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Nuclear Imaging and PET


Fundamentals of Radionuclide Imaging

Radionuclide imaging techniques are widely used in the evaluation of patients with known or suspected coronary artery disease (CAD). The basic principle underlying this approach is the use of radiolabeled agents or radiopharmaceuticals that are injected intravenously and enter viable cells (e.g., myocytes, autonomic neurons) or bind to cell receptors or other targets. These techniques use radiolabeled drugs or radiopharmaceuticals, which are injected intravenously and trapped in myocardial tissue or other cell types. This radioactivity within the heart decays by emitting gamma rays. The interaction between these gamma rays and the detectors in specialized scanners—single-photon emission computed tomography (SPECT) and positron emission tomography (PET)—creates a scintillation event or light output, which can be captured by digital recording equipment to form an image of the heart. Like computed tomography (CT) and magnetic resonance imaging (MRI), radionuclide images also generate tomographic (three-dimensional) views of the heart. Contemporary PET and SPECT scanners are frequently combined with a CT scanner (so-called hybrid PET/CT and SPECT/CT). CT is used primarily to guide patient positioning in the field of view and for correcting inhomogeneities in radiotracer distribution due to attenuation by soft tissues (so-called attenuation correction). However, the CT scanner is frequently used to obtain diagnostic data, including coronary artery calcium score and, occasionally, CT coronary angiography.

Protocols for Myocardial Perfusion and Viability Imaging

Imaging protocols are tailored to the individual patient based on clinical questions, patient’s risk, ability to exercise, and body mass index, among other factors. Electrocardiogram (ECG)-triggered gated rest and stress images are acquired after the intravenous injection of the radiopharmaceutical and used to define the extent and severity of myocardial ischemia and scar, as well as regional and global cardiac function and remodeling.

Selecting a Stress Protocol

The choice of exercise versus pharmacologic stress has well-defined guidelines depending upon the patient’s condition, clinical question, and safety considerations. Exercise stress is always preferred over pharmacologic stress in patients who can exercise adequately due to the wealth of additional information that is provided—exercise capacity, hemodynamic response (maximal heart rate, heart rate recovery and reserve, peak blood pressure), stress-induced symptoms, exercise-induced arrhythmias, and ST-segment response. This approach permits coupling of clinical response and stress myocardial perfusion findings.

In patients unable to exercise adequately, pharmacologic stress with vasodilators (adenosine, dipyridamole, or regadenoson) or direct chronotropic/inotropic stimulation with dobutamine is used ( Table 12.1 ). Pharmacologic stress is also preferred in patients with left bundle branch block (LBBB) or paced ventricular rhythm, as it reduces the frequency of false-positive tests related to mechanical dyssynchrony. Among the pharmacologic stress options, vasodilator stress is preferred primarily because it produces the greatest flow heterogeneity, thereby facilitating detection of regional perfusion defects. In patients with contraindications to vasodilator stress (e.g., asthma, AV block, etc.), dobutamine is a safe alternative. Finally, vasodilator stress is commonly used as an adjunct to exercise in patients unable to achieve a maximal exercise stress test.

TABLE 12.1
Pharmacologic Stress Agents in Nuclear Cardiology
Dipyridamole Adenosine Regadenoson Dobutamine
Effect on coronary blood flow × 3–4 × 3–5 × 2–3 × 2
Dose 0.56 mg/kg 140 u/kg per min 0.4 mg Initial 3 minutes infusion of 5–10 μg/kg per min, incremental increases (2–3- minute intervals) to 20, 30, and 40 μg/kg per min. Atropine can be used to increase heart rate if target not achieved
Duration of action/half-life 30–45 minutes < 10–15 seconds Three phases:

  • 1.

    Initial phase (maximal physiologic effect) 2–4 minutes

  • 2.

    Intermediate phase (loss of pharmacologic effect) ∼30 minutes

  • 3.

    Final phase (decline in plasma concentration) ∼2 hours

∼2 minutes
Duration of infusion 4 minutes 4–6-minute infusion ∼10 second Depends on hemodynamic response
Maximal hyperemia 3–4 minutes after infusion 84 seconds (average) 1–4 minutes after injection Peak infusion
Timing of radionuclide injection 3–5 minutes after infusion At 3 minutes for a 6-minute infusion, at 2 minutes for a 4-minute infusion ∼40 seconds after bolus injection Goal of ≥ 85% age-predicted maximum heart rate
Reversal of effect Aminophylline; used commonly Aminophylline; used rarely Aminophylline; used occasionally β-blocker (preferably esmolol), used uncommonly

Imaging Protocols

A number of different protocols have been developed, validated, and tested for accuracy. Imaging protocols must be tailored to individual patients based on the clinical question, radiotracer used, and time constraints. For SPECT myocardial perfusion imaging (MPI) ( Table 12.2 ), technetium 99m-labeled ( 99m Tc-labeled) tracers are the most commonly used imaging agents because they are associated with the best image quality and the lowest radiation dose to the patient. After intravenous injection, myocardial uptake of 99m Tc-labeled tracers is rapid (1–2 minutes). After uptake, these tracers become trapped intracellularly in mitochondria and show minimal change over time. Although used commonly in the past for perfusion imaging, 201 thallium protocols are now rarely used because they are associated with a higher radiation dose to the patient.

TABLE 12.2
Properties of Available SPECT Radiopharmaceuticals
201 Thallium 99m Technetium
sestamibi		 99m Technetium
tetrofosmin
Source Cyclotron Generator Generator
Physical half-life 73 hours 6 hours 6 hours
Clinical application MPI and viability MPI MPI
Redistribution Yes No No
Whole-body effective dose ∼27 mSv per rest/stress study ∼10 mSv per rest/stress study ∼9 mSv per rest/stress study
Length of complete study (rest/stress imaging) ∼4 hours ∼2–3 hours ∼2–3 hours

PET MPI is an alternative to SPECT and is associated with improved diagnostic accuracy and lower radiation dose to patients due to the fact that radiotracers are typically short-lived ( Table 12.3 ). The ultra-short physical half-life of some PET radiopharmaceuticals in clinical use (e.g., 82 rubidium) is the primary reason that PET imaging is generally combined with pharmacologic stress, as opposed to exercise, as pharmacologic stress allows for faster imaging of these rapidly decaying radiopharmaceuticals. However, exercise is possible for relatively longer-lived radiotracers (e.g., 13 N-ammonia). For myocardial perfusion imaging, 82 rubidium does not require an onsite medical cyclotron (it is available from a 82 strontium/ 82 rubidium generator) and, thus, is the most commonly used radiopharmaceutical. 13 N-ammonia has better flow characteristics (higher myocardial extraction) and imaging properties than 82 rubidium but it does require access to a medical cyclotron in close proximity to the PET scanner. In comparison to SPECT, PET has improved spatial and contrast resolution and it provides absolute measures of myocardial perfusion (in mL/min per g of tissue), thereby providing a quantitative measure of regional and global coronary flow reserve that is unique. Quantitative measures of myocardial blood flow and flow reserve help improve diagnostic accuracy and risk stratification.

TABLE 12.3
Properties of Commonly Used PET Radiopharmaceuticals
13 N-ammonia 82 RUBIDIUM 18 F-fluorodeoxyglucose 15 O-water ∗
Source Cyclotron Generator Cyclotron Cyclotron
Physical half-life 9.96 minutes 76 seconds 110 minutes 2.1 minutes
Clinical application MPI MPI Myocardial viability MPI
Exercise stress Yes No NA No
Myocardial blood flow measurement (mL/min per g) Yes Yes NA Yes
Whole-body effective dose ∼2.96 mSv per rest/stress study ∼3.72 mSv per rest/stress study ∼7 mSv per study ∼2.75 mSv per rest/stress study
Length of complete study (rest/stress imaging) ∼70 minutes ∼25 minutes ∼2 hours ∼25 minutes

∗ 15 O-water is not FDA approved for clinical use and is only used in research studies.

For the evaluation of myocardial viability in patients with severe left ventricular (LV) dysfunction, myocardial perfusion imaging (with SPECT or PET) is usually combined with metabolic imaging (i.e., 18 F-fluorodeoxyglucose [FDG] PET). In hospital settings lacking access to PET scanning, 201 thallium SPECT imaging is a useful alternative.

Comprehensive Evaluation of Coronary Artery Disease

Detection of Coronary Artery Stenosis

The basic principle of radionuclide MPI for detecting CAD is based on the ability of a radiotracer to identify a transient regional perfusion deficit in a myocardial region subtended by a coronary artery with a flow-limiting stenosis. A reversible myocardial perfusion defect is indicative of ischemia ( Fig. 12.1A ), whereas a fixed perfusion defect generally reflects scarred myocardium from prior infarction ( Fig. 12.1B ). Generally, myocardial perfusion defects during stress develop downstream from epicardial stenosis with 50% to 70% luminal narrowing or greater and become progressively more severe with increasing degree of stenosis. It is noteworthy that coronary stenosis of intermediate severity (e.g., 50–90%) is associated with significant variability in the resulting maximal coronary blood flow, which in turns affects the presence and/or severity of regional perfusion defects. For any degree of intermediate luminal stenosis, the observed physiologic variability is multifactorial and includes (1) geometric factors of coronary lesions not accounted for by a simple measure of minimal luminal diameter or percent stenosis, including shape, eccentricity, and length, as well as entrance and exit angles, all of which are known to modulate coronary resistance; (2) development of collateral blood flow; and (3) the presence of diffuse coronary atherosclerosis and microvascular dysfunction (combination of endothelial and smooth muscle cell dysfunction in resistive vessels, and microvascular rarefaction), all consistent findings in autopsy and intravascular ultrasound studies of patients with CAD. All these factors account for the frequent disagreements between angiographically defined CAD and its associated physiologic severity.

FIG. 12.1, Examples of reversible (A) and fixed (B) defects. In (A) , moderate- to severe-intensity reversible defects involving the basal and mid-anterior and lateral walls extending to the distal and apical ventricle are present. In (B) , there is a severe-intensity fixed defect involving the anteroseptal and anterior wall at the basal, mid, and distal LV extending to the apex with no clinically meaningful reversibility.

Quantification of Myocardial Ischemia

Regional myocardial perfusion is usually assessed by semi-quantitative visual analysis of the rest and stress images. The segmental scores are then summed into global scores that reflect the total burden of ischemia and scar in the left ventricle ( Fig. 12.2 ). Objective quantitative image analysis is a helpful tool for a more accurate and reproducible estimation of total defect size and severity and is generally used in combination with the semi-quantitative visual analysis. The semi-quantitative (visual) and quantitative scores of ischemia and scar are linearly related to the risk of adverse cardiovascular (CV) events and are useful in guiding patient management, especially the need for revascularization, and for assessing response to medical therapy. The presence of transient LV dilatation during stress imaging (so-called transient ischemic dilatation or TID) is an ancillary marker of risk that reflects extensive subendocardial ischemia and often accompanies radionuclide MPI studies with extensive and severe perfusion abnormalities ( Fig. 12.3A ). It is often an important finding, particularly when it occurs in patients with no or only mild perfusion abnormalities, suggesting the presence of more extensive balanced subendocardial ischemia. The presence of this abnormality has often been shown to be a harbinger of increased risk. Similarly, the presence of transient pulmonary radiotracer retention and right ventricular uptake during stress along with a drop in left ventricular ejection fraction (LVEF) post-stress (a sign of post-ischemic stunning) are also markers of multivessel LV ischemia ( Figs.12.3B and C ; ).

FIG. 12.2, Segmental scoring system used for interpretation and reporting of MPI. The perfusion images on the upper left reveal a severe-intensity reversible defect involving the basal, mid-, and distal anteroseptal region extending to the apex. The polar plot bullseye images on the upper right capture this defect as well. LAD, Left anterior descending artery; LCX, left circumflex artery; LV, left ventricle; RCA, right coronary artery.

FIG. 12.3, Example of myocardial perfusion imaging (MPI) high-risk features (multivessel defects, transient ischemic dilatation [TID], pulmonary uptake, drop in left ventricular ejection fraction [LVEF] post stress). (A) Images reveal a moderate- to severe-intensity defect involving the mid to distal lateral and inferior walls extending to the apex and distal septum. Additionally, the projection images ( below ) reveal lung uptake of tracer on the stress views ( left ) not present on the rest view ( right ). (B) The decrease in LVEF is shown between the images on the upper and lower portions of the figure associated with these abnormalities. See corresponding Video 12.1 . (C) The catheterization correlate of the images (lesions in the distal left anterior descending artery (LAD), a diagonal artery (Diag), the left circumflex (LCX), and the right coronary artery (RCA) ( arrows ).

Quantification of Myocardial Blood Flow and Coronary Flow Reserve

Myocardial blood flow (in mL/min per g of myocardium) and coronary flow reserve (CFR; defined as the ratio between peak stress and rest myocardial blood flow) are important physiologic parameters that can be measured by routine post-processing of myocardial perfusion PET images. These absolute measurements of tissue perfusion are accurate and reproducible. Pathophysiologically, CFR estimates provide a measure of the integrated effects of epicardial coronary stenoses, diffuse atherosclerosis and vessel remodeling, and microvascular dysfunction on myocardial perfusion, and, as such, the value obtained is a more sensitive measure of myocardial ischemia. In the setting of increased oxygen demand, a reduced CFR can upset the supply–demand relationship and lead to myocardial ischemia, subclinical LV dysfunction (diastolic and systolic), symptoms, and death. As discussed hereafter, these measurements of CFR have important diagnostic and prognostic implications in the evaluation and management of patients with known or suspected CAD ( Fig. 12.4 ).

FIG. 12.4, Example of single vessel defect on PET MPI with diffuse abnormal coronary flow reserve (CFR) and left main (LM) disease. Perfusion images ( upper right ) reveal a severe-intensity reversible defect involving the lateral wall at the basal, mid, and distal LV. The CFR data (Table) reveal limitations of flow reserve both in the left circumflex (LCX) and left anterior descending artery (LAD) territories, the latter not evident on the PET MPI images. Inset below : Concept of coronary flow reserve. MBF, Myocardial blood flow.

Assessment of Myocardial Viability

Myocardial perfusion and metabolic imaging are commonly used to evaluate the patient with ischemic LV dysfunction, especially when the question of revascularization is being considered. Radionuclide imaging provides important quantitative information, including (1) myocardial infarct size; (2) extent of stunning and hibernating myocardium; (3) magnitude of inducible myocardial ischemia; and (4) LV function and volumes (see Fig. 12.3 and Fig. 12.5 ).

FIG. 12.5, Example of quantification of myocardial viability and scar in ischemic cardiomyopathy using PET MPI. A severe intensity perfusion defect involving the length of the septum to the apex is present on the rest images, with a small, basal inferolateral defect. The 18 F-fluorodeoxyglucose [FDG] (metabolism) images reveal uptake in the septal, but not the inferolateral, region, suggestive of hibernating myocardium in the former. LAD, Left anterior descending artery; LCX, left circumflex artery; LV, left ventricle; RCA, right coronary artery.

Both 201 thallium and, especially, 99m Tc agents provide accurate and reproducible measurements of regional and global myocardial infarct size. The use of metabolic imaging with PET has been extensively validated and is commonly used for assessing myocardial viability. 18 FDG is used to assess regional myocardial glucose utilization (an index of tissue viability) and is compared with perfusion images to define metabolic abnormalities associated with infarction and hibernation. Reduced perfusion and increased FDG uptake at rest (so-called perfusion–FDG mismatch) identifies areas of viable but hibernating myocardium, whereas regions showing both reduced perfusion and FDG uptake at rest (so-called perfusion–FDG match) are consistent with myocardial scar ( Fig. 12.6 ). These metabolic patterns have important implications for selecting patients for revascularization.

FIG. 12.6, Patterns of positron emission tomography (PET) viability; examples of PET myocardial perfusion imaging (MPI) match and mismatch. On the left, severe-intensity defects of the mid- to distal anterior wall and apex are present on perfusion and metabolism images (match). On the right, a mild resting abnormality in this same region is present with uptake of tracer on the metabolism images (mismatch). FDG, 18 F-fluorodeoxyglucose; RB-82, rubidium-82 chloride.

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