Myocardial Perfusion SPECT

Conventional single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) evaluates the presence, extent, and degree of myocardial ischemia or infarction (ie, flow-limiting defects). SPECT is a nuclear medicine topographic imaging technique that uses gamma rays. It is similar to conventional nuclear medicine planar imaging using gamma cameras; however, the computer in SPECT provides 3-dimensional (3D) images. SPECT is based on the flow-dependent and/or metabolism-dependent selective uptake of a radioactive tracer by functional myocardial tissue. This method was developed to evaluate myocardial perfusion and viability and is applied both at rest and after exercise or pharmacologic stress to assess inducible ischemia due to flow-limiting coronary stenoses.

MPI is widely used in patients with coronary artery disease, and reconstruction algorithms improve the diagnostic accuracy and image quality. Hybrid SPECT/CT scanning combines the 2 types of images and allows attenuation correction and reduction of scanning time.[1, 2, 3, 4, 5, 6]

The technique involves the intravenous injection of small amounts of radioactive tracer (gamma-emitting radioisotope), which is avidly taken up by the cardiomyocytes so that the initial myocardial tracer distribution is in proportion to the viable myocardium. The use of cadmium-zinc-telluride (CZT) has improved the performance of SPECT  by improving detection sensitivity and spatial resolution, as well as reducing the radiation dose.[7, 8, 9]  The CZT detector works as a semiconductor with direct conversion of gamma radiation to electric signal.[10]

The history of cardiac nuclear medicine dates back to 1973, which marked the introduction of the exercise stress-test myocardial scan by H. William Strauss[11]  and the first application of thallium-201 myocardial perfusion imaging by Elliot Lebowitz. Since then, it has been increasingly used in clinical cardiology. Technical developments that have fueled this increase are single-photon emission tomographic (SPET) imaging, pharmacologic stress, and electrocardiogram (ECG)-gated imaging. ECG-gated SPECT images allow for the assessment of the global left ventricular ejection fraction (LVEF), regional wall motion, and regional wall thickening at rest in patients with documented stress-induced wall motion and perfusion abnormalities.[12, 13]

The underlying principle is that under conditions of stress, the diseased myocardium receives less blood flow than normal myocardium. SPECT imaging performed after stress reveals the distribution of the radiopharmaceutical and, therefore, the relative blood flow to the different regions of the myocardium. Comparing stress images to a further set of images obtained at rest aids in diagnosis.

Images taken during dynamic exercise or pharmacologically induced stress (using vasodilators such as adenosine or a beta-agonist such as dobutamine) and rest injections enable independent assessment of myocardial perfusion and viability.

(Note the summary figure and other images below.)

Device summary. To acquire single-photon emission computed tomography (SPECT) images, the patient lies still in a supine position, and the gamma camera is rotated around the patient. Courtesy of Patrick J. Lynch, Yale University.

Single-photon emission computed tomography (SPECT) images compared with illustrations of the heart from similar views. The SPECT images (bottom row) show the distribution of the tracer and therefore the relative blood flow to the different regions of the myocardium. The top rows are illustrations of the heart to compare with the SPECT images from similar views. Notice there are more enhancements in the area that corresponds to the left ventricle because of its greater thickness. Courtesy of Patrick J. Lynch, Yale University.

Planar imaging. The gamma camera detects the gamma rays emitted from the tracer, and the image of where the tracer is found in the organs is transmitted to the computer. In planar technique, the computer provides a 2-dimensional myocardial perfusion image. Courtesy of Patrick J. Lynch, Yale University.

SPECT imaging performed after stress. The upper row shows short-axis slices after pharmacologic stress; the lower row shows the same slices when the body is at rest in conventional cardiac SPECT with Tc-99m tetrofosmin as a radiotracer. Arrows indicate a small perfusion defect on the backside of the heart (visible only on the stress images), showing ischemia in this region of the heart wall. Courtesy of Philipp A Kaufmann, MD, and Oliver Gämperli, MD, University Hospital Zurich.

Patient consent

In the area of medicolegal protection, an informed consent to performa exercise testing must be obtained. A detailed explanation of the procedures, procedure planning, and the indication for the test should be provided. The health care professional obtaining consent should also outline the possible adverse effects and complications.

Analysis

According to the American Society of Nuclear Cardiology, SPECT myocardial perfusion images should be analyzed as follows[14, 15] : 

• Evaluate the raw images or the reconstructed maximum intensity projection image in cine mode, and review of sinogram and linogram images, to determine the presence of potential sources of image artifact and the distribution of extracardiac tracer activity.
• Interpret images with respect to the location, size, severity, and reversibility of perfusion defects, as well as cardiac chamber sizes, and the presence or absence of increased pulmonary uptake (especially ²⁰¹Tl). 
• Evaluate results of quantitative perfusion analysis.
• Evaluate functional data obtained from gated images.
• Consider the clinical data, stress ECG, and hemodynamic data that may influence the final interpretation of the study.

In patients who present with acute, stable chest pain, SPECT has been shown to be more cost-effective than any other diagnostic modality to date[16] and more accurate than exercise ECG in detecting myocardial ischemia. Special indications include determination of the hemodynamic significance of anomalous coronary arteries[17] and muscle bridging[18] and coronary aneurisms in the setting of Kawasaki disease.[19]

Inferior and posterior abnormalities and small areas of infarction can be identified, as well as the occluded blood vessels and the mass of infarcted and viable myocardium.

In patients with known coronary artery disease, SPECT has been proven to be a powerful technique in predicting the likelihood of future cardiac events.[20]

In assessing viable myocardium in a specific coronary artery distribution after a heart attack, stress images in SPECT may help determine the degree of inducible ischemia or viable myocardium amenable to revascularization.[21, 22, 23]

Absolute contraindications to dynamic exercise include the following:

• In patients with non-ST-segment elevation acute coronary syndrome or unstable angina, once stabilized, exercise stress can be considered 24-72 hours after chest pain, depending on clinically assessed risk.[24] ST-segment elevation myocardial infarction (MI) within the previous 4 days.[25]

• Left main coronary artery stenosis that is likely to be hemodynamically significant; left ventricular failure with symptoms at rest; recent history of life-threatening arrhythmias; severe dynamic or fixed left ventricular outflow tract obstruction (aortic stenosis and obstructive hypertrophic cardiomyopathy); severe systemic hypertension (systolic blood pressure > 220 mm Hg and/or diastolic blood pressure >120 mm Hg); recent pulmonary embolism or infarction, thrombophlebitis, or active deep vein thrombosis; and active endocarditis, myocarditis, or pericarditis are absolute contraindications.[26]

Relative contraindications to dynamic exercise include the following:

• Left bundle branch block (LBBB), bifascicular block, and ventricular paced rhythms (because dynamic exercise leads to perfusion abnormalities of the septum and adjacent walls in the absence of obstructive coronary disease)[27]

• Inability or poor motivation to perform dynamic exercise

• Recent exercise ECG that failed to achieve an acceptable workload (≥85% of the maximum predicted heart rate)

Absolute contraindications to vasodilator stress include the following:

• Recent acute coronary syndrome is a contraindication. Once stabilized, stress with vasodilators can be considered 24-72 hours after chest pain, depending on clinically assessed risk.[24]

• Suspected or known severe bronchospasm, second-degree and third-degree atrioventricular block in the absence of a functioning pacemaker, sick sinus syndrome in the absence of a functioning pacemaker, hypotension (systolic blood pressure < 90 mm Hg), and xanthine intake in the last 12 hours, or dipyridamole use in the last 24 hours are contraindications.[28]

Relative contraindications to vasodilator stress include the following:

• Bradycardia of less than 40 beats/min: Initial dynamic exercises normally increases the rate sufficiently to start the infusion.[28]

• Recent cerebral ischemia or infarction

Absolute contraindications to dobutamine stress include the following:

• Same as for dynamic exercise

• Known hypokalemia[29]

Relative contraindications to dobutamine stress include left bundle branch block, bifascicular block, and paced rhythm, for the same reason as for dynamic exercise.

Radiation exposure

Myocardial perfusion imaging has the highest average effective dose (15.6 mSv) and the highest percentage (22.1%) of all effective doses compared with other major radiologic procedures, including CT studies.[30] Low-dose ionizing radiation has been linked with up to 2% of solid cancers and leukemia. A small but cumulative danger from radiation due to SPECT is noted. However, radioactive tracers such as rubidium-82 reduce the radiation dose to the patient by a factor of 10 compared to technetium-99m. A complete myocardial perfusion examination with a dose less than 3 mSv may be achieved in the future.[31, 32]

According to a study by Einstein et al, compared with standard Anger SPECT (A-SPECT) cameras, high-efficiency (HE) cameras with specialized collimators and solid-state cadmium-zinc-telluride detectors offer the potential to maintain image quality while reducing the radiation dose. They found that ultra-low-dose high-efficiency SPECT (ULD HE SPECT) rest imaging correlates highly with standard-low-dose (SLD) A-SPECT. ULD HE SPECT was shown to have improved image quality, to have comparable extracardiac activity, and to achieve radiation dose reduction to 1 mSv for a single injection.[33]

In a Netherlands study of 24 patients who underwent clinically indicated myocardial perfusion imaging with cadmium zinc telluride (CZT) SPECT and a body weight-dependent (3 MBq/kg) technetium-99m-tetrofosmiin tracer dose, differences in segmental uptake values, ejection fraction, and end-diastolic volume were greater for shorter scans than for the 8-minute reference scan. Six minutes was the shortest acquisition time in stress MPI that did not affect the diagnostic value for a tracer dose of 3 MBq/kg.[34]  On average, the diagnostic value was influenced in 7.7 segments per patient using the 2-minute scans, in comparison to 2.0 and 0.8 segments per patient using the 4- and 6-minute scans, respectively. In addition, the 4-min scans led to a significantly reduced image quality compared to the 8-min scans (P< 0.05). This was not the case for the 6-minute scan.[34]

The use of a hybrid CZT SPECT/64-slice CT system for dose reduction was studied to determine maximal degree of dose reduction without compromising image quality and quantification precision of clinical MPS. Ultra-low dose (< 190 MBq) myocardial perfusion imaging, even with short imaging times (< 6 min), was found to be feasible using a hybrid CZT SPECT/CT camera without compromising image quality or significantly altering quantification of myocardial perfusion or LV function.[35]

According to the authors, an additional 50% reduction of current low-dose recommendations from American Society of Nuclear Cardiology (ASNC) guidelines for 99mTc-labeled myocardial perfusion imaging is highly feasible while retaining short imaging protocols. For patients of normal MPS, there were no differences in defect size (DS), LV volumes, and ejection fraction (EF), regardless of 50% or 75% dose reduction. For patients of abnormal MPS, at 50% dose reduction, there was a significant difference in global DS but not in regional DS in the left anterior descending (LAD), left circumflex (LCX), and right coronary artery (RCA) regions. At 75% dose reduction, however, the difference was statistically significant in all areas, including global DS. Nonetheless, differences in the DS were minimal. The LV end-diastolic and end-systolic volumes and LVEF were not significantly different, regardless of 50% or 75% DR.[35]

Allergic potential to radiocontrast

Contrary to the risk of radiocontrast-induced allergy seen in CT angiography and coronary angiography, SPECT has a small risk of dye allergy. This is because in SPECT the radioisotopes used are in nanomole quantities and the vehicle used is normal saline. No known adverse reactions to the chemical molecules are recognized (sestamibi or tetrofosmin).

Other considerations

The presence of a healthcare professional that is up-to-date with basic life support is required for the duration of all stress procedures. Personnel trained in advanced life support should be rapidly available. Emergency equipment, drugs, and support personnel should also be available.

The incidence of fatal myocardial infarction/cardiac death in patients undergoing stress for myocardial perfusion imaging for exercise, dobutamine,[36, 37] dipyridamole,[38] or adenosine[39]  has been shown to be 0.01, 0.0, 0.05 and 0.0%, respectively.[39] The incidence of nonfatal myocardial infarction/major cardiac complication in patients undergoing stress for myocardial perfusion imaging for exercise, dobutamine, dipyridamole, or adenosine has been shown to be 0.02, 0.3, 0.05 and 0.1%, respectively.[36, 37, 38, 40, 39]

Dynamic exercise

Dynamic exercise is the stress technique of choice in patients with suspected or known CAD, provided that the patient is able to exercise at an acceptable workload (≤85% of the maximum predicted heart rate).[41, 42]

The patient should withdraw from drugs that may interfere with a physiologic exercise response. Beta antagonists and calcium channel antagonists should be discontinued for 5 half-lives before the test unless medically contraindicated. Patients should avoid caffeine-containing foods, beverages, and drugs for a minimum of 12 hours before the test. This allows the use of vasodilator agents in cases where the exercise is terminated and pharmacologic stress is undertaken. Patients should be instructed to dress appropriately for exercise. Fasting is not essential. Although many centers routinely fast patients before imaging, the advantages of this policy is unproven.

Pharmacologic stress

Pharmacologic stress is an excellent alternative to dynamic exercise. Pharmacologic stress with vasodilators is the procedure of choice for patients unable to exercise adequately[43] or for those with LBBB or paced rhythm.[44]

Patients stressed with the vasodilators adenosine or dipyridamole (vasodilator stress) must abstain from caffeinated foods, beverages, and drugs for a minimum of 12 hours before the test and preferably for 24 hours.[45] Aminophylline and theophylline must be stopped 24 hours before the test.[46] Patients on dipyridamole should discontinue the drug for a minimum of 24 hours before vasodilator stress.

Patients stressed with dobutamine should stop beta antagonists for 5 half-lives or at least 24 hours before the test unless contraindicated.

No anesthesia is required before SPECT testing.

Positioning

The patient should be supine with both arms above the head, as shown below.

Positioning. The patient should be supine with both arms above the head. Courtesy of Philips Healthcare.

Knee support may also be helpful because patient’s comfort is essential to minimize motion. Prone imaging has been used in some centers to reduce the incidence of inferior attenuation artifact[47] but can produce anterior artifacts and is not recommended in isolation.

Female patients should be imaged without underwear. A chest band can be used to minimize breast attenuation and to ensure reproducible positioning during later image acquisition.

The value of SPECT in the diagnosis of CAD was confirmed in a meta-analysis, which demonstrated that it is highly effective in assessing myocardial perfusion, with a quoted sensitivity of 86%, a specificity of 74%, and a normalcy rate of 89%.[16]

The negative predictive value of the test has been shown to be as high as 98%, offering excellent prognostic value. A normal technetium-201 or technetium-99m scan is generally associated with low risk of future cardiac events (< 1%/yr). A report of 2946 patients with a normal scan showed a low risk for cardiac death or myocardial infarction (< 0.5%/yr and < 0.3%/yr, respectively) at 1.8-year follow-up.[48]

High-risk features on SPECT that predict an increased risk of cardiac events include extensive ischemia involving more than 20% of the left ventricle, defects in more than one coronary vascular supply region, reverse ischemia in multiple segments, transient or persistent left ventricular cavity dilatation, left ventricular ejection fraction less than 45%,[48] and increased lung uptake of thallium or sestamibi.[49, 50, 51] These factors predict an annual mortality of more than 3%. For patients with normal, mildly abnormal, moderately abnormal, or severely abnormal perfusion defects, the annual rate of cardiac death in one study was 0.5%, 2.7%, 2.9%, and 4.2%, respectively.[48]

Standard (not-gated) radionuclide scanning of the heart includes data from throughout the cardiac cycle in a single image, without discrimination of systole and diastole. Using a technique called ECG gating, sequential data can be obtained with timing to the cardiac cycle, thus providing images specific to phases of systole and diastole.[41]  With this technique, gated myocardial SPECT can be used to obtain quantitative information about myocardial perfusion, thickness, and contractility. This, in turn, allows calculations of left ventricular ejection fraction, stroke volume, and cardiac output.

The laboratory workup needed before a patient undergoes SPECT is namely related to contraindications, including testing for cardiac enzymes to rule out acute coronary syndrome.

Exercise testing must be undertaken by an appropriately trained healthcare professional. If a physician is not performing the test, a physician experienced in cardiovascular stress should be available for assistance in case of an emergency.[52] Rapid access to personnel trained in advanced life support should be available.

Dynamic exercise can be undertaken using a treadmill or a bicycle ergometer.

Regardless of the exercise protocol, an intravenous line should be secured and flushed to ensure patency before starting the test.

The patient’s heart rate, blood pressure, and ECG should be monitored at rest and throughout the test. In a standard rest/stress protocol, a patient is imaged twice: once at rest and then after the patient is stressed by exercise or pharmacologic stimulation.[53] Monitoring with a 12-lead ECG is required for the detection of ST-segment and T-wave changes and for the diagnosis of arrhythmias.

For administration of adenosine, an intravenous line is required and a 3-way connector should be used to allow tracer injection without interruption of the adenosine infusion. The adenosine is infused at 0.14 mg/kg/min IV for 6 minutes (total cumulative dose of 0.84 mg/kg). Heart rate, blood pressure, and ECG should be measured and recorded at baseline and every 2 minutes during the infusion. The radiopharmaceutical agent (ie, thallium-201) is injected after 3-4 minutes of the adenosine infusion. Thallium-201 is physically compatible with adenosine and may be injected directly in the adenosine infusion set.

Intravenous dipyridamole is infused at a rate of 0.142 mg/kg/min IV for 4 minutes (not to exceed a cumulative dose of 0.57 mg/kg). Vital signs and ECG are measured and recorded at baseline and every 2 minutes. The radiopharmaceutical should be injected 4 minutes after completion of the infusion.

Dobutamine infusion is commonly used when dynamic exercise is not feasible and contraindications to vasodilator stress are recognized. It is given as an intravenous infusion at incremental doses. Vital signs and ECG are recorded. The radiopharmaceutical should be injected when more than 85% of the age and sex adjusted maximum predicted heart rate is reached. The dobutamine infusion should be continued for 1 minute after the injection of thallium-201 or 1-2 minutes after the injection of technetium-99m-labeled tracers and is then stopped.

The image obtained by the gamma cameras is a 2-dimensional (2D) view of a 3-dimensional (3D) distribution of radionuclide. SPECT imaging is performed by using a gamma camera to acquire multiple 2D images (called projections) from different angles. A computer then yields a 3D image by using by using a tomographic reconstruction algorithm for the multiple projections. This 3D dataset can then be manipulated to show thin slices along any chosen axis of the body, similar to those obtained from other topographic techniques, such as MRI, CT, or positron emission tomography (PET).

Reconstruction images typically have resolutions of 64x64 or 128x128 pixels, with the pixel size ranging from 3 to 6 mm. The number of projections required is chosen to be approximately equal to the width of the resulting images. In general, the resulting reconstructed images have lower resolution, have more noise than planar images, and are susceptible to artifacts.

To acquire SPECT images, the patient lies still in a supine position, and the gamma camera is rotated around the patient. The patient must not move during the scan time. Movement can cause significant degradation of the reconstructed images,[54]  although movement compensation reconstruction techniques can help. A highly uneven distribution of the radiopharmaceutical also has the potential of causing artifacts. An intense area of activity (eg, the bladder) can cause extensive streaking of the images and obscure neighboring areas of activity. The traditional filtered back projection reconstruction algorithm has this limitation. However, alternative techniques like the interactive reconstruction algorithm is less sensitive to artifacts and can also correct for attenuation and depth dependent blurring.

Several projections are obtained at defined points during the rotation (on average, every 3-6°). In most cases, a full 360° is used to obtain an optimal reconstruction. Typically, it takes 15-20 seconds to obtain each projection, for a total scan time of 15-20 minutes.

Multiheaded gamma cameras are able to acquire projections in a shorter amount of time. A dual-headed camera (each gamma camera spaced 180° apart) allows 2 projections to be acquired simultaneously, with each head requiring a 180° rotation. A triple-head camera requires only a 120° rotation. With multiheaded SPECT systems, imaging can often be completed in less than 10 minutes.

Because the radionuclide slowly redistributes, performing both sets of images on the same day is not possible. Therefore, a second attendance is sometimes required 1-7 days later. However, with a TI-201 myocardial perfusion study with dipyridamole, rest images can be acquired as little as 2 hours post stress. If stress imaging is normal, rest imaging is unnecessary. For this reason, stress imaging is obtained first.

Attenuation of the gamma rays within the patient can lead to significant underestimation of activity in deep tissues, compared to superficial tissues. and can therefore decrease specificity of SPECT imaging.[28]  Approximate correction is possible, based on relative position of the activity. However, optimal correction is obtained with measured attenuation values. Modern SPECT equipment has an integrated x-ray CT scanner. Because x-ray CT images are an attenuation map of tissues, this data can be incorporated into the SPECT reconstruction to correct for the attenuation.

CT attenuation correction (CTAC) images are considered nondiagnostic; however, clinically significant incidental findings requiring follow-up have been reported.[55, 56]

A radioisotope is used for this type of diagnostic test. The most commonly used tracers are thallium-201 thallous chloride (thallium), technetium-99m-2-methoxy-isobutyl-isonitrile (99mTc MIBI) and 99mTc 1,2-bis [bis(2-ethoxyethyl)phosphino] ethane (tetrofosmin). Thallium-201 and the 2 technetium-labeled radiopharmaceuticals (MIBI and tetrofosmin) are commercially available.

A pharmacologic stress with vasodilators is the procedure of choice for patients unable to exercise adequately or for those with LBBB or paced rhythm. The 2 more commonly used vasodilators are adenosine and dipyridamole.

Dobutamine infusion is commonly used when dynamic exercise is not feasible and contraindications to vasodilator stress are noted.

Thallium-201

Thallium-201 was introduced as a perfusion tracer because of its high (about 80%) first pass myocardial extraction fraction and provides a good estimate of myocardial blood flow.[35] The myocardial uptake of thallium-201 is a sarcolemmal membrane Na/K ATPase-dependent active process requiring cell membrane integrity. It is therefore indicative of myocardial viability. Thallium-201 uptake by myocytes is a reflection both of regional perfusion and viability. Its physical half-life is prolonged (73 h), limiting the overall amount that can be administered.

Technetium-99 Labeled Radiotracers

Technetium-99m sestamibi, a lipophilic cationic compound, and Tc-99m tetrofosmin, a diphosphine agent, are the Tc-99m labeled radiotracers. The uptake of these agents across myocytes cell membranes is by passive diffusion and generally parallels myocardial perfusion, in contrast to the active uptake thallium-201.[36] The uptake of these compounds depend on the presence of intact electrochemical gradients across sarcolemmal and mitochondrial membranes. A significant difference from thalium-201 is that these agents show minimal distribution within the myocardium. They also have a shorter half-life of 6 hours.

Another less commonly used agent is teboroxime. It differs from thallium and sestamibi in that its uptake appears to be relatively insensitive to myocardial injury.[37] Therefore, teboroxime may serve as a pure blood flow agent that does not depend on cellular viability. In contrast to sestamibi, teboroxime is characterized by rapid uptake and washout, with a clearance half-time in the myocardium of only a few minutes.

Class Summary

The two more commonly used vasodilators for pharmacologic myocardial perfusion imaging is adenosine and dipyridamole. These drugs produce primary coronary vasodilation that is mediated by the A2A adenosine receptors.[57] Adenosine and dipyridamole are equally effective diagnostically, but adenosine has the advantages of a short half-life, rapid reversal of side effects after the test is completed, and possibly more predictable vasodilation. On the other hand, because of its longer half-life, patients can receive a dipyridamole infusion and then undergo any level of supplemental exercise.

Adenosine (Adenoscan)

Adenosine is a potent vasodilator in most vascular beds, except in renal afferent arterioles and hepatic veins where it produces vasoconstriction. It is indicated as an adjunct to thallium-201 myocardial perfusion scintigraphy in patients unable to exercise adequately.

Dipyridamole

Dipyridamole injection is a coronary vasodilator. The mechanism of vasodilation has not been fully elucidated, but may result from inhibition of uptake of adenosine, an important mediator of coronary vasodilation. It is indicated as an alternative to exercise in thallium myocardial perfusion imaging for the evaluation of coronary artery disease in patients who cannot exercise adequately.

Class Summary

Dobutamine is indicated as a stress agent in patients who are not candidates for vasodilator stress testing including those with reactive airways disease or those who have recently taken theophylline or have recent significant caffeine intake.

Dobutamine

Dobutamine is a potent beta1-receptor agonist and a week beta2-receptor agonist. The beta1 stimulation produces positive inotropic and chronotropic effects, and the beta2 stimulation produces peripheral vasodilation.