Contrast Perfusion Imaging

The new echocardiographic contrast agents consist of inert perfluorocarbon gases encapsulated in a biodegradable shell. Contrast microbubbles have a small diameter (<10 |im) that allows them to cross the pulmonary capillary bed. These agents are commercially available and are approved for endocardial border definition in patients with suboptimal echocardiography images. When exposed to ultrasound,

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Figure 3-5. Receiver operating characteristic display, indicating 95% confidence intervals for various imaging techniques used for the evaluation of myocardial viability. The most effective modalities are located closer to the upper right corner of the graph. In this display, a smaller square reflects narrower confidence intervals. FDG PET, 18F-fluorodeoxyglucose positron emission tomography; LD, low dose; Tc99m MIBI, technitium-99m sestamibi; Tl201, thallium 201. (From Bax JJ, Wijns W, Cornel JH, et al: Accuracy of currently available techniques for prediction of functional recovery after revascularization in patients with left ventricular dysfunction due to chronic coronary artery disease: Comparison of pooled data. J Am Coll Cardiol 1997;30:1451-1460.)

these microbubbles act as strong reflectors because of their liquid-gas interface. Over the last decade, there has been growing interest in the application of contrast microbubbles for the assessment of myocardial perfusion. Because the LV myocardium has a dense capillary bed, the injection of contrast microbubbles results in myocardial enhancement that is proportional to the myocardial blood volume. During vasodilator stress, in the presence of a flow-limiting stenosis, there is a reduction in capillary blood flow and myocardial blood volume in the segments supplied by the stenotic vessel. This may be detected as either a delay in myocardial enhancement after contrast injection or a relative reduction in enhancement in ischemic compared with normal segments (Figs. 3-6 and 3-7).

Studies have shown relatively good agreement between myocardial contrast echocardiography and single-photon emission computed tomography (SPECT) for the detection of ischemia.10,11 A study performed in a group of patients determined to be at high risk but without resting wall motion abnormalities reported a sensitivity of 85% by myocardial contrast echocardiography versus 74% by SPECT for the detection of obstructive CAD.12 The high spatial and temporal resolution of myocardial contrast echocar-diography makes it suitable for the detection of non-transmural ischemia and milder ischemia, in which blood flow may be reduced but blood volume is preserved (late enhancement). However, data have been limited to few reports, and, in some studies where the sensitivity has been reported to be high, the specificity has been low. A recently published multicenter trial performed in 123 patients reported a sensitivity of 84% but a specificity of 56%.13 Moreover, current protocols for image acquisition and interpre-

Figure 3-6. Myocardial contrast perfusion study showing a stress-induced (adenosine) perfusion defect not present at rest in the middle and apical anteroseptal region (arrows) in a patient with severe stenosis of the middle left anterior descending coronary artery.

Figure 3-7. Myocardial contrast perfusion study showing a perfusion defect present both at rest and during stress (adenosine) in the basal septal region (arrows) in a patient with an occluded right coronary artery.

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tation are considerably more technically demanding than those required for SPECT imaging. Therefore, at the present time, the clinical use of myocardial contrast echocardiography for perfusion assessment is limited to a few centers.

Stress Nuclear Perfusion Imaging

The assessment of myocardial perfusion by nuclear scintigraphic methods relies on the administration of a radionuclide isotope that is accumulated by the myocardium in proportion to blood flow. Nuclear perfusion imaging is performed with either single photon-emitting or dual photon-emitting isotopes using SPECT or positron emission tomography (PET) systems.

SPECT is the most common system used for myo-cardial perfusion imaging. Most SPECT studies are done with thallium 201, technetium-99m sestamibi, and technetium-99m tetrofosmin. Currently, the technetium 99m-labeled tracers are preferred for their higher photon energy, which results in less attenuation artefact. These isotopes emit single photons that travel through tissues and need to be detected on a position-sensitive detector. The direction of the traveling photon is determined by adding a lead collimator that acts as an X-ray filter between the source and the detector. This collimator rejects most of the photons not traveling along certain directions; as a result, only a percentage of the emitted photons are used for imaging. Spatial resolution is given by the space between the bars in the collima-tor. Increasing spatial resolution requires higher rejection of photons, reducing efficiency and increasing radiation exposure to the patient.

Most dual photon-emitting isotopes are cyclotron produced. These isotopes decay with the emission of a positron, which, after a series of collisions with atomic electrons from the tissues, is annihilated with a nearby electron and produces two high-energy photons emitted in opposite directions. A PET system relies on the simultaneous detection of these photons. These photons travel toward detectors positioned around the subject, where they interact, are absorbed, and produce an electrical signal. The detector signals are processed by specialized coincidence circuitry, and, if the difference in the time of arrival of these photons is smaller than a predetermined value (typically 10 ns), then a signal is recorded. Unlike SPECT imaging, PET does not require collimation, because the position of the emitting target is determined by the simultaneous registration of the two photons at 180 degrees apart. Therefore, the efficiency of PET is several magnitudes greater, providing higher resolution, lower noise, and lower radiation exposure. The signals recorded are used to reconstruct a 3D image. The spatial resolution of PET images is closely related to the physical size of the detector elements.

With either SPECT or PET cardiac perfusion studies, images are obtained after stress and at rest. For segmentation of the LV, a 17-segment model is applied. Images are interpreted visually or with the use of automated quantification based on normalized data. Myocardial scar is determined by the presence of a relative perfusion defect (compared to the segment with highest counts) that persists on both stress and resting images. Ischemia is determined by the presence of a perfusion defect on stress images that improves or resolves on the resting images (Figs. 3-8 through 3-11).

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Figure 3-8. Single-photon emission computed tomography (SPECT) technetium-99m sestamibi exercise stress study showing normal myocardial perfusion during stress and at rest.

Figure 3-9. Single-photon emission computed tomography (SPECT) technetium-99m sestamibi exercise stress study showing a large myocardial perfusion defect in the posterolateral walls during stress (white arrows) with complete reversibility on the resting study, indicating ischemia.

Figure 3-8. Single-photon emission computed tomography (SPECT) technetium-99m sestamibi exercise stress study showing normal myocardial perfusion during stress and at rest.

Figure 3-9. Single-photon emission computed tomography (SPECT) technetium-99m sestamibi exercise stress study showing a large myocardial perfusion defect in the posterolateral walls during stress (white arrows) with complete reversibility on the resting study, indicating ischemia.

Figure 3-10. Single-photon emission computed tomography (SPECT) technetium-99m sestamibi exercise stress study showing a mid-size myocardial perfusion defect in the anteroseptal and apical walls during stress (white arrows) without reversibility on the resting study, indicating scar.

Figure 3-11. Single-photon emission computed tomography (SPECT) technetium-99m sestamibi exercise stress study showing a large myocardial perfusion defect in the anteroseptal, anterior, and inferior walls during stress (white arrows) with partial reversibility (inferior and septal walls, green arrow) on the resting study, indicating both scar and ischemia.

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Exercise Nuclear Perfusion Imaging

Exercise stress is well suited for SPECT imaging. At peak exercise, either on a treadmill or on a bicycle ergometer, patients are injected with the radioisotope. Acquisition of the stress images is performed from a few minutes to 1 hour after exercise, depending on the radioisotope used. Resting images are obtained before or after the exercise images, after the administration of a separate dose of the isotope. Different isotopes may be used for resting and for stress imaging, such as thallium 201 injected at rest and technetium-99m sestamibi injected at peak stress.

The mean reported sensitivity and specificity for exercise SPECT are 86% and 74%, respectively.14 However, most of the studies reported are potentially subject to verification bias, which means that the sensitivity may be overestimated and the specificity underestimated. To estimate the true specificity of the test, the normalcy rate has been studied in populations at low risk of having CAD, and the mean normalcy rate in these populations was reported to be 89%. Sensitivity and specificity were higher for the detection of multivessel disease, followed by single-vessel disease in the left anterior descending artery distribution, in the right coronary artery, and in the circumflex artery. False-positive results are often attributed to attenuation artifacts from large breasts in women, or to the diaphragm in obese individuals. Excessive bowel radioactivity may also result in negative or false-positive results.

More recently, the introduction of ECG-gated SPECT imaging has allowed assessment of LV function in addition to perfusion. Studies have shown a good correlation for assessment of LV ejection fraction between SPECT and other tomographic modali-ties.15 However, LV volumes may be underestimated and ejection fraction overestimated in ventricles with a small LV cavity and hypertrophy of the walls, because of partial volume effects. The accuracy of SPECT determination of LV volumes and ejection fraction is also limited in patients with extensive perfusion defects and LV aneurysm, because the entire geometry of the LV cavity cannot be defined. However, the additional information derived from regional systolic function in gated studies has improved the diagnostic accuracy of the test. Frequently, artefacts caused by soft tissue attenuation may be discriminated from true ischemia or scar by the demonstration of normal regional wall motion.

Another recent advancement in SPECT imaging has been the introduction of attenuation correction. Commercially available SPECT attenuation correction systems measure the nonhomogeneous attenuation distribution, using external collimated radionuclide sources or X-ray computed tomography (hybrid systems). Application of attenuation correction in patients with excessive subdiaphragmatic activity corrects by enhancing the affected regions of the myocardium, such as the inferior and posterior LV walls. Several studies have shown significant improvement in specificity and modest improvements in sensitivity with the use of attenuation te rat at e d c ia rdi ar

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Figure 3-12. Rates of cardiac death per year as a function of scan result and type of treatment. Purple bars represent patients undergoing medical treatment after single-photon emission computed tomography (SPECT); teal bars represent patients undergoing revascularization after SPECT. *P < .01 versus patients undergoing revascularization early after SPECT; **P < .001 within patients undergoing revascularization early after SPECT. (From Hachamovitch R, Berman DS, Shaw LJ, et al: Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: Differential stratification for risk of cardiac death and myocardial infarction. Circulation 1998;97:535-543.)

correction.16,17 A recent study demonstrated that specificity decreases dramatically in obese patients as indexed body mass increases without attenuation correction, but it remains high in all groups with attenuation correction.18

Several studies have shown that a normal exercise stress SPECT study predicts a very low likelihood (<1%) of adverse events such as cardiac death or myocardial infarction for at least 12 months, and that this level of risk is independent of gender, age, symptom status, and even presence of anatomic CAD. In those patients with abnormal scans, baseline clinical characteristics such as diabetes, as well as the extent and severity of SPECT perfusion abnormalities, permit definition of incremental levels of risk and which populations of patients will benefit most from revascularization (Fig. 3-12).19

Pharmacologic Nuclear Perfusion Imaging

In the United States, many patients who are referred for evaluation of suspected or known CAD are unable to exercise. Both adenosine and dipyridamole are vasodilator agents that, in the absence of epicardial artery stenosis, increase myocardial blood flow three to five times over baseline. In the presence of a stenosis, a relative perfusion defect may be seen; it indicates either failure to increase regional blood flow compared to myocardial segments supplied by a normal vessel or reduced myocardial blood flow due to coronary steal. For this reason, in some patients with multivessel disease and balanced ischemia, the pharmacologic stress SPECT study may appear as normal. The mean reported sensitivity and specificity

of adenosine SPECT for the detection of CAD are similar to those of exercise SPECT studies—90% and 75%, respectively. With dipyridamole SPECT, sensitivity is similar (89%), but the specificity is lower (65%). As previously discussed, verification bias may exaggerate true sensitivity and underestimate specificity. The sensitivities and specificities are also higher for multivessel than for single-vessel disease.

Pharmacologic stress SPECT studies may be performed also with dobutamine. The mean reported sensitivity and specificity for this test are 82% and 75%, respectively. In contrast to dobutamine echo-cardiography, monitoring of ischemia-induced functional abnormalities is difficult with SPECT. For this reason, dobutamine is not a preferred stressor in most clinical instances.

Pharmacologic SPECT is a powerful prognosticator in populations of patients with suspected CAD and in those who at risk and are being evaluated before noncardiac surgery. The risk of death in patients with normal scans has been reported to be low but higher than in patients with negative exercise SPECT (1% to 3% per year). This probably reflects higher comor-bidities in selected populations of patients who cannot exercise. In patients undergoing noncardiac surgery, a pharmacologic stress test has a significant negative predictive value but a low positive predictive value.19a,19b For that reason, it has been recommended that this test be applied only to populations of patients with moderate clinical risk, such as those with anginal symptoms, prior infarction, and/or diabetes.

Pharmacologic stress imaging may be performed with PET. The higher spatial resolution, higher efficiency, and lower attenuation make PET a superior method in certain patient groups, such as obese patients. Cardiac PET has also been validated for the quantitative assessment of regional myocardial perfusion, LV function, and viability. Current PET stress myocardial perfusion protocols require pharmaco-logic stress because of the short half-life of rubidium-82. This is the preferred radioisotope for assessment of perfusion in clinical practice, given that it can be produced on site without a cyclotron from a column generator. Two other radioisotopes approved for cardiac PET use in the United States are nitrogen-13 ammonia (perfusion) and 18F-FDG (metabolism-viability). In patients with suboptimal-quality SPECT results, follow-up cardiac PET has demonstrated superior accuracy. A majority of the PET studies obtained in patients with equivocal SPECT results are unequivocally normal or low risk.20

PET is one of the most sensitive methods for identifying myocardial viability in patients with ischemic LV dysfunction. PET defines viable myocardium as the presence of a perfusion-metabolism mismatch. Images are obtained with a perfusion isotope such as rubidium-82 and a metabolic agent such as 18F-FDG. Scar myocardium exhibits reduced uptake of both tracers, whereas ischemic viable myocardium shows preserved metabolic activity (Fig. 3-13). The extent of viability by PET has been shown in numerous studies to predict functional myocardial recovery after revascularization. Patients with viable myocardium by PET who undergo revascularization have improved survival compared to those with viable myocardium who receive medical therapy or those without viability regardless of treatment.

Magnetic Resonance Imaging

MRI is an excellent method for the assessment of global and regional systolic LV function. The most widely used steady-state free precession technique (SSFP) allows clear identification of endocardial borders caused by a high blood pool signal. In addition, the tomographic approach allows measurement of volumes without geometric assumptions, resulting in accurate measurements even in those patients with previous myocardial infarction and distorted LV geometry. Image quality is preserved even in obese patients, making it ideal for those patients with technically difficult echocardiographic images. In addition, with the use of intravenous paramagnetic contrast agents, MRI may provide an accurate assessment of myocardial perfusion.

Dobutamine MRI

MRI may be used to obtain global and regional LV function at rest and during bicycle or pharma-cologic stress. Dobutamine is the most commonly used stressor for the evaluation of ischemia-induced regional wall motion abnormalities. The mean reported sensitivity and specificity for the detection of obstructive CAD are 89% and 84%, respectively. The protocols used are similar to those used in echo-cardiography for the evaluation of both ischemia and viability. One of the limitations of dobutamine MRI is the inability to obtain accurate ECG monitoring of ST-segment deviation during the test. For this reason, many centers have favored the use of vasodilator stress and MRI perfusion imaging.

MRI Perfusion Imaging

The intravenous injection of a paramagnetic agent such as gadolinium diethylenetriaminepentaacetic acid (DTPA) may be used to evaluate myocardial perfusion. Gadolinium DTPA is an extracellular agent that, during its first pass, enhances the intravascular compartment. This is followed by extracellular deposition. Areas of fibrosis and scarring in the LV accumulate gadolinium over time, exhibiting "delayed enhancement." With the use of a fast imaging protocol with steady-state precession (FISP)-based sequence, the first-pass enhancement of the myocardium may be imaged by MRI almost in real time. MRI allows identification of areas of myocardial hypoenhancement at rest in the presence of severely reduced myocardial blood flow (Fig. 3-14). In most circumstances, however, resting blood flow is normal in segments supplied by stenotic vessels because of compensatory arteriolar vasodilation. However, adeno-sine or dipyridamole may induce ischemia in these cases by reducing myocardial perfusion pressure.

Figure 3-13. Positron emission tomography (PET) myocardial viability study obtained in a patient with ischemic left ventricular dysfunction. Both resting and stress rubidium-82 images show an extensive anteroapical perfusion defect (arrow). The fluorine-18 fluorodeoxyglucose (FDG) images show matched preserved metabolic activity, indicating hypoperfused but viable myocardium (arrows).

Figure 3-13. Positron emission tomography (PET) myocardial viability study obtained in a patient with ischemic left ventricular dysfunction. Both resting and stress rubidium-82 images show an extensive anteroapical perfusion defect (arrow). The fluorine-18 fluorodeoxyglucose (FDG) images show matched preserved metabolic activity, indicating hypoperfused but viable myocardium (arrows).

The high spatial resolution of cardiac MRI permits visualization of nontransmural ischemia or infarction. A study comparing cardiac MRI and SPECT for the detection of CAD demonstrated similar sensitivities for both techniques for the detection of transmural ischemia or infarction.21 However, SPECT identified only 28% of subendocardial infarcts, whereas MRI identified 92%. MRI studies have shown abnormal myocardial perfusion also in patients with syndrome X22 and in others with microvascular disease.

Quantitative analysis of the MRI perfusion images can be performed to determine the ratio of stress to resting blood flow, known as the myocardial perfusion reserve (MPR). Studies have shown that, in patients with obstructive coronary disease, MPR increases after percutaneous intervention.23

Delayed gadolinium-enhanced MRI is a powerful technique to evaluate the presence of scar in patients with ischemic LV dysfunction. The extent of infarct transmurality, as determined by MRI, predicts functional recovery in patients referred for revasculariza-tion (Figs. 3-15 and 3-16).24

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