injection of 3 mCi (111 MBq) of 201Tl-thallous chloride. Horizontal long-axis views demontrate normal perfusion evi- denced by uniform uptake of activity throughout the left ventricle at stress and rest. Ischemia is noted by reduced perfusion and uptake of activity in the lateral ventricular wall during the stress image that fills-in at the 4-hour rest redistribution image. (Reprinted by permission, from Radiophar- maceuticals in Nuclear Pharmacy and Nuclear Medicine. © 2004 by the American Pharmacists As- sociation).

Normal

Stress Study 4-hr Redistribution

Ischemia

Figure 11. Adenosine 201Tl stress/rest/reinjection myocardial perfusion study. The top two rows of short axis images show the stress images (top row) and redistribution images (second row) obtained 4 hours later. The images demonstrate perfusion defects involving the septum and inferior walls of the heart with poor washout over the 4-hour period. Reinjection images (bottom row) were obtained 24 hours later just after reinjection with 1 mCi (37 MBq) 201Tl at rest. There is improvement in the septum and inferior walls consistent with ischemia and viable myocardium in these regions. (Reprinted by permission, from Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine. © 2004 by the American Pharmacists Association).

Stress

Redistribution

Reinjection

21 Figure 12. Chemical structures of various 99mTc-complexes used in mycocardial perfusion imaging. (Reprinted by permission, from Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine. © 2004 by the American Pharmacists Association).

R 1+ EtO OEt P P N EtO OEt R R O Tc O N C N C C EtO OEt P P Tc EtO OEt C C C 99mTc-(tetrofosmin) O + N N 2 2 R N R R N CH -CH O 3 2 N S S H CH3 Tc CH -CH C C CH2-CH3 3 2 H S S N O R = CH2 C CH3 OCH2-CH3

99m CH3 O Tc-N-(NOEt) CH 2 N 3 B 99mTc-Sestamibi O N N O Tc N N O H N O H O Cl 99mTc-Teboroxime

Technetium Tc-99m sestamibi (Cardio- The vial is allowed to cool 15 minutes lite, Dupont) injection is a sterile, aqueous before use. The labeled product is stored at solution prepared from a kit consisting of a 15 to 25°C and is stable for 6 hours. Its ra- lyophilized mixture of tetrakis (2-methoxy diochemical purity must be ≥ 90%. isobutyl isonitrile) Copper (I) tetrafluorobo- It is not uncommon for sestamibi kits to rate (1.0 mg), sodium citrate dihydrate (2.6 be compounded with amounts of 99mTc- mg), L-cysteine HCl monohydrate (1.0 mg), sodium pertechnetate activity greater than mannitol (20 mg), and stannous chloride di- the package insert limit, however this prac- hydrate (0.025 to 0.075 mg) sealed under tice should be appropriately validated. nitrogen. Following package insert instruc- Technetium-99m sestamibi is indicated 99m tions, Tc-sestamibi is prepared by adding for imaging the heart to assess myocardial 99m 25 to 150 mCi (925 to 5550 MBq) of Tc perfusion. Following intravenous injection, sodium pertechnetate in 1 to 3 mL to the kit 99mTc-sestamibi clears rapidly from the and mixing vigorously to dissolve the pow- blood and is extracted by the myocardium in der. The vial is then placed into a boiling proportion to blood flow up to 2.5 mL/min/ water bath for 10 minutes. During this time g, or approximately 3 times resting flow. Its the following reactions take place: extraction fraction at rest is about 65%.67 Step 1. About 1% of the ID localizes in the heart at 2+ rest and remains relatively fixed in the myo- TcO− +⎯⎯⎯ citrateSn →− Tc Citrate 4 cardium. The uptake of 99mTc-sestamibi is Step 2: 201 + about one-fourth that of Tl, but the admin- ⎡⎤Cu()( I MIBI )+− Tc Citrate ⎯⎯⎯heat → ⎡⎤ Tc ()( I MIBI ) 99m ⎣⎦46⎣⎦ istered activity of Tc-sestamibi is much higher (10 to 30 mCi [370 to 1110 MBq]), improving count density in the heart during

22 imaging. When compared to thallium’s low properties of 201Tl and 99mTc for myocardial photon energy (69 to 80 keV) the 140 keV imaging studies and Table 4 compares the photons of 99mTc-sestamibi have less tissue properties of myocardial perfusion imaging attenuation and produce sharper, higher con- agents. trast images. Table 3 compares the general

Table 3. Comparison of Tl-201 and Tc-99m for Myocardial Perfusion Imaging Property Thallium-201 Technetium-99m Photon Energy 69 – 80 keV 140 keV Scatter and absorption Less scatter and absorption Low resolution High resolution Half-life 73 hr 6 hr Low dosage (2 – 3 mCi) High dosage (20 – 30 mCi) Long collection times Short collection times Low count densities High count densities Effective Dose 1.3 rad(cGy)/mCi 1.1 rad(cGy)/mCi Availability Cyclotron-Commercial Mfr Generator-local First-pass Study No Yes (Reprinted by permission from Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine. © 2004 by the American Pharmacists Association).

Table 4. Myocardial Perfusion Imaging Agent Properties Property Tl-201 Chloride Tc-99m Sestamibi Tc-99m Tetrofosmin Chemistry +1 Cation +1 Cation +1 Cation Hydrophilic Lipophilic Lipophilic Shelf Life 6 days after calibration 6 hours 12 hours Photon Energy (abun- 68 – 80 keV (94%) 140 keV (88%) 140 keV (88%) dance) Uptake Mechanism Active Passive Diffusion (associ- Passive Diffusion (associ- Na-K ATPase Pump ated with intact membrane ated with intact mem- potentials) brane potentials) Extraction Fraction ~ 85% ~ 65% ~60% Heart Uptake ~ 4% ~ 1.2% ~ 1.0% (% Injected Dose) Administered Activity 2 – 4 mCi (74 - 148 10 – 30 mCi (370 – 1110 10 – 30 mCi (370 – 1110 MBq) MBq) MBq) Heart Distribution Redistributes Fixed (mitochondria asso- Fixed ciated) (cytosol associated) Effective Dose 1.3 rad(cGy)/mCi 0.056 rad(cGy)/mCi 0.041 rad(cGy)/mCi (Reprinted by permission from Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine. © 2004 by the Ameri- can Pharmacists Association).

23 Myocardial uptake studies indicate that take during exercise. The biologic half-life 99mTc-sestamibi enters the myocardium by is about 6 hours from the heart and ap- passive diffusion due to its lipophilicity and proximately 0.5 hr from the liver following is retained for a prolonged period of time. In rest or exercise.74 Thus, the heart-to-liver isolated, cultured chick myocytes, uptake ratios at 30, 60, and 120 minutes are 0.5 , was shown to be related to the integrity of 0.6, and 1.1, respectively after a rest injec- myocyte plasma and mitochondrial mem- tion, and 1.4, 1.89, and 2.3 after exercise brane potentials.68 Subcellular distribution injection. Therefore, rest imaging is best be- studies in rat heart demonstrate that ap- gun at 60 minutes or later after injection of proximately 90% of 99mTc-sestamibi is asso- 99mTc-sestamibi; however some practitioners ciated with mitochondria in an energy- shorten the dose-to-image time to 15 to 30 dependent manner as a free cationic com- minutes for SPECT exercise studies because plex.69 The attraction of 99mTc-sestamibi to of higher heart-to-liver ratios. Dose-to- mitochondria is promoted by a negative po- image time should be 45 to 60 minutes if tential generated in the mitochondrial mem- adenosine or dipyridamole stress is used to brane of viable myocytes, implying that allow more time for splanchnic activity to be 99mTc-sestamibi is a marker of myocardial cleared. viability and perfusion.68,69 Other studies The critical organ following a rest injec- show that the uptake of 99mTc-sestamibi by tion is the upper large intestinal wall (3.7 the heart is not affected by oubain. This rad(cGy)/20 mCi) and the effective dose is suggests that the localization in the myo- 1.11 rad(cGy)/20 mCi.75 cytes is not exclusively due to the action of Imaging with 99mTc-sestamibi is typi- the sodium/potassium ATPase membrane cally begun 60 minutes after a rest injection pump.70 and about 30 minutes after an exercise injec- In humans, the mean heart retention of tion. Because 99mTc-sestamibi does not re- 99mTc-sestamibi is 1 ± 0.4% of the ID 60 distribute appreciably, separate rest and minutes after intravenous injection at rest, stress injections are required to differentiate and 1.4 ± 0.3% following exercise.48 Activ- myocardial ischemia from scar. The study ity that is fixed in the myocardium demon- can be performed as a 2-day or a 1-day pro- strates insignificant redistribution.71-73 Fol- tocol. There is no significant difference in lowing intravenous injection, over 90% of diagnostic accuracy between these proto- 30,76 99mTc-sestamibi clears from the blood in less cols. With the 2-day protocol the patient than 5 minutes. Compared to 201Tl, 99mTc- is stressed, injected with 20 to 25 mCi (740 sestamibi blood levels immediately after in- to 925 MBq) and imaged. The rest study is jection are higher, presumably because of performed the next day with a similar dos- lower extraction, whereas late blood levels age. This protocol has appeal in a patient are lower, presumably because of the lack of whose pretest likelihood of CAD is low be- redistribution.48 Technetium-99m sestamibi cause the rest study can be cancelled if the 30 is excreted intact principally by the kidneys stress study is normal. If the 1-day proto- and the hepatobiliary system. By 24 hours, col is used, a rest-stress sequence is pre- urinary excretion is 30% and 24% of the ID ferred (Figure 13). This is the most common following rest and exercise studies, respec- procedure. A rest dose of 8 to 10 mCi (296 tively. By 48 hours fecal excretion is 37% at to 370 MBq) is injected and imaging is be- rest and 29% after exercise.48 The lower fe- gun in 45 to 60 minutes. Following the rest cal excretion after exercise is due to reduced dose image treadmill exercise is performed splanchnic blood flow and lower liver up- and a stress injection of 25 to 30 mCi (925

24 to 1110 MBq) is given followed by imaging dence of misinterpreting reversible defects in 15 to 30 minutes. The activity in the heart as fixed when compared with the rest-stress during the stress study overwhelms the re- procedure.77 This problem was ascribed to sidual activity from the rest dose because of stress dose crosstalk interfering with the the increased blood flow to the heart and the later resting study78 and to a lower count large stress dose administered. The 1-day density from the low-activity stress dose procedure may take up to 2 to 3 hours to administered.30 Therefore this procedure is complete depending on the time needed to not recommended, but if done should be re- acquire patient images. This protocol is use- served for those patients with a low prob- ful when a rapid diagnosis is needed espe- ability of disease in whom a normal initial cially in a patient with high pretest likeli- stress study is anticipated.78 hood of CAD, but may present a problem To improve patient throughput without with diabetic patients because of the pro- compromising diagnostic accuracy a dual- longed fasting requirements.30 If there are no isotope procedure has been developed (Fig- perfusion abnormalities during the stress ure 17).30 In this procedure, 201Tl is injected study, homogeneous uptake of radiotracer at rest and a 201Tl-SPECT acquisition is throughout the myocardium will be seen. In made. The patient is then stressed on a a normal study using a 99mTc agent, no per- treadmill and 25 to 30 mCi (925 to 1110 fusion abnormalities are seen on either the MBq) of 99mTc-sestamibi is injected. A stress or rest images (Figure 14). Myocardial SPECT stress image is then acquired 15 regions with relatively reduced radiophar- minutes after injection. The entire procedure maceutical uptake on the stress portion of can be completed in 1.5 to 2.0 hours. the myocardial perfusion study that normal- There are several advantages afforded by ize or partially normalize on the rest study 99mTc-sestamibi’s lack of redistribution. Im- represent regions of stress induced ischemia age acquisition can be repeated in the event associated with flow-limiting coronary ar- of a positioning error, patient motion, or in- tery disease (Figure 15). Myocardial regions strument malfunction. A second advantage with fixed perfusion defects on both the is the ability to inject a patient during an stress and rest portions of the exam can rep- acute ischemic event with imaging per- resent either scarring from prior myocardial formed later at a more convenient time. An infarction (Figure 16) or possibly an attenua- example of this is being able to rule out tion artifact usually caused by the diaphragm myocardial ischemia in patients with unsta- or breast. Since 99mTc-sestamibi (and 99mTc- ble angina who have spontaneous chest tetrofosmin) is fixed in the myocardium, a pain.79 Technetium-99m-sestamibi is in- gated SPECT study would allow evaluation jected at the time of pain. A few hours later, of fixed perfusion defects by examining when the patient has stabilized, a cardiac myocardial wall motion and thickening. scan is obtained. A normal scan strongly Fixed perfusion defects with associated suggests that the pain is not of coronary ori- normal wall motion and thickening are gin. An abnormal scan may suggest signifi- likely related to attenuation artifacts. Fixed cant coronary disease. A subsequent study in defects with abnormal focal wall motion ab- the absence of chest pain, demonstrating a normalities and decreased thickening are decrease in size of an initial perfusion de- generally associated with scar. fect, supports the diagnosis of a transient To improve patient throughput a 1-day coronary flow disturbance. Another example stress-rest procedure was initially proposed, involves the evaluation of acute infarction to however it was shown to have a higher inci- determine the amount of myocardium

25 Figure 13. 99mTc-sestamibi one-day rest/ stress imaging protocol. (Modified and reprinted by permission of the Society of Nuclear Medicine from: Berman DS, et al. Myocardial perfusion imaging with technetium-99m-sestamibi: comparative analysis of available imaging protocols. J Nucl Med 1994;35:681-688.)

99mTc-Sestamibi Rest / Stress Protocol

Rest Inj Stress Inj 8 - 10 mCi 25 - 30 mCi

REST STRESS SPECT TM SPECT

0 60 min 15 - 30 min

Figure 14. Normal 99mTc-sestamibi myocardial perfusion study. Images of the heart are shown in three planes. The top row represents short-axis views of the heart from apex on the left to mid-heart on the right at stress. Matching views on the rest portion of the study are shown on the next row. The third and fourth rows are continuation of the short axis views at stress and rest from the mid-heart to the base or valve plane. The next two rows (frames 29 – 37) are the vertical long axis views, stress on top and rest underneath. These views are from the septum on the left to the lateral wall on the right. The last two rows are the horizontal long axis views, stress on top and rest underneath. These views run from the inferior wall on the left to the anterior wall on the right. There are no significant perfusion defects seen either during stress or at rest to suggest flow-limiting coronary artery disease. (Re- printed by permission, from Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine. © 2004 by the American Pharmacists Association).

26 Figure 15. 99mTc-sestamibi study demonstrating myocardial ischemia. Short axis views at stress (top row) and at rest (bottom row). There are significant perfusion defects seen on the stress portion of the study that are not present at rest, consistent with multi-vessel flow-limiting coronary artery disease. (Reprinted by permission, from Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine. © 2004 by the American Pharmacists Association).

Figure 16. 99mTc sestamibi study demonstrating a fixed defect in the inferior wall both at stress and at rest. There was hypokinesis in the inferior wall on the gated images as well as decreased thickening in the inferior wall during systole most consistent with scarring from a prior myocardial infarction. (Reprinted by permission, from Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine. © 2004 by the American Pharmacists Association).

27 Figure 17. 201Tl/99mTc dual-isotope imaging protocol. (Reprinted by permission of the Society of Nuclear Medicine from: Berman DS, et al. Myocardial perfusion imaging with technetium-99m- sestamibi: comparative analysis of available imaging protocols. J Nucl Med 1994;35:681-688.) 201Tl / 99mTc – Dual-Isotope Protocol

Stress Inj Rest Inj 25 mCi 99mTc-Sestamibi 3 mCi 201TlCl REST STRESS Tl-201 Tc-MIBI SPECT TM SPECT

0 15 30 45 60 75 90 min

80 + 50 salvaged following thrombolytic therapy. (tetrofosmin)2O2] (Figure 12). Techne- In this situation the patient is injected upon tium Tc-99m tetrofosmin injection is a ster- admission, thrombolytic therapy is begun ile, aqueous solution prepared from a kit and imaging is performed within 4 to 6 containing a lyophilized mixture of tetro- hours to identify infarcted plus jeopardized fosmin (0.23 mg), stannous chloride di- myocardium at the time of the event. A re- hydrate (30 µg), disodium sulfosalicylate peat study at a later date identifies only in- (0.32 mg), sodium D-gluconate (1.0 mg), farcted myocardium. Analysis of the two and sodium bicarbonate (1.8 mg) sealed un- studies identifies the amount of muscle sal- der nitrogen. The kit is stored at 2 to 8°C vaged. before reconstitution. 99m A third advantage of Tc-sestamibi is Following package insert recommenda- the ability to evaluate myocardial perfusion tions the labeling of tetrofosmin is accom- and ventricular function with a single injec- plished by introducing a venting needle into tion of tracer by means of ECG gating. This the kit and adding up to 240 mCi (8880 permits the simultaneous evaluation of exer- MBq) of 99mTc sodium pertechnetate (in 4 to cise perfusion with resting ventricular func- 8 mL and not > 30 mCi (1110 MBq)/mL tion, allowing an estimation of myocardial concentration). This is followed by removal viability. An exercise perfusion defect with of 2 mL of gas from the vial to introduce air preserved regional wall motion at rest im- and incubation at room temperature for 15 plies ischemia, whereas regional akinesis minutes. During this time the following re- could be associated with either scar or se- action sequence occurs. verely ischemic or stunned myocardium.78 Tc-Gluconate TcO4 + Gluconate Technetium Tc 99m Tetrofosmin Injec- tion X X X X P P + Tc-Gluconate P P X X Technetium Tc-99m tetrofosmin (My- O Tc O X X X X + oview™, Amersham) is a monovalent cati- P P X X X = -CH -CH -O-Et onic lipophilic complex of the Tc(V) dioxo 2 2 core, O = Tc = O+, and two bis(2- ethoxyethyl)phosphino]ethane ligands [Tc- This reaction employs a gluconate transfer ligand to facilitate the complexation re- 28 action between the technetium oxo core and Approximately 66% of the injected activ- tetrofosmin. Since the tetrofosmin ligand is ity is excreted in 48 hours, with about 40% in neutral the 99mTc-tetrofosmin complex has urine and 26% in feces.84 The critical organ is an overall charge of 1+ from the O = Tc = the gall bladder wall with an absorbed radia- O+ core. The labeled product is stored at 2 to tion dose of 0.123 rad(cGy)/mCi (stress) and 25°C after technetium labeling and is stable 0.180 rad(cGy)/mCi (rest). for 12 hours. Its radiochemical purity must The mechanism of 99mTc-tetrofosmin up- be ≥ 90%. take in myocytes has been investigated. Data Technetium-99m tetrofosmin is indi- indicate that uptake is by a metabolism- cated for imaging the heart to assess myo- dependent process that does not involve cardial perfusion. Its application is similar to cation channel transport. The most likely that of 99mTc-sestamibi. Following intrave- mechanism for this is by potential-driven nous injection in humans 99mTc-tetrofosmin diffusion of the lipophilic cation across the clears rapidly from the blood and by 10 sarcolemmal and mitochondrial mem- 85 minutes post injection, less than 5% of the branes. Technetium-99m tetrofosmin ap- ID remains, with less remaining following pears to be associated more with the cytosol exercise.51 Uptake in skeletal muscle is the than within mitochondria whereas sestamibi main reason for high background clearance demonstrates a higher concentration within 86 after exercise. Following a rest injection, the mitochondria. Quantitative analysis of 99m heart activity declines slowly over time, be- Tc-tetrofosmin retention in the heart ing 1.2%, 1.0%, and 0.7% of the ID at 1, 2, demonstrates that washout is very slow and 4 hours, respectively. Values are slightly (4%/hour after exercise and 0.6%/hour after 87 higher after an exercise injection. Liver up- rest). Ischemic-to-normal myocardium ra- take at these same times are 2.1%, 0.9%, and tios of tetrofosmin ranged only from 0.75 to 0.3% of the ID. Heart-to-liver ratios at 30 0.72 from 5 minutes to 4 hours following and 60 minutes after dosing, respectively, injection, indicating insignificant redistribu- are 0.6 and 1.2 at rest and 1.2 and 3.1 after tion of this agent over time. Technetium- exercise, reflecting high and rapid hepatobil- 99m sestamibi, however, has been shown to iary clearance. The rapid clearance of 99mTc- exhibit a small degree of redistribution be- tetrofosmin from abdominal organs allows tween 1 and 3 hours of dosing due to faster 88 images to be performed soon after injec- clearance rates from normal segments. 99m tion.81 Ischemic-to-normal wall ratios with Tc- Tetrofosmin’s uptake in the heart is pro- sestamibi were statistically higher at 3 hours portional to coronary blood flow up to 2 (0.84) than at 1 hour (0.73), which may af- mL/min/g.82 This is similar to the uptake and fect the detection of CAD in cases where the flow relationship seen with 99mTc- ischemic defect is slight or mild. sestamibi72 and thallium.53 All of the SPECT agents underestimate flow at high flow rates Technetium Tc 99m Teboroxime Injec- and overestimate flow at very low flow tion rates, which is a function of the time tracer Technetium Tc-99m teboroxime (Car- is available for extraction.82 When compared dioTec™, Squibb Diagnostics) is a neutral, to thallium extraction in the rabbit heart, tet- lipophilic complex of the general class of rofosmin exhibits a myocardial extraction of compounds known as boronic acid adducts about 60% that of thallium while the heart of technetium dioxime (BATO). It is pre- uptake of both tracers is correlated with pared by the general method of template blood flow.83 synthesis wherein a metal ion serves as a template to organize the course of complex 29 multistep reactions.89 99mTc-teboroxime is teboroxime is not fixed in the myocardium unique from other 99mTc complexes in that and rapidly diffuses out shortly after injec- the ligand is not present preformed in the kit tion. Its myocardial kinetics are so rapid that before addition of pertechnetate, but is imaging must be started within 2 minutes of formed around technetium as the template tracer injection and be completed by 6 to 9 atom. The essential reactants in the kit are minutes postinjection.91 While imaging pro- cyclohexanedione dioxime, chloride as the tocols have been worked out to successfully axial ligand, and methyl boronic acid along conduct perfusion imaging with 99mTc- with stannous chloride and other adjuvants. teboroxime, logistical problems hamper its The 99mTc-labeled complex is prepared by practical usefulness. Presently, the product is heating the kit reactants with up to 100 mCi no longer on the market. (3700 MBq) of 99mTc sodium pertechnetate in a volume of 1 mL for 15 minutes at Technetium Tc 99m NOEt 3- 100ºC. The final complex is one of a hepta- The nitrido atom N was developed by 92,93 coordinate Tc(III) core atom bound to a Baldas to complex with Tc(V). Subse- chlorine atom and to the six nitrogens of the quently a Tc-nitrido compound, [bis (N-ethyl- 99m three vicinal dioximes. One end of the mole- N-ethoxydithiocarbamato)nitrido Tc(V), or cule is capped by a boron atom covalently Tc-N-(NOEt)2, was developed which has bound to one oxygen atom from each of the shown promise for myocardial perfusion im- 94 dioximes (Figure 12). The complex is stable aging. It is a neutral lipophilic myocardial for 6 hours after preparation. Radiochemical imaging agent with a Tc≡N2+ core. Its chemi- purity must be ≥ 90%. The high lipophilicity cal structure demonstrates a Tc(V) atom tri- of the complex may cause binding with sy- ple-bonded to a strong pi-electron donor ni- 3- ringe components necessitating an overfill tride atom (N ) and four sulfur atoms (Fig- of patient doses to remove the required ac- ure 12). The complex is prepared in a 2-step 94 tivity. procedure. The first step involves reduction of 99m Following intravenous administration in Tc sodium pertechnetate in acidic conditions humans peak myocardial uptake of 2.3% ID by trisodium tri(m-sulfophenyl) phosphine in occurs within 2 minutes.90 Ten minutes after the presence of S-methyl N-methyl dithiocar- injection only 10% of the dose remains in bazate, H2NN(CH3)C(=S)SCH3, as the nitrido blood and 33% of the dose is present in the nitrogen donating agent. This mixture is liver due to rapid hepatobiliary clearance. By heated at 100°C for 20 minutes producing an 24 hours 22% of the dose is excreted in the intermediate species bearing the Tc≡N2+ urine. Liver clearance is slow compared to core. The mixture is cooled and neutralized heart clearance such that heart-to-liver ratios with buffer and the dithiocarbamate ligand is decline rapidly from 0.1 at 5 minutes after added, whereupon ligand exchange occurs injection to 0.05 at 10 minutes and beyond. immediately to form the final 99mTc-nitrido 99m Residual liver activity may present a problem dithiocarbamate complex, Tc-N-(NOEt)2. if a second dose is given. The first-pass myo- A lyophilized kit has been developed (Tc-N- 99m cardial extraction of Tc-teboroxime (80 to (NOEt)2 ,CIS Bio-International, France) us- 90%) was the highest when compared with ing stannous chloride that permits labeling at 99mTc-sestamibi (40 to 60%) and thallium (75 neutral pH.94 to 85%).91 Consequently, 99mTc-teboroxime Following intravenous injection 99mTc- has less diffusion limitation and can more N-(NOEt)2 localizes in the myocardium reliably assess higher blood flow levels than proportional to blood flow. Following myo- 99m 99m 99m Tc-sestamibi or thallium. However, Tc- cardial uptake Tc-N-(NOEt)2 redistrib-

30 utes from the heart and has been compared across the capillary endothelium and sar- with thallium-201 for myocardial perfusion colemma of the myocyte. However, back- imaging.95 Currently, this compound is not diffusion of unfixed tracer occurs so that the marketed in the United States. amount retained decreases as coronary blood flow increases. At coronary blood flows of 1 PET RADIOPHARMACEUTICALS and 3 mL/min/g the average first-pass reten- PET imaging in myocardial disease of- tion is 83% and 60%, respectively.41 Once fers several advantages over SPECT imag- taken up into the myocyte 13N-ammonia is ing. In the past, the major advantage of PET rapidly fixed as 13N-glutamine by the enzy- over SPECT has been the ability to provide matic conversion of glutamic acid by gluta- attenuation-corrected images. At present, mine synthetase. Nitrogen-13 ammonia is most SPECT cameras now have attenuation cyclotron-produced and its 10-minute half- correction capability. Attenuation correc- life restricts its use to facilities with an on- tion is routinely done with PET, but it may site cyclotron. not always be done with SPECT. Attenua- Nitrogen-13 ammonia is used for evalu- tion correction decreases the incidence of ating myocardial blood flow. Typically 10 to attenuation artifacts and increases specific- 20 mCi (370 to 740 MBq) is administered 96 ity. Other advantages of PET include in- intravenously with imaging starting about 5 creased sensitivity and spatial resolution minutes later to allow clearance of excess (PET, 6 to 10 mm; SPECT, 10 to15 mm), tracer from the blood. The 10-minute half- which translates into a higher degree of ac- life of 13N requires about a 30-minute wait curacy of PET versus SPECT in the detec- between rest and stress injections to allow 96 tion of CAD with perfusion tracers. Quan- for decay.96 tification of blood flow is also possible with PET. Additionally, metabolism studies can Rubidium Chloride Rb 82 Injection be done with 18F-FDG, 11C-acetate, and 11C- Rubidium chloride Rb 82 Injection palmitate. 18F-FDG is considered to be the (82Rb-rubidium chloride) is a generator- gold standard for evaluating myocardial vi- produced radionuclide with a half-life of 75 ability. The principal disadvantages of PET sec. It is the daughter nuclide of 82Sr which are availability and cost. has a 25-day half-life, giving the generator a useful life of 4 to 6 weeks. Following intra- PET Perfusion Agents venous injection of 82Rb-rubidium chloride the rubidium cation is taken up across the Ammonia N 13 Injection sarcolemmal membrane via the sodium/po- The gold standard for quantitating organ tassium ATPase pump. Rubidium-82, there- blood flow is radiolabeled microspheres, a fore, is a potassium analog. A substantial non-diffusible tracer that has an extraction 41 amount of non-transported tracer back- fraction of 1.0 at all levels of blood flow. diffuses from the interstitial space and is Perfusion measurements in the nuclear washed away in increasing amounts non- medicine clinic are typically made with dif- linearly as coronary blood flow increases.41 fusible tracers that exhibit extraction frac- The mean extraction fraction at 1 and 3 tions less than 1.0 because of diffusion limi- mL/min/g is 59% and 26%, respectively.41,97 tations of these tracers. Nitrogen-13 ammo- Administration of 82Rb-rubidium chlo- nia has proven to be one of the most effec- ride for perfusion imaging is automated and tive perfusion tracers in PET. Its first-pass 40 to 60 mCi (1480 to 2220 MBq) is in- extraction is high (>90%) due to the rapid jected intravenously with imaging beginning diffusion of uncharged lipophilic ammonia after a 90 to 120 sec wait to achieve satisfac- 31 tory heart-to-blood ratios following blood In the first step of glucose metabolism, clearance of tracer. The rapid decay of 82Rb hexokinase converts glucose and 18F-FDG permits multiple studies to be performed into glucose-6-phosphate and 18F-FDG -6- about every 10 minutes. A disadvantage of phosphate, respectively. While glucose-6- 82Rb is its high-energy positron (3.15 phosphate participates further as a substrate 18 MeVmax) which travels further from its site for glycolysis or glycogen synthesis, F- of origin before annihilation compared to FDG-6-phosphate is not a substrate for these lower-energy positrons. This effectively de- pathways. Because it cannot readily diffuse creases intrinsic resolution.97 back out of the cell, 18F-FDG-6-phosphate becomes trapped and accumulates in cells Water O 15 Injection that are in active metabolism. Oxygen O-15 (T1/2 2 min) as labeled water is a freely diffusible tracer whose first- Under normal aerobic fasting conditions, pass extraction is ~95%. It is independent of the heart primarily uses fatty acids for is en- blood flow and is metabolically inert and ergy needs. After a glucose load elevated therefore appears to be an ideal tracer for insulin levels in blood causes an increase in perfusion studies. However, water O 15 in- glucose metabolism in preference to fatty jection (15O-water) also distributes into tis- acids. In the ischemic heart, areas of sues adjacent to the heart (lung and heart ischemic muscle switch to anerobic glycoly- blood pool), which complicates imaging by sis with glucose as the principal substrate requiring the use of background subtraction and these areas will demonstrate an in- techniques.41 Oxygen-15 water is adminis- creased uptake of 18F-FDG. This forms the tered as an intravenous bolus of 30 mCi basis for using 18F-FDG as a marker of (1110 MBq) with imaging beginning imme- myocardial metabolism and cell viability. diately, or patients inhale 15O-carbon diox- Fluorine F-18 FDG is not a useful tracer of ide for 3 to 4 minutes with continuous imag- myocardial blood flow because its uptake is ing. In vivo the 15O-carbon dioxide is con- not related to flow but to phosphorylation. verted to 15O-water by carbonic anhydrase.41 The phosphorylation step is dependent on Following imaging, and allowing for com- the rate of glucose metabolism which is in- plete decay, the blood pool is labeled by a dependent of blood flow. single breath dose of 15O-carbon monoxide The 18F-FDG radiopharmaceutical is which labels red blood cells by forming 15O- supplied as an injection and is used for as- carboxyhemoglobin. Blood pool images are sessing myocardial viability. At a PET facil- taken and subtracted from heart perfusion ity with a cyclotron and radiochemistry ca- images to assess net myocardial perfusion. pability, a typical protocol would be to perform a perfusion/metabolism study with per- PET METABOLISM AGENTS fusion being evaluated first with 13N- ammonia, 82Rb-rubidium chloride, or 15O- Fludeoxyglucose F 18 Injection water, followed by an 18F-FDG metabolism Fluorine F-18 (T1/2 110 min) labeled as study (Figure 20). At PET facilities without 2-fluoro-2-deoxyglucose (fludeoxyglucose 18 a cyclotron or radiochemistry support a or F-FDG) (Figure 18) is the premier 99mTc-agent is used for the perfusion study metabolic marker for glucose metabolism in followed by an 18F-FDG metabolism study. tissues of the body. Fluorine-18 FDG, being Because of the difference in physical half- a hydrophilic molecule, is taken up into cells lives, 13N-ammonia is frequently used be- via facilitated diffusion similar to glucose, cause it allows longer imaging times with but its metabolism is different (Figure 19). higher count density images compared to 32 Figure 18. Chemical structures of glucose, deoxyglucose, and fludeoxyglucose (FDG). (Re- printed by permission, from Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine. © 2004 by the American Pharmacists Association). CH OH 2 CH2OH CH2OH O O O OH OH OH OH OH OH

OH OH OH OH H 18F

D-Glucose 2-deoxy-D-Glucose 2-fluoro-2-deoxy-D-Glucose (FDG)

Figure 19. The various metabolic processes occurring in the myocyte illustrating the membrane uptake mechanisms for monovalent cations (201Tl+ and 82Rb+) via Na-K ATPase and FDG and glucose via the glucose transporter. While glucose is metabolized completely, FDG is trapped as FDG-6-phosphate following enzymatic conversion by hexokinase. Fatty acids, as the preferred metabolic substrate for energy, can be converted into triglycerides, phospholipid stores, or shunted, via the carnitine shuttle, into mitochondria for beta oxidation. (Reprinted by permission of W.B. Saunders Co from: Schwaiger M., et al. Evaluation of coronary artery disease with positron emission tomography. Semin Nucl Med 1992; 22: 210-223.)

201Tl+82Rb+ FDG Glucose Glucose Na-K Transport ATPase Protein FDG Glucose Myocyte Hexokinase Glucose-6- FDG-6-PO4 (Trapped) PO4 Glycogen Pyruvate

Mitochondria Carnitine βeta Shuttle Oxidation Triglycerides Acyl- Acyl- Acetyl- TCA Cycle Phospholipids Carnitine CoA CoA

Acyl-

CoA CO2

Fatty Acids Acetate CO 2

33 Figure 20. PET perfusion/metabolism imaging protocol to assess myocardial viability. (Re- printed by permission of the Society of Nuclear Medicine from: Maddahi J, et al. Role of thallium- 201 and PET imaging in evaluation of myocardial viability and management of patients with coronary artery disease and left ventricular dysfunction. J Nucl Med 1994;35:707-715.) PET Perfusion / Metabolism Imaging Protocol

13N-Ammonia Inj 18F-FDG Inj 20 mCi 10 mCi

Transmission Scan Perfusion Scan Metabolism Scan

02027477797

(Minutes)

82Rb or 15O.98 The metabolism phase of the bernating myocardium which is active me- study involves intravenous injection of 18F- tabolically and therefore viable (Figure 21). FDG (10 mCi [370 MBq]) following a load- Carbon C 11 Palmitate ing dose of glucose to facilitate transport of Carbon C 11 palmitate (11C-palmitate) is 18F-FDG into myocardial cells. The loading used to provide information about myocar- dose of glucose is important because in the dial fatty acid metabolism (see Figure 19). fasting state, fatty acid is the principal sub- The free fatty acid is largely distributed in strate for myocyte energy requirements and the myocardium in proportion to blood flow 18F-FDG is taken up very little under these whereupon it crosses the sarcolemmal mem- conditions. Compared to 12-hr fasted sub- brane, presumably by passive diffusion or jects, subjects given 50 g of glucose orally possibly facilitated transport.41 Retention or prior to the 18F-FDG study demonstrate trapping of 11C-palmitate requires energy- heart-to-blood activity ratios 2.5 times dependent esterification to 11C acyl-CoA, higher.99 The pattern of activity uptake be- which can enter either of two routes. In one tween the perfusion and metabolism images fraction it moves via the carnitine shuttle to is key to the diagnosis. If the 13N-ammonia the inner mitochondrial membrane where β- and 18F-FDG activity distributions are iden- oxidation cleaves two carbon fragments off tical in the region of a perfusion defect (a the long carbon chain, directing acetyl CoA match), the defect is likely caused by lack of to the tricarboxylic acid (TCA) cycle for both perfusion and active metabolism and is complete oxidation to carbon dioxide and due to scar. If there is increased uptake of water. The other fraction of acyl-CoA is fur- 18F-FDG in a region seen as a perfusion ther esterified and deposited as triglyceride deficit with ammonia (a mismatch), the in- and phospholipid stores. terpretation is that the region represents hi-

34 Figure 21. Regional myocardial blood flow palmitate and image acquisition, stored im- and glucose utilization in a normal volun- ages of the ventricles are used to identifiy teer (A) and two patients with ischemic regions of interest from which time-activity heart disease (B and C), evaluated with N- curves are generated for analysis of uptake 13 ammonia (NH3) and F-18 2-deoxyglu- and clearance kinetics. The slopes of these cose (FDG) and PET. Only one midventricu- curves can then be used to assess regional 41 lar cross-sectional image of blood flow (left) metabolism in the myocardium. and glucose utilization (right) is shown per Sodium Acetate C 11 Injection subject. Note the homogeneous tracer uptake 11 in the normal subject. In patient B, blood flow Sodium acetate C 11 injection ( C- is decreased in the anterior wall (broken line) acetate) is avidly extracted by the myocar- associated with a proportional decrease in dium and activated to acetyl-CoA, which is oxidized in the mitochondria to 11C-carbon FDG uptake. This pattern reflects scar tissue. 11 By contrast, in patient C, blood flow is mark- dioxide and water (see Figure 19). C- edly decreased in the anterior wall and the an- acetate permits an evaluation of flux through terior septum, while glucose utilization in the the TCA cycle and overall myocardial oxygen consumption because of its close link to hypoperfused segment is markedly enhanced. 41 Preservation of glucose utilization in hypoper- oxidative phosphorylation. A measure of fused and dysfunctional segments represents myocardial oxidative capacity can be made tissue viability. (Reprinted by permission of by an analysis of uptake and clearance W.B. Saunders Co from: Schelbert HR. Cur- curves. These curves change with regional rent status and prospects of new radionuclides abnormalities in blood flow and metabolism. Thus, in ischemic regions, the initial uptake and radiopharmaceuticals for cardiovascular 11 nuclear medicine. Semin Nucl Med 1987;17: of C-acetate decreases in proportion to 145-181.) myocardial blood flow and clearance curves are reduced significantly.41 11 NH3 FDG Fluorine F-18 FDG and C-palmitate are tracers that measure specific substrates in myocardial metabolism, whereas 11C- A acetate measures overall oxidative metabolism. Fluorine F-18 FDG measures the initial steps of exogenous glucose utilization, whereas 11C-palmitate traces the entire metabolic pathway of fatty acid metabolism. In the fasted state, when fatty acid metabo- B lism is highest in the myocardium, 18F-FDG will demonstrate very little uptake in the heart, but 11C-palmitate uptake and clearance curves will reflect rapid kinetics. The combination of 11C-palmitate or 18F-FDG 11 C with C-acetate permits assessment of the contribution of fatty acid or glucose metabolism to overall oxidative metabolism or in the ischemic condition, an assessment of Following intravenous administration of anaerobic versus oxidative glucose metabo- 15 to 20 mCi (555 to 740 MBq) of 11C- lism.41

35 VIABILITY ASSESSMENT lowing revascularization. In three independ- A principal reason for myocardial perfu- ent studies reporting on rest-redistribution sion imaging is to predict whether ischemic thallium imaging, the mean PPA was found dysfunctional myocardial segments are vi- to be 72% (range 57% to 92%) and the mean able and therefore restorable to normal func- NPA was found to be 70% (range 62% to tion following revascularization. 77%).101-103 In three additional studies, fol- The four principal conditions that can lowing exercise-redistribution-reinjection cause left ventricular dysfunction are: (1) thallium imaging, negative predictive accu- transmural myocardial infarction, which in- racies in studies conducted without 201Tl re- volves full-thickness myocardial necrosis, injection were 43%, 53%, and 48%, but with (2) non-transmural myocardial infarction, reinjection these values improved to 100%, which is necrosis limited to the subendocar- 75%, and 75%, respectively, demonstrating dium or is scattered throughout the myocar- the value of thallium reinjection on improv- dium, (3) myocardial stunning, and (4) hi- ing diagnostic accuracy (see Figure bernating myocardium.98 Revascularization 11).65,67,104 For this reason, thallium reinjec- is not expected to be beneficial for the first tion is now a standard technique in SPECT two conditions. Myocardial stunning results imaging for assessing myocardial viability. from severe acute ischemia followed by PET’s ability to predict recovery of left reperfusion, both of which cause myocardial ventricular function after revascularization injury and dysfunction.100 Myocardial hi- procedures has been assessed with myocar- bernation results in dysfunction being dial perfusion/metabolism studies using 15O- caused by chronic reduction in coronary water, 13N-ammonia, 11C-acetate, and 18F- blood flow. In stunning, reduced contraction FDG. In seven studies reviewed by Maddahi is mismatched with increased perfusion, the average reported positive predictive ac- whereas in hibernation reduced contraction curacy for a myocardial perfusion/FDG me- is matched by reduced perfusion.100 In both tabolism mismatch pattern was 83% (range situations the dysfunction is reversible and 72% to 95%) and the average negative pre- will resolve after restoration of myocardial dictive accuracy for a matching pattern was blood flow to the affected region. Time is 84% (range 75% to 100%).98 Thus, while required in the case of stunning to restore both 201Tl and PET imaging methods have muscle; improved blood flow is required in high accuracies, PET perfusion/metabolism the case of hibernation. imaging appears to have greater diagnostic Nuclear medicine studies have been power in predicting improvement of left shown to be valuable in predicting the vi- ventricular function in patients with CAD ability of stunned and hibernating myocar- compared to thallium SPECT. dium. Thallium viability studies have been Most institutions now use a 99mTc agent reviewed by Maddahi.98 The terms positive (sestamibi or tetrofosmin) for myocardial predictive accuracy and negative predictive perfusion studies. The question remains, in accuracy are often used in viability assess- the situation of chronic left ventricular dys- ment studies. Positive predictive accuracy function, whether 99mTc-sestamibi can dis- (PPA) predicts the percentage of myocardial tinguish between viable hibernating myo- regions with reversible defects that will im- cardium and fibrosis, as has been shown prove following revascularization, while with the 201Tl rest-reinjection technique.11,62 negative predictive accuracy (NPA) predicts Several studies indicate that 99mTc-sestamibi the percentage of myocardial regions with- has limitations in identifying viability in hi- out reversibility that will not improve fol- bernating myocardium. Cuocolo compared

36 99mTc-sestamibi and 201Tl in chronic CAD, qualitatively to thallium for viability as- demonstrating that approximately 60% of sessment in CAD following exercise-rest myocardial regions identified as viable by studies, 99mTc-tetrofosmin imaging was thallium reinjection were categorized as found to underestimate myocardial viability “nonviable” by a resting 99mTc-sestamibi compared to thallium reinjection and the dif- study.105 In a comparison of 99mTc-sestamibi ference correlated with severity of the per- with 18F-FDG-PET in patients with CAD, sistent defect on rest images.112 99mTc-sestamibi was found to underestimate Intact membrane function and metabolic myocardial viability.106 Five to 11% of se- processes are required for myocyte viability. vere defects with 99mTc-sestamibi uptake at Thus, markers of membrane integrity and rest ≤ 30% of peak activity were viable by metabolic function, theoretically, should be 18F-FDG-PET, whereas 13% to 61% of equally effective in assessing myocardial moderate to severe defects (31% to 70% of viability. The differences in the reported ac- peak activity) were found to be viable by curacies between SPECT and PET imaging 18F-FDG-PET. A case report, comparing agents for assessing viability may reside in 201Tl exercise-redistribution with reinjection the different abilities of these modalities to and exercise-rest 99mTc-sestamibi, in a pa- detect the physiologic processes that are oc- tient with multivessel chronic CAD evalu- curring. Hence, PET would seem to have the ated before and after revascularization, advantage currently because of its better demonstrated that thallium could distinguish resolution, ability to correct for photon at- between viable and nonviable regions tenuation, and ability to assess metabolic whereas sestamibi could not.107 Thus, it ap- function independent of perfusion.113 pears that 99mTc-sestamibi, as a perfusion marker, may be able to assess viability in BLOOD POOL IMAGING AGENTS stunned myocardium where perfusion is The essential requirements for a blood adequate, such as following reperfusion pool imaging radiopharmaceutical for evalu- therapy for acute myocardial infarction, but ating dynamic heart function include, (1) that it is not able to adequately identify vi- slow blood clearance to provide steady ability in hibernating myocardium in chronic blood pool activity during the time of data CAD where there is sustained reduction in acquisition, (2) minimal localization of ra- blood flow.100 Thus, in those clinics without dioactivity in nearby organs and extravascu- 18F-FDG-PET capability, the thallium rest lar space that would interfere with meas- /redistribution protocol or the thallium urements of the heart blood pool, and (3) stress/redistribution/reinjection protocol would high photon flux, which is necessary for be the procedures of choice for assessing high-resolution and high-sensitivity meas- myocardial viability. urements of dynamic heart function with the Clinical studies have shown that 99mTc- gamma camera. The latter requirement is 99m tetrofosmin accurately detects coronary ar- most easily met by Tc, and the first two 99m tery disease when compared with thallium requirements are met by labeling Tc to 108-110 and 99mTc-sestamibi.111 The heart-to- red blood cells. liver ratios at rest and after dipyridamole stress indicate higher ratios for 99mTc- Technetium Tc 99m Red Blood Cells tetrofosmin compared to 99mTc-sestamibi, Various methods of labeling red blood but there is no significant difference in the cells with technetium are possible. These quality of images or diagnostic interpreta- include the in vitro method, the in vivo tion of these two agents.112 When compared method, and the modified in vivo method.

37 In Vitro Method The labeling mechanism is as follows: 99m addition of RBCs to the reaction vial causes The in vitro method for preparing Tc- 99m a portion of the stannous ion to cross the red labeled red blood cells ( Tc-RBCs) was cell membrane into the cell. Too much ACD perfected with a kit developed at the Brook- 114,115 impairs this diffusion process and is the rea- haven National Laboratory. This tech- son for its limited amount. All of the stan- nique was modified by Srivastava to permit nous ion does not enter the cells, and sodium labeling in whole blood without isolating the 116 hypochlorite is added to oxidize this ex- red cells. A commercial kit is now avail- tracellular stannous ion. This is effective able (Ultratag RBC - Mallinckrodt Inc) because hypochlorite cannot cross the red based on this method. The blood cells are cell membrane to oxidize intracellular tin. usually autologous but may be donor cells if The citrate solution in syringe II is added to carefully typed and cross-matched and sequester excess extracellular stannous ion checked for viral contamination. The kit to enhance its oxidation by hypochlorite. At consists of three components: this point 99m 1. 10-mL Reaction Vial: Lyophilized Tc sodium pertechnetate is mixture of stannous chloride di- added which readily diffuses into the cells, encounters intracellular stannous ion, be- hydrate 105 µg, sodium citrate di- comes reduced and bound in the cell. If ex- hydrate 3.67 mg, and dextrose anhy- tracellular stannous ion were present, it drous 5.5 mg at pH 7.1 to 7.2. would reduce the pertechnetate extracellu- 2. Syringe I: sodium hypochlorite 0.6 larly and prevent it from entering the cell. mg in 0.6 mL at pH 11 to 13. This would lower the labeling efficiency. 3. Syringe II: citric acid monohydrate Radiochemical purity can be checked by 8.7 mg, sodium citrate dihydrate 32.5 mixing 0.2 mL of 99mTc-RBCs with 2 mL mg, and dextrose anhydrous 12 mg saline and centrifuging. Assay of the super- in total volume of l.0 mL at pH 4.5 natant (unbound activity) and the red cell to 5.5. precipitate (bound activity) will provide a The cells are labeled as follows: measure of labeling efficiency. The labeling 1. Collect 1 to 3 mL patient’s blood. efficiency must be ≥ 90% and is typically > 95%.117 Use 0.15 mL ACD or 10 to15 units 99m heparin per mL blood maximum. Do Tc-RBCs are a blood pool imaging not use EDTA or oxalate as antico- agent indicated for cardiac imaging and for agulants. the detection of gastrointestinal bleeding 2. Transfer blood to the reaction vial to with an IV dosage range of 10 to 20 mCi dissolve crystals. Incubate 5 minutes. (370 to 740 MBq). The critical organ is the spleen with an absorbed radiation dose of 3. Add contents of syringe I. Mix by 117 gentle inversion 5 times. 0.11 rad(cGy)/mCi. 4. Add contents of syringe II. Mix by gently inversion 5 times. In Vivo Method 5. Add 10 to 100 mCi (370 to 3,700 The in vivo method of labeling red cells MBq) sodium pertechnetate in up to was first suggested by Pavel118 and 3 mL. Stokely119 for use in cardiac blood pool 6. Mix gently 5 times. Incubate 20 studies. The method was based on the intra- minutes to label cells. venous injection of stannous pyrophosphate (Sn-PPi) 20 minutes to 24 hours prior to IV administration of 99mTc sodium pertech-

38 netate which then labeled the “tinned” red stannous ion as Sn-PPi from a Pyrolite® kit cells. The Pavel technique involved reconsti- intravenously. Equivalent amounts of stan- tuting one vial of Mallinckrodt TechneScan nous pyrophosphate from other marketed PYP (which contained about 15.4 mg stan- kits can also be used. Twenty minutes later, nous pyrophosphate (Sn-PPi) and on aver- 3 mL of tinned red blood cells are with- age, about 2 mg Sn2+) with 5 mL saline, and drawn through a heparinized Butterfly infu- injecting the patient with 1.4 mg Sn-PPi per sion set into a shielded syringe containing 1000 mL whole blood volume. Based on 20 mCi (740 MBq) of pertechnetate. The these parameters the average 70 kg adult mixture is incubated for 10 minutes with male (~5400 mL whole blood) would re- gentle agitation and then reinjected into the ceive about 7.5 mg Sn-PPi (one-half vial) patient. Labeling yields > 90% are achieved per dose, equivalent to ~ 15 µg Sn (II)/kg. with this method because the red cells com- Within 20 to 30 minutes of injecting the Sn- pete for pertechnetate only with the plasma PPi, 15 to 25 mCi (555 to 925 MBq) of in the syringe. 99mTc sodium pertechnetate is administered intravenously to label the red cells for blood Labeling Mechanism of Tc Red Blood pool imaging. Cells Hamilton investigated the amounts of Following incubation of stannous pyro- stannous ion required to label red cells and phosphate with red blood cells some of the reported that maximal in vivo labeling effi- stannous ion crosses the cell membrane, ap- ciency is obtained with an IV dose of 10 µg parently transported inside the cell by a spe- 121 Sn (II)/kg or greater.120 Although Pavel re- cific transport system where it is believed ported labeling efficiencies of ~ 96% with to be associated with an intracellular pro- 124 the in vivo technique, others reported only tein. The pertechnetate anion can readily about 75% labeling efficiency.121,122 Calla- diffuse into the cell, become reduced by the han noted that when the in vivo technique stannous ion, and subsequently bind to he- was used for gastrointestinal bleeding stud- moglobin, which prevents it from diffusing 124 ies, variable amounts of gastric and urinary back out of the cell. In vitro studies have activity interfered with the study. Investiga- shown that within the hemoglobin molecule 99m tion into the possible causes of this ex- approximately 20% of Tc and 90% of tin 99m travascular activity led to the deduction that are associated with heme and 80% of Tc 125 immediately following intravenous injection and 10% of tin are associated with globin. of free pertechnetate with the in vivo Transport studies in human erythrocytes method there occurs a competition for have demonstrated that the pertechnetate pertechnetate between the red cells and the anion is transported across the membrane extracellular fluid space, gastric mucosa, via the band-3 protein transport system in 126 thyroid and salivary glands. This led to the exchange for chloride or bicarbonate ion. development of the modified in vivo method It is worth noting that this transport can be for labeling red cells.123 inhibited by dipyridamole and may play a factor in decreasing the labeling efficiency Modified In Vivo Method of red cells in patients who receive therapeu- tic or diagnostic doses of this drug.126 The modified in vivo method was devel- In humans the biologic half-life in blood oped to increase the labeling efficiency of of 99mTc-RBCs prepared by the in vitro 99mTc-RBCs and to provide a firm label technique is biexponential, with 5% of the prior to intravenous injection.123 With this activity having a 20-minute half-life and technique the patient receives ~ 500 µg of 95%, a 29-hour half-life.127 Cells labeled in 39 vivo are assumed to behave with a normal activity (20 to 30 mCi [740 to 1110 MBq]). biologic half-life of red cells, i.e., about 80 During the first couple of beats following days. initial injection of the pertechnetate bolus of activity, the right ventricle can be isolated GATED EQUILIBRIUM RADIONU- on the images (Figure 22). Regions of inter- CLIDE VENTRICULOGRAPHY est can be drawn around the right ventricle A principal application of blood pool during diastole and systole and a right ven- imaging agents is myocardial ventriculogra- tricular ejection fraction can be estimated phy for the assessment of wall motion ab- using the formula: normalities and measurement of ventricular RVEF or LVEF = ejection fraction and volume. The assess- ()()End−−− Diastolic Counts End Systolic Counts ment is made with a two-part study: the ()()End−− Diastolic Counts Background Counts first-pass study and the equilibrium study. A first-pass study permits assessment of right and left chamber function following administration of a bolus of 99mTc-pertechnetate

Figure 22. Normal first-pass study to evaluate right ventricular performance. Shortly after a 30 mCi (1110 MBq) bolus of 99mTc sodium pertechnetate was administered in a right arm vein, radiotracer can be seen in the superior vena cava, right atrium (solid arrow), right ventricle (dotted region) and pulmonary outflow tract (open arrow). The right ventricle can be isolated because radiotracer has not yet advanced to the lungs or left ventricle. A time activity curve for the right ventricle was used to determine right ventricular end-diastole and end-systole. Regions of interest drawn around the right ventricle during end-diastole and end-systole gave a normal estimated right ventricular ejection fraction of 51%. (Reprinted by permission, from Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine. © 2004 by the American Pharmacists Association).

RV Ejection Fraction 51%

40 Once the pertechnetate is injected it la- tion abnormalities and decreased thickening bels red cells in vivo permitting an ECG- are generally associated with scar. gated equilibrium study, which typically follows the first-pass study. The equilibrium INFARCT-AVID IMAGING AGENTS study is conducted to assess left ventricular Infarct-avid agents, otherwise known as function. The equilibrium study is also “hot spot” markers, demonstrate an in- known as the multigated acquisition or creased accumulation of radiotracer activity MUGA study because the activity labeled to in regions of infarcted myocardium. Several the red cell blood pool is monitored as it types of radiolabeled agents have been de- passes through the heart by acquiring images veloped for infarct imaging based on the triggered or gated on the R-wave of the elec- pathophysiologic changes that occur in the trocardiogram. The total activity passing infarct region. While these agents have pro- through the heart during one cardiac cycle is vided useful diagnostic information in the divided into frames of activity which are past, presently, faster, more sensitive, spe- stored in a computer (Figure 23). Typically cific, and less costly serum markers have 32 or more frames are acquired during each replaced infarct-avid imaging agents as the cycle so that incremental changes in left standard of care. However, new radiotracers ventricular activity can be stored from end- for imaging myocardial infarction are being diastole to end-systole. Many cardiac cycles investigated. (and frames) of data are stored over a long image acquisition time so that a statistically Technetium Tc 99m Pyrophosphate significant amount of activity is accumu- Technetium-labeled bone agents were lated in each frame. The total amount of ac- first used for infarct localization following tivity stored in the frames at each gated time the serendipitous finding of heart uptake on point are then plotted versus total cycle time bone scans in patients who had recent in- to obtain a time-activity curve of blood farcts. In the 1970’s these agents proved flowing through the left ventricle. From this useful in the diagnosis of myocardial infarc- plot, and the equation given above, the left tion because at that time there was a lack of ventricular ejection fraction (LVEF) can be sensitive enzyme assays for early diagnosis determined from end-diastolic and end- of MI. Investigations led to the discovery systolic activities in the chamber. Figure 24 that, physiologically, ischemic damage to illustrates two patient studies for the deter- the myocardial cell membrane produces an imbalance in the myocyte’s intracellular- mination of LVEF; one normal (LVEF = ++ 73%) and one abnormal (LVEF = 30%). extracellular Ca concentration. Under Normal LVEF is 55% or greater. normal conditions the calcium ion concentration intracellularly is about 10-7 M and in Gated SPECT also allows one to further -3 evaluate fixed perfusion defects seen in a extracellular fluid it is about 10 M (Figure myocardial perfusion study by examining 1). Following infarction with disruption of myocardial wall motion and thickening. the myocyte membrane, calcium ions diffuse Fixed perfusion defects with associated into the infarcted cells providing a focus for normal wall motion and thickening are in- the uptake and binding of technetium- dicative of viable functional myocardium labeled agents. and are likely related to attenuation artifacts In 1974, Bonte introduced the use of 99mTc-pyrophosphate for imaging myocar- usually caused by the diaphragm or breast. 128 Fixed defects with abnormal focal wall mo- dial infarction. Its mechanism of localization was shown to be related to residual blood flow to the infarcted region, calcium 41 Figure 23. Gating mechanism to obtain serial single-frame images of left ventricle contraction through one cardiac cycle. See text for explanation. (Reprinted by permission of Bristol-Meyers Squibb Medical Imaging).

42 Figure 24. Left ventricular ejection fraction (LVEF) assessment. Images of the heart at end- diastole and end-systole with time-activity curves demonstrating, (A) normal LVEF of 73% and, (B) abnormal LVEF of 30%. (Reprinted by permission, from Radiopharmaceuticals in Nu- clear Pharmacy and Nuclear Medicine. © 2004 by the American Pharmacists Association).

End-Diastole End-Systole End-DiastoleEnd-DiastoleEnd-Systole

LVEF = 73% LVEF = 30%

ion influx, and deposition of intracellular peripheral zones of the infarct where there is hydroxyapatite in infarcted cells.129,130 adequate blood flow, with considerably less Following myocardial infarction mem- uptake in central zones of the infarct where brane damage occurs which permits an in- blood flow is reduced.130 Temporally, after flux of plasma proteins and calcium ions, fixed coronary occlusion, 99mTc-pyrophos- some of which deposit in mitochondria phate begins to localize in the infarcted tis- where hydroxyapatite crystals form. The sue within 12 to 24 hours. Scintigrams be- proposed mechanism of 99mTc-pyrophos- come more positive during 24 to 72 hours phate localization is sorption to various and remain abnormal for 6 days after infarc- forms of tissue calcium stores, including tion, fading thereafter and becoming nega- amorphous calcium phosphate, crystalline tive by day 14 (Figure 25). The standard hydroxyapatite, and calcium complexed dose for myocardial infarct imaging was 15 with various macromolecules at the infarc- mCi (555 MBq) with imaging in 3 to 4 tion site. Maximal concentrations occur in hours.

43 Figure 25. Infarct avid scans obtained 4 bind the radiolabeled antimyosin antibody. 111 and 8 days following extensive acute left Following dosing of In-antimyosin, imag- ventricle infarction. Images are obtained 2 ing is performed 24 hr or later to allow for hours after intravenous injection of 15 mCi background activity to clear. Although this (555 MBq) of 99mTc-pyrophosphate. (Re- agent has demonstrated high sensitivity and printed by permission, from Radiopharmaceu- specificity for localizing myocardial in- 132,133 ticals in Nuclear Pharmacy and Nuclear farcts, it is no longer on the market. Medicine. © 2004 by the American Pharma- cists Association). Technetium Tc 99m Glucaric Acid Technetium Tc 99m glucaric acid is a six-carbon sugar which was seridipitously found to localize in myocardial infarctions during the development of a technetium label for the antimyosin antibody.134 Techne- tium-99m glucarate is taken up into irrepa- rably damaged myocytes where it is associated with highly basic histones.134 In one investigational study it was found to be taken up rapidly into infarcted myocardium early after the event with best identification occurring if the radiotracer is administered within 9 hours of the infarction.135 Because 99m The sensitivity of 99mTc-pyrophosphate it is taken up soon after infarction, Tc- glucarate has a potentially significant ad- for detecting transmural infarcts was re- 99m 111 ported to be about 90%, but only about 40% vantage over Tc-pyrophosphate and In- for subendocardial infarcts.131 The overall antimyosin. Further investigational studies specificity has been found to be 64% in a will better define is future usefulness. multicenter study. Its lack of specificity is due in part to myocardial uptake in patients Technetium Tc 99m Annexin V with stable angina without infarct and in re- Technetium Tc 99m annexin V is a ra- gions of old infarcts several months after the diolabeled form of annexin V, an endoge- acute episode. Additionally, the long time nous protein that has a high affinity for ex- 99m posed phosphatidylserine on apoptotic required before for Tc-pyrophosphate 136 uptake is positive post infarct (24 to 48 hrs) cells. Apoptotic cells have been identified precludes its use for early diagnosis. in areas of severe ischemia and infarction. During natural apoptosis (programmed cell Indium In 111 Imciromab Pentetate death) in the body an enzymatic process is Indium-111 imciromab pentetate (Myos- initiated that causes the phospholipid phos- cint™ - Centocor), otherwise known as phatidylserine to become expressed on the 111In-antimyosin, is a monoclonal antibody outer membrane surface of dying cells, Fab fragment with specificity for myosin. Its where it is able to bind the annexin V ligand. localization is based on the disruption of the The purpose of this interaction is unknown sarcolemmal membrane of dying myocytes but the binding affinity between annexin V exposing myosin filaments which are nor- and phosphatidylserine is high. This gives radiolabeled annexin V the potential to be- mally segregated from the extracellular 127 fluid. Once exposed, the myosin may then come a cardiac imaging agent. Further investigational studies with this agent are 44 needed to define its diagnostic roll in cardiac sis and experimental validation. Am J imaging.128 Cardiol 1978; 41: 267-78.

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53 QUESTIONS c. dobutamine d. caffeine Begin Lesson 2 here. 5. Each of the following agents can be used 1. Which one of the following statements is to assess myocardial perfusion except: false? a. Tc-99m sestamibi a. Approximately 30 to 60% of all nu- b. Tc-99m red blood cells clear medicine procedures involve c. Tc-99m tetrofosmin heart studies. d. Tl-201 thallous chloride b. Radionuclide ventriculography is the most widely performed heart imag- 6. All of the following are myocardial ing study for assessing myocardial metabolic imaging agents except: viability. a. F-18 fludeoxyglucose c. Currently, infarct-avid imaging plays b. C-11 acetate a lesser role in heart imaging than in c. Rb-82 rubidium chloride the past. d. C-11 palmitate d. Approximately 84% of heart studies involve the assessment of myocardial 7. Which one of the following agents is perfusion. best suited for assessing myocardial viability in hypoxic myocardium? 2. The detection of restricted coronary a. C-11 acetate blood flow in the heart is most sensitive b. C-11 palmitate when: c. Tl-201 thallous chloride a. coronary blood flow is at maximum d. F-18 fludeoxyglucose levels. b. the stenotic vessel-to-normal vessel 8. The most effective way to relieve the blood flow ratio is 2.4 or greater. symptoms of adverse effects from c. coronary flow reserve is at a mini- adenosine administration is to: mum. a. immediately administer 100 mg of d. coronary blood flow is at resting lev- aminophylline. els. b. give the patient a caffeinated bever- age. 3. The amount of coronary artery stenosis c. administer esmolol as an antidote. that will likely cause chest pain (angina) d. discontinue the adenosine infusion. during myocardial stress from insuffi- cient oxygenation to the myocardium is: 9. The dosage of intravenous dipyridamole a. 25% for a myocardial perfusion study for a b. 45% 110-pound patient is: c. 70% a. 7 mg d. 85% b. 24 mg c. 28 mg 4. An endogenous substance that is in- d. 42 mg volved in the autoregulation of coronary artery blood flow is: 10. Which one of the following statements is a. dipyridamole true? b. adenosine a. Adenosine and dipyridamole are effective coronary vasodilators with

54 similar plasma half-lives but are con- c. Patients who complain of shortness traindicated in patients with heart of breath or wheezing should be block. given 50 to 100 mg of esmalol intra- b. Dobutamine is a beta-1 agonist that venously. produces effects on the heart similar d. Radiotracer injection is administered to exercise but is contraindicated in immediately following dipyridamole patients who have ingested food con- infusion. taining caffeine. c. A patient who has asthma and cannot 14. During myocardial perfusion imaging exercise is a good candidate for re- with pharmacologic stress, which one of ceiving dobutamine for cardiac the following does not reflect the correct stress. timing of radiopharmaceutical injection? d. When compared with pharmacologic a. Radiopharmaceutical should be ad- stress, exercise stress produces a ministered immediately following a greater accumulation of perfusion 6-minute adenosine infusion. imaging tracers in the splanchnic b. Radiopharmaceutical should be ad- viscera, which may interfere with ministered 3 to 5 minutes following heart imaging. completion of dipyridamole infusion. c. Radiopharmaceutical should be ad- 11. Heart uptake and retention of which one ministered 2 minutes before the end of the following myocardial imaging of dobutamine infusion. agents is associated with intact myocyte d. Radiopharmaceutical should be ad- plasma and mitochondrial membrane po- ministered 7 to 9 minutes from the tentials? start of dipyridamole infusion. a. Tl-201 thallous chloride. b. Tc-99m sestamibi. 15. Which one of the following statements c. N-13 ammonia. about Tl-201 thallous chloride is true? d. Rb-81 rubidium chloride. a. Thallium’s myocardial extraction is proportional to myocardial blood 12. Which one of the following myocardial flow up to 4 mL/min/g of myocar- imaging agents has the fastest clearance dium. from the heart following intravenous b. Approximately 1% of the injected administration? dose localizes in the heart. a. Tc-99m sestamibi. c. The critical organ is the heart. b. Tl-201 thallous chloride. d. Thallium is a myocardial perfusion- c. Tc-99m teboroxime. viability agent. d. Tc-99m tetrofosmin. 16. Increased specificity in the diagnosis of 13. Which one of the following statements ischemia versus infarction can be about dipyridamole is true? achieved if: a. Maximal coronary vasodilatation is a. 4 mCi of Tl-201 is injected instead of achieved about 3 minutes following 2 mCi in a thallium exercise/rest cessation of the intravenous infusion study. of dipyridamole. b. a thallium exercise/redistribution/ b. Maximal coronary vasodilatation is reinjection protocol is used. achieved with a 6-minute infusion at c. a sestamibi exercise/rest protocol is a dosage of 0.14 mg/kg/min. used. 55 d. adenosine is used instead of exercise 22. Which one of the following statements for the stress study. about Tl-201 thallous chloride myocardial exercise stress-redistribution study is 17. The SPECT procedure of choice for as- true? sessment of myocardial viability in a pa- a. Three to 4 hours following the stress tient with known coronary artery disease study, regions of normal myocar- and ventricular dysfunction is a: dium demonstrate a decrease in thal- a. thallium rest/redistribution study. lium activity while regions of b. sestamibi rest/exercise study. ischemic myocardium demonstrate c. tetrofosmin rest/exercise study. an increase in activity. d. sestamibi adenosine/rest study. b. Regions of myocardial scar demonstrate more rapid washout of activity 18. In pharmacologic coronary vasodilator during thallium redistribution than stress procedures the patient should ab- do ischemic regions. stain from caffeinated food and bever- c. Regions of myocardial ischemia ages prior to the procedure for at least: demonstrate perfusion defects on the a. 1 hour. stress study which persist on the re- b. 12 hours. distribution study. c. 24 hours. d. Perfusion defects on the stress study d. 48 hours. that fail to fill-in on the 4-hr redistribution study is strong evidence for 19. Which one of the following best de- the presence of scar. scribes heart uptake as a percent of the injected dose? 23. Which one of the following is the agent a. Sestamibi > Thallium > Tetrofosmin of choice for assessing myocardial vi- b. Tetrofosmin > Thallium > Sestamibi ability with SPECT imaging? c. Thallium > Sestamibi > Tetrofosmin a. Tc-99m pyrophosphate d. Thallium > Tetrofosmin > Sestamibi b. Tc-99m tetrofosmin c. Tc-99m sestamibi 20. Which one of the following best de- d. Tl-201 thallous chloride scribes the effective dose (rad/mCi administered) for myocardial perfusion 24. All of the following are advantages of tracers? Tc-99m sestamibi when compared to Tl- a. Sestamibi > Thallium > Tetrofosmin 201 thallous chloride for myocardial im- b. Tetrofosmin > Thallium > Sestamibi aging, except: c. Thallium > Sestamibi > Tetrofosmin a. Higher detection sensitivity and im- d. Thallium > Tetrofosmin > Sestamibi age resolution b. Ability to perform first-pass ven- 21. Which one of the following best de- triculography scribes the myocardial extraction of heart c. Ability to repeat image acquisition imaging agents? d. Better sensitivity for detecting hiber- a. Sestamibi > Thallium > Tetrofosmin nating myocardium b. Tetrofosmin > Thallium > Sestamibi c. Thallium > Sestamibi > Tetrofosmin d. Thallium > Tetrofosmin > Sestamibi

56 25. Which one of the following statements 29. Which one of the following statements about the biological properties of Tc- about Tc-99m tetrofosmin is false? 99m sestamibi is correct? a. It localizes in the heart by passive a. Tc-99m sestamibi washes out of the diffusion. heart quickly following intravenous b. It is retained principally bound in the injection. myocyte cytosol. b. Tc-99m sestamibi has an affinity for c. It has a shelf life of 8 hours follow- myocyte mitochondria. ing preparation. c. Tc-99m sestamibi is taken up as a d. It’s radiochemical purity must be ≥ monvalent cation via the myocyte 90 percent. Na/K membrane pump. d. Heart uptake of Tc-99m sestamibi is 30. Which one of the following PET radio- readily blocked by oubain. tracer combinations is typically used to evaluate myocardial viability? Begin Lesson 3 here. a. Rb-82 rubidium chloride/C-11 palmitate 26. Which one of the following statements b. O-15 water/F-18 FDG comparing Tc-99m tetrofosmin and Tl- c. N-13 ammonia/C-11 acetate 201 thallous chloride is correct? d. N-13 ammonia/F-18 FDG a. The myocardial extraction of both agents is similar. 31. Which one of the following PET agents b. The redistribution properties of both is used for assessing overall oxidative agents are similar. metabolism in the heart? c. Both agents are monovalent cations. a. F-18 fludeoxyglucose d. Both agents are equivalent in assess- b. C-11 acetate ing myocardial viability. c. C-11 palmitate d. O-15 water 27. Which one of the following pairs of myocardial imaging agents are most 32. Which one of the following PET nu- similar regarding their biologic proper- clides has the shortest physical half-life? ties? a. O-15 a. Thallium and sestamibi b. Rb-82 b. Sestamibi and tetrofosmin c. N-13 c. Tetrofosmin and thallium d. C-11 d. Thallium and fludeoxyglucose 33. All of the following PET agents are 28. Which one of the following agents is markers of coronary blood flow except: taken up into the heart by facilitated dif- a. N-13 ammonia fusion? b. O-15 water a. F-18 fludeoxyglucose c. Rb-82 chloride b. Tl-201 thallous chloride d. F-18 FDG c. Tc-99m sestamibi d. Rb-82 rubidium chloride 34. The PET blood flow marker of choice is: a. Rb-82 chloride b. O-15 water c. N-13 ammonia d. F-18 FDG

57 35. All of the following are associated with 40. The labeling efficiency of Tc-99m red the uptake of FDG into heart muscle ex- blood cells employing the in vivo label- cept: ing method is about: a. lipophilicity a. 60 percent b. anaerobic glycolysis b. 75 percent c. facilitated diffusion c. 85 percent d. phosphorylation d. 98 percent

36. Positive predictive and negative predic- 41. Which one of the following statements tive accuracies for assessing myocardial regarding myocardial ventriculography viability and restoration of ventricular is false? function are highest with which one of a. A first-pass study allows assessment the following studies? of right ventricular function. a. A thallium rest/redistribution study b. An ECG multigated acquisition b. A thallium exercise/redistribution/ (MUGA) study allows assessment of reinjection study left ventricular function only. c. A PET perfusion/metabolism study c. Ventricular volumes and ejection d. A sestamibi rest/stress study fractions can be assessed. d. First-pass and MUGA studies can be 37. Which one of the following agents is done with Tl-201 thallous chloride or able to assess myocardial perfusion ab- Tc-99m sestamibi or Tc-99m labeled normalities with a single dose injection? red blood cells. a. Tc-99m sestamibi b. Tc-99m tetrofosmin 42. A normal left ventricular ejection frac- c. F-18 fludeoxyglucose tion is equal to or greater than: d. Tl-201 thallous chloride a. 35 percent b. 45 percent 38. A revascularization procedure will likely c. 55 percent improve ventricular function in which d. 65 percent one of the following conditions? a. Hibernating myocardium 43. The purpose of the Tl-201 thallous chlo- b. Stunned myocardium ride/Tc-99m sestamibi dual-isotope im- c. Transmural infarction aging protocol is to: d. Non-transmural infarction a. Shorten the study time b. Improve study specificity 39. All of the following are desirable proper- c. Increase study sensitivity ties of a radiopharmaceutical for blood d. Reduce radiation dose pool imaging except: a. Slow blood clearance over time 44. A patient in an emergency situation with b. Minimum accumulation of activity unstable angina requiring immediate in the extravascular space medical care for the condition could best c. High photon flux be evaluated for possible myocardial d. Long physical half-life ischemia at a later time by which one of the following studies? a. Tl-201 rest/redistribution study b. Tl-201 rest/Tc-99m sestamibi stress study

58 c. Tc-99m sestamibi rest study cardial wall motion and decreased d. Tc-99m sestamibi stress study thickening on a gated SPECT study. b. a fixed defect on a Tc-99m sestamibi 45. The radiochemical purity requirement of rest/stress study with normal myo- Tc-99m sestamibi or Tc-99m tetrofos- cardial wall motion and myocardial min must be greater than or equal to: thickening on a gated SPECT study. a. 85 percent c. a reversible defect on a Tc-99m tet- b. 90 percent rofosmin rest/stress study. c. 95 percent d. a reversible defect on a Tl-201 d. 98 percent rest/redistribution study.

46. Which one of the following package in- 49. Which one of the following is not asso- sert instructions for labeling and use of ciated with the mechanism of localiza- Tc-99m sestamibi is false? tion of Tc-99m pyrophosphate in a myo- a. Up to 150 mCi of Tc-99m sodium cardial infarct? pertechnetate can be added to the kit. a. Residual blood flow to the infarct re- b. Heating time in a boiling water bath gion is 10 minutes. b. Influx of calcium ions into the c. Two milliters of air must be intro- infarcted cells duced into the vial before heating. c. Membrane-associated phosphatidyl- d. The radiolabeled product is stable for serine on dying myocytes 6 hours. d. Mitochondrial deposits of hydroxyapatite crystals 47. Which one of the following agents is a neutral lipophilic species? 50. The mechanism of localization of which a. Tc-99m sestamibi one of the following infarct-avid agents b. Tc-99m tetrofosmin is involved with binding to basic his- c. Tc-99m (NOEt)2 tones in damaged myocytes? d. F-18 fludeoxyglucose a. Tc-99m pyrophosphate b. Tc-99m glucarate 48. Each of the following study findings c. Tc-99m annexin V would support a diagnosis of viable d. In-111 imciromab pentetate myocardium except: a. a fixed defect on a Tc-99m sestamibi rest/stress study with abnormal myo-